CN111574529A

CN111574529A - Muscarinic receptor M3 antagonists and β 2-adrenergic receptor agonist bridged ring derivatives

Info

Publication number: CN111574529A
Application number: CN202010100295.5A
Authority: CN
Inventors: 张晨; 祝国智; 卢泳华; 高秋; 廖雨亭; 李瑶; 严庞科
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2019-02-18
Filing date: 2020-02-18
Publication date: 2020-08-25

Abstract

The invention relates to a bridged ring compound shown in a general formula (III) with dual activities of muscarinic receptor M3 antagonism and β 2-adrenergic receptor agonism, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, a preparation method and application thereof in preparing medicaments for treating airway obstructive diseases,

Description

Muscarinic receptor M3 antagonists and β 2-adrenergic receptor agonist bridged ring derivatives

Technical Field

The invention relates to a bridged ring compound shown in a general formula (III) with dual activities of muscarinic receptor M3 antagonism and beta 2-adrenergic receptor agonism, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, a preparation method and application in preparing medicaments for treating airway obstructive diseases.

Background

Asthma and chronic pulmonary obstructive disease (COPD) are the most common pulmonary diseases. Among them, the incidence of COPD is rising year by year, and is expected to become the third fatal disease worldwide in 2030. The first choice of drugs currently in use for such diseases is bronchodilators, which are divided into muscarinic receptor antagonists and β 2-adrenergic agonists. Muscarinic receptor antagonists can reduce vagal cholinergic levels of airway smooth muscle, causing bronchiectasis. Among the clinically used muscarinic receptor antagonists inhaled are ipratropium bromide, oxitropium bromide, glycopyrronium bromide, tiotropium bromide, aclidinium bromide and umeclidinium bromide. Beta 2-adrenergic agonists stimulate adrenergic receptors of airway smooth muscle, cause bronchodilation, and reverse the response of bronchoconstrictors to various mediators, such as acetylcholine. Clinically used beta 2-adrenergic agonists are salbutamol, salmeterol, arformoterol, formoterol, vilanterol and indacaterol. Further clinical studies have found that combining muscarinic receptor antagonists and β 2-adrenergic agonists into a combination formulation is more effective than a single formulation in treating asthma and COPD, such as Anoro Ellipta (umeclidinium bromide/vilanterol), Ultibro Breezhaler (glycopyrronium bromide/indacaterol), tiotropium bromide/formoterol and ipratropium bromide/salbutamol, but is more demanding in formulation preparation.

Compounds that possess both muscarinic receptor antagonist activity and β 2-adrenergic agonist activity (MABA) have received considerable attention in the treatment of asthma and COPD, and such bifunctional drugs are capable of producing bronchodilatory effects through two distinct and possibly synergistic modes of action and possess single molecular pharmacokinetics. In addition, compounds with muscarinic receptor antagonist activity and β 2-adrenergic agonist activity can also be combined with corticosteroid (ICS) anti-inflammatory agents drugs in two therapeutic agents (MABA/ICS) to provide a triple-acting therapeutic effect (Expert opin. investig. drugs (2014) 23(4): 453-.

(1) WO2012168359 discloses a muscarinic receptor antagonist and beta 2-adrenergic agonist drug, and relates to the following structure

Q is selected from the group consisting of Q1, Q2, Q3, Q4, Q5 or Q6,

m is selected from O or NR₃-；

G is selected from arylene or heteroarylene;

R⁴selected from J1, J2, J3, J4 or J5,

the specific description in this patent is not considered to be part of the present invention.

(2) WO2014086927 discloses a compound for the treatment of chronic lung obstructive disease,

q is selected from Q1, Q2 or Q3,

m is selected from NR₃-；

G is selected from arylene;

R⁴is selected from

(3) WO2014086924 discloses a compound for the treatment of chronic lung obstructive disease,

q is selected from Q1, Q2 or Q3,

g is selected from arylene;

R³is selected from

Therefore, there is a need to develop new muscarinic receptor antagonist and β 2-adrenergic agonist (MABA) drugs to provide more effective monotherapeutic doses or combination formulations to provide more clinical medication options for patients.

Disclosure of Invention

The invention aims to introduce a novel class of muscarinic receptor antagonist and beta 2-adrenergic agonist compounds, in particular compounds shown in a general formula (III), preparation thereof, compositions containing the structures, compositions with other active ingredients and therapeutic application thereof.

The invention relates to a compound shown in a general formula (III) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a eutectic crystal or a prodrug thereof:

wherein:

is an β -adrenoceptor binding group, and in some embodiments, A is selected from

In some embodiments, a is selected from

E is selected from

In some embodiments, E is selected from

In some embodiments, E is selected from

Q₁、Q₂Each independently is absent, C_1-6Alkylene radical, C_3-8Cycloalkylene radical, C_3-8Heterocycloalkylene, said alkylene, cycloalkylene, heterocycloalkylene being optionally further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituent substitution; in some embodiments, Q₁、Q₂Each independently is absent, methylene, ethylene, propylene, butylene, pentylene, cyclopropylene, butylene, cyclopentylene, cyclohexylene, aziridinyl, azacyclobutylene, azacyclopentylene, azacyclohexylene, these radicals optionally being further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituted; in some embodiments, Q₁、Q₂Each independently is absent or C_1-6An alkylene group; in some embodiments, Q₁、Q₂Each independently is methylene, ethylene or propylene;

b is selected from absent, C_3-8Cycloalkylene radical, C_1-6Alkylene radical, C_3-8Heterocycloalkylene, arylene or heteroarylene, said cycloalkylene, alkylene, heterocycloalkylene, arylene or heteroarylene being optionally further substituted by a halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s); in some embodiments, B is selected from absent, C_3-8Heterocycloalkylene, arylene or heteroarylene, said heterocycloalkylene, arylene or heteroarylene being optionally further substituted by halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s); in some embodiments, B is selected from absent, C_3-8Heterocycloalkylene or arylene optionally further substituted by halogen atom, C_1-6Alkyl radical, C_1-6Substituted with a haloalkyl; in some embodiments, B is selected from absent, azacyclobutyl, azacyclopentyl, cyclohexylene, pyridyldiyl, furandiyl, thiophenediyl, pyrazolediyl, oxazolediyl, thiazolediyl or phenylene, these groups optionally further being substituted by halogen atoms, C_1-6Alkyl or C_1-6Substituted with a substituent of haloalkyl; in some embodiments, B is selected from absent, azacyclobutyl, azacyclopentyl, azacyclohexylene, or phenylene, which groups may optionally be further substituted by halogen atoms, C_1-6Alkyl or C_1-6Substituted with a substituent of haloalkyl; in some embodiments, B is selected from absent, phenylene or azacyclohexylene;

c and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) O-, -C (OO) -, -S-, -S (O) -, -S (O)₂-、-OS(O)₂-、-N(R^w)-、-NR^wC(O)-、-OC(O)NR^w-、-NR^wC(O)-(CH₂)_t-、-NR^wC(O)NR^w’-、 -NR^wS(O)₂-、-NR^wS(O)₂NR^w-、-(CH₂)_t-OC(O)-、-O-C(O)-(CH₂)_t-O-C(O)-、-O-(CH₂)_t-NR^wC(O)-、 -O-(CH₂)_t-O-C(O)-、-NR^w-(CH₂)_t-OC(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) O-, -N (R)^w)-、-NR^wC(O)-、-OC(O)NR^w-、-NR^wC(O)-(CH₂)_t-、-NR^wC(O)NR^w’-、-NR^wS(O)₂-、-NR^wS(O)₂NR^w-、-(CH₂)_t-OC(O)-、-O-C(O)-(CH₂)_t-O-C(O)-、-O-(CH₂)_t-NR^wC(O)-、 -O-(CH₂)_t-O-C(O)-、-NR^w-(CH₂)_t-OC(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、-NR^wC(O)NR^w’-、

-NR^wS(O)₂-、 -O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、

Or

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、-NR^wS(O)₂-、-O-(CH₂)_t-O-C(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、

Or

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w) -or-NR^wC (O) -; in some embodiments, C and C' are each independently selected from-O-, -C (O) -, -O-C (O) -, or-NR^wC(O)-；

D is selected from absent, C_1-6Alkylene, -C (CH)₃)₂-, arylene, C_2-6Alkenylene, heteroarylene, C_3-8Heterocycloalkylene or C_2-6Alkynylene, said alkylene, arylene, heteroarylene or heterocycloalkylene being optionally further substituted by a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6Substituted with a haloalkyl; in some embodiments, D is selected from absent, C_3-8Heteroarylene, arylene or heteroarylene, said arylene, heteroarylene or heteroarylene being optionally further substituted by a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6Substituted with a haloalkyl; in some embodiments, D is selected from absent, arylene, heteroarylene, optionally further substituted with a halogen atom, C_1-6Substituent substitution of alkoxy; in some embodiments, D is selected from aryleneSaid arylene group being optionally further substituted by a halogen atom, C_1-6Substituent substitution of alkoxy; in some embodiments, D is selected from phenylene, optionally further substituted with a halogen atom, C_1-6Substituent substitution of alkoxy;

m is selected from absent or selected from-O-, -NR^w-, -OC (O) -or-S-; in some embodiments, M is selected from absent or selected from-O-; in some embodiments, M is selected from-O-;

f is selected from arylene or heteroarylene, said arylene or heteroarylene being optionally further substituted by halogen, hydroxy, oxo, mercapto, nitro, amino, cyano, -CON (R)^w)₂、-NHCOR^w、-CO₂R^w、C_1-6Alkylsulfanyl group, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkyl, aryl, haloaryl, heteroaryl or C_1-6Substituted by a substituent of alkoxy; in some embodiments, F is selected from arylene optionally further substituted with halogen, hydroxy, oxo, mercapto, nitro, amino, cyano, -CON (R)^w)₂、-NHCOR^w、-CO₂R^w、C_1-6Alkylsulfanyl group, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkyl, aryl, haloaryl, heteroaryl or C_1-6Substituted by a substituent of alkoxy; in some embodiments, F is selected from arylene; in some embodiments, F is selected from phenylene;

g is selected from-O-or-NR¹³-; in some embodiments, G is selected from-NR¹³-；

R¹Is a bridged ring, said bridged ring optionally further substituted by C_1-6Alkyl, halogen, -OH, -CN, R¹⁵、-NO₂Provided that it does not comprise

In some embodiments, R¹Is a bicyclic or tricyclic hydrocarbon bridge ring comprising0 to 3 optional O, N, S heteroatoms, optionally substituted by C_1-6Alkyl, halogen, -OH, -CN, R¹⁵、-NO₂Provided that it does not comprise

In some embodiments, R¹Is selected from

In some embodiments, R¹Is selected from

In some embodiments, R¹Is selected from

R²、R³、R⁴、R⁵Each independently selected from H, hydroxy, halogen atom, C_1-6Alkyl radical, C_1-6Haloalkyl or C_1-6An alkoxy group; in some embodiments, R²、R³、R⁴、R⁵Each is independently selected from H or hydroxyl; in some embodiments, R²Selected from hydroxy, R³、R⁴、R⁵Each is independently selected from H;

R⁶selected from H or C_1-6An alkyl group; in some embodiments, R⁶Is selected from H;

R¹²selected from H, halogen atom or amino; in some embodiments, R¹²Selected from H, F, Cl or an amino group;

R^wand R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radical, C_3-8heterocycloalkyl-C_1-6Alkyl, aryl, heteroaryl, aryl-C_1-6Alkyl, heteroaryl-C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, said radical optionally being further substituted by 0 to 5C_1-6Alkyl radical, C_1-6Haloalkyl group, halogen atom, C_1-6Alkoxy radical, C_1-6Substituted with a substituent of haloalkoxy; in some embodiments, R^wAnd R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radical, C_3-8heterocycloalkyl-C_1-6Alkyl, aryl or aryl-C_1-6Alkyl, said group optionally further substituted by 0 to 5C_1-6Alkyl radical, C_1-6Haloalkyl group, halogen atom, C_1-6Alkoxy radical, C_1-6Substituted with a substituent of haloalkoxy; in some embodiments, R^wAnd R^w’Each independently selected from H or C_1-6An alkyl group; in some embodiments, R^wAnd R^w’Each independently selected from H, methyl, ethyl, isopropyl, butyl, isobutyl or tert-butyl;

alternatively, R^wAnd R^w’May form a ring with the atoms to which they are attached; alternatively, in some embodiments, R^wAnd R^w’May form a four-, five-or six-membered ring with the atoms to which they are attached;

R⁷、R⁸each independently selected from H or C_1-6An alkyl group; in some embodiments, R⁷、R⁸Each independently selected from H, methyl, ethyl, propyl or isopropyl;

R¹⁵and R⁹Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

p is selected from 0, 1,2, 3 or 4; in some embodiments, p is selected from 0; in some embodiments, p is selected from 1; in some embodiments, p is selected from 2; in some embodiments, p is selected from 3; in some embodiments, p is selected from 4;

q is selected from 0, 1,2, 3 or 4; in some embodiments, q is selected from 0; in some embodiments, q is selected from 1; in some embodiments, q is selected from 2; in some embodiments, q is selected from 3; in some embodiments, q is selected from 4;

s is selected from 0, 1,2, 3 or 4; in some embodiments, s is selected from 0; in some embodiments, s is selected from 1; in some embodiments, s is selected from 2; in some embodiments, s is selected from 3; in some embodiments, s is selected from 4;

k is selected from 0, 1,2, 3 or 4; in some embodiments, k is selected from 0; in some embodiments, k is selected from 1; in some embodiments, k is selected from 2; in some embodiments, k is selected from 3; in some embodiments, k is selected from 4;

t is selected from 0, 1,2, 3 or 4; in some embodiments, t is selected from 0; in some embodiments, t is selected from 1; in some embodiments, t is selected from 2; in some embodiments, t is selected from 3; in some embodiments, t is selected from 4;

y is selected from 0, 1,2, 3, 4 or 5; in some embodiments, y is selected from 0; in some embodiments, y is selected from 1; in some embodiments, y is selected from 2; in some embodiments, y is selected from 3; in some embodiments, y is selected from 4; in some embodiments, y is selected from 5;

r is selected from 0, 1,2 or 3; in some embodiments, r is selected from 0; in some embodiments, r is selected from 1; in some embodiments, r is selected from 2; in some embodiments, r is selected from 3;

R¹¹and R^11’Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

P is absent or selected from-O-, -S-, -SO₂-、-CO-、-NR¹⁰CH＝CH-、-N(R¹⁰)SO₂-、-N(R¹⁰)COO-、 -N(R¹⁰)C(O)-、-SO₂N(R¹⁰)-、-CO(O)N(R¹⁰) -or-C (O) N (R)¹⁰) -; in some embodiments, P is absent or selected from-CO-; in some embodiments, P is absent;

t is selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl, aryl, heteroaryl, said alkyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by a halogen atom, hydroxy, oxo, -SH, -NO₂、-CN、-CON(R¹⁰)₂、-NH₂、-NHCOR¹⁰、-CO₂R¹⁰、 C_1-6Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy; in some embodiments, T is selected from H, C_1-6Alkyl or heteroaryl; in some embodiments, T is selected from H or C_1-6An alkyl group; in some embodiments, T is selected from H, methyl, ethyl, propyl, isopropyl, or isobutyl;

X^-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy; in some embodiments, R¹⁰Selected from H, C_1-10Alkyl or C_1-6A haloalkyl group; in some embodiments, R¹⁰Selected from H, methyl, ethyl, isopropyl or trifluoromethyl;

R¹³selected from H, C_1-6Alkyl radical, C_1-6Alkylaryl group, C_3-8Cycloalkyl or heteroaryl; in some embodiments, R¹³Is selected from H or C_1-6An alkyl group; in some embodiments, R¹³Is selected from H;

R¹⁴selected from aryl, heteroaryl, C_3-8Cycloalkyl or C_3-8Heterocycloalkyl, said aryl, heteroaryl, cycloalkyl or heterocycloalkyl being optionally further substituted by a halogen atom, -OH, -CN, -CONH₂、-COOH、C_1-10Alkyl or C_1-10Substituent substitution of alkoxy; in some embodiments, R¹⁴A substituent selected from phenyl, pyridyl, pyrimidinyl, thienyl, cyclohexyl or azacyclohexyl, said group optionally further substituted with a substituent of F, Cl, Br, I, methyl, ethyl, isopropyl, methoxy, ethoxy; in some embodiments, R¹⁴Selected from phenyl.

The first scheme is as follows: a compound represented by the general formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

wherein:

is β -adrenoceptor binding group;

e is selected from

Q₁、Q₂Each independently is absent, C_1-6Alkylene radical, C_3-8Cycloalkylene radical, C_3-8Heterocycloalkylene, said alkylene, cycloalkylene, heterocycloalkylene being optionally further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituent substitution;

b is selected from absent, C_3-8Cycloalkylene radical, C_1-6Alkylene radical, C_3-8Heterocycloalkylene, arylene or heteroarylene, said cycloalkylene,Alkylene, heterocycloalkylene, arylene or heteroarylene optionally further substituted by halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s);

D is selected from absent, C_1-6Alkylene, -C (CH)₃)₂-, arylene, C_2-6Alkenylene, heteroarylene, C_3-8Heterocycloalkylene or C_2-6Alkynylene, said alkylene, arylene, heteroarylene or heterocycloalkylene being optionally further substituted by a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6Substituted with a haloalkyl;

m is selected from absent or selected from-O-, -NR^w-, -OC (O) -or-S-;

f is selected from arylene or heteroarylene, said arylene or heteroarylene being optionally further substituted by halogen, hydroxy, oxo, mercapto, nitro, amino, cyano, -CON (R)^w)₂、-NHCOR^w、-CO₂R^w、C_1-6Alkyl radicalSulfanyl, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkyl, aryl, haloaryl, heteroaryl or C_1-6Substituted by a substituent of alkoxy;

g is selected from-O-or-NR¹³-；

R^wAnd R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radical, C_3-8heterocycloalkyl-C_1-6Alkyl, aryl, heteroaryl, aryl-C_1-6Alkyl, heteroaryl-C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, said radical optionally being further substituted by 0 to 5C_1-6Alkyl radical, C_1-6Haloalkyl group, halogen atom, C_1-6Alkoxy radical, C_1-6Substituted with a substituent of haloalkoxy;

alternatively, R^wAnd R^w’May form a ring with the atoms to which they are attached;

R⁷、R⁸each independently selected from H or C_1-6An alkyl group;

R¹⁵and R⁹Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

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

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

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

p is absent or selected from-O-, -S-, -SO₂-、-CO-、-NR¹⁰CH＝CH-、-N(R¹⁰)SO₂-、-N(R¹⁰)COO-、 -N(R¹⁰)C(O)-、-SO₂N(R¹⁰)-、-CO(O)N(R¹⁰) -or-C (O) N (R)¹⁰)-；

T is selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl, aryl, heteroaryl, said alkyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by a halogen atom, hydroxy, oxo, -SH, -NO₂、-CN、-CON(R¹⁰)₂、-NH₂、-NHCOR¹⁰、-CO₂R¹⁰、 C_1-6Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy;

x-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy;

R¹³selected from H, C_1-6Alkyl radical, C_1-6Alkylaryl group, C_3-8Cycloalkyl or heteroaryl;

R¹⁴selected from aryl, heteroaryl, C_3-8Cycloalkyl or C_3-8Heterocycloalkyl, said aryl, heteroaryl, cycloalkyl or heterocycloalkyl being optionally further substituted by a halogen atom, -OH, -CN, -CONH₂、-COOH、C_1-10Alkyl or C_1-10Substituent of alkoxy.

Scheme II: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

a is selected from

R²、R³、R⁴、R⁵Each independently selected from H, hydroxy, halogen atom, C_1-6Alkyl radical, C_1-6Haloalkyl or C_1-6An alkoxy group;

R⁶selected from H or C_1-6An alkyl group;

R¹²selected from H, halogen atom or amino;

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

the remaining group definitions are the same as in scheme one.

The third scheme is as follows: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

a is selected from

The remaining group definitions are the same as in scheme one.

And the scheme is as follows: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

R¹⁴is selected from phenyl;

the remaining group definitions are the same as in scheme one.

And a fifth scheme: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

R¹is a bicyclic or tricyclic hydrocarbon bridge containing 0 to 3 optional O, N, S heteroatomsQuilt selection C_1-6Alkyl, halogen, -OH, -CN, R¹⁵、-NO₂Substituted with the substituent(s);

provided that it does not contain

R¹⁵And R⁹Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

p is absent or selected from-O-, -S-, -SO₂-、-CO-、-NR¹⁰CH＝CH、-N(R¹⁰)SO₂-、-N(R¹⁰)COO-、 -N(R¹⁰)C(O)-、-SO₂N(R¹⁰)-、-CO(O)N(R¹⁰) -or-C (O) N (R)¹⁰)-；

X^-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkyl sulfonyl radical、C_1-10Alkyl or C_1-10Substituent substitution of alkoxy;

the remaining group definitions are the same as in scheme one.

Scheme six: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

R¹is selected from

Wherein

R¹¹And R^11’Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

X^-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy;

the remaining group definitions are the same as in scheme five.

The scheme is seven: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

R¹is selected from

The remaining group definitions are the same as in scheme six.

And the eighth scheme is as follows: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

e is selected from

Q₁、Q₂Each independently is absent, C_1-6Alkylene radical, C_3-8Heterocycloalkylene, said alkylene, heterocycloalkylene being optionally further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituent substitution;

b is selected from absent, arylene, heteroarylene, C_3-8Cycloalkylene or C_3-8Heterocycloalkylene, said heterocycloalkylene, arylene, cycloalkylene or heteroarylene optionally further substituted with a halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s);

c and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、-NR^wC(O)NR^w’-、

-NR^wS(O)₂-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、

D is selected from absent, arylene or heteroarylene, said arylene or heteroarylene being optionally further substituted by a halogen atom or C_1-6Alkoxy substituent substitution;

m is selected from absent or-O-;

R^wand R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radical, C_3-8heterocycloalkyl-C_1-6Alkyl, aryl or aryl-C_1-6Alkyl, said group optionally further substituted by 0 to 5C_1-6Alkyl radical, C_1-6Haloalkyl group, halogen atom, C_1-6Alkoxy radical, C_1-6Substituted with a substituent of haloalkoxy;

R⁷、R⁸each independently selected from H or C_1-6An alkyl group;

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

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

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

the remaining group definitions are the same as in scheme one.

The scheme is nine: a compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

e is selected from

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

R^w”independently selected from H, halogen atoms or C_1-6An alkoxy group;

R^windependently selected from H, C_1-6Alkyl or C_3-6cycloalkyl-C_1-6An alkylene group;

the remaining group definitions are the same as in scheme eight.

And a scheme ten: a compound represented by the general formula (I) or (I-1) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

b is selected from absent, arylene, C_3-8Cycloalkylene, heteroarylene or C_3-8Heterocycloalkylene, said heterocycloalkylene, arylene, cycloalkylene or heteroarylene optionally further substituted with a halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s);

c and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) -activated、-O-C(O)O-、-C(OO)-、-S-、-S(O)-、 -S(O)₂-、-OS(O)₂-、-N(R^w)-、-NR^wC(O)-、-OC(O)NR^w-、-NR^wC(O)NR^w’-、-NR^wS(O)₂-、 -NR^wS(O)₂NR^w-、-(CH₂)_t-OC(O)-、-O-C(O)-(CH₂)_t-O-C(O)-、-O-(CH₂)_t-NR^wC(O)-、 -O-(CH₂)_t-O-C(O)-、-NR^w-(CH₂)_t-OC(O)-、

m is selected from absent or-O-;

R⁷、R⁸each independently selected from H or C_1-6An alkyl group;

R¹¹and R^11’Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

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

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

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

x-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent of alkoxy.

Scheme eleven: a compound of formula (I) or (I-1) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

e is selected from

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

R^w”independently selected from H, halogen atoms or C_1-6An alkoxy group;

the remaining groups are defined as in scheme ten.

Scheme twelve: a compound represented by the general formula (I) or (I-1) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof, wherein

E is selected from

The remaining group definitions are the same as in scheme eleven.

In some embodiments, a is selected from

In some embodiments, a is selected from

Or

In some embodiments, a is selected from

In some embodiments, R²、R³、R⁴、R⁵Each independently selected from H, hydroxy, halogen atom, C_1-6Alkyl radical, C_1-6Haloalkyl or C_1-6An alkoxy group.

In some embodiments, R²、R³、R⁴、R⁵Each independently selected from H or hydroxy.

In some embodiments, R²Selected from hydroxy, R³、R⁴、R⁵Each independently selected from H.

In some embodiments, R⁶Selected from H or C_1-6An alkyl group.

In some embodiments, R⁶Is selected from H.

In some embodiments, R¹²Selected from H, halogen atom or amino.

In some embodiments, R¹²Selected from H, F, Cl or an amino group.

In some embodiments, r is selected from 0, 1,2, or 3. In some embodiments, r is selected from 0. In some embodiments, r is selected from 1. In some embodiments, r is selected from 2. In some embodiments, r is selected from 3.

In some embodiments, a is selected from

In some embodiments, F is selected from arylene or heteroarylene, optionally further substituted with a halogen atom, hydroxy, oxo, mercapto, nitro, amino, cyano, -CON (R)^w)₂、-NHCOR^w、-CO₂R^w、C_1-6Alkylsulfanyl group, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkyl, aryl, haloaryl, heteroaryl or C_1-6Substituted by a substituent of alkoxy.

In some embodiments, G is selected from-O-.

In some embodiments, G is selected from-NR¹³-。

In some embodiments, R¹³Selected from H, C_1-6Alkyl radical, C_1-6Alkylaryl group, C_3-8Cycloalkyl or heteroaryl.

In some embodiments, R¹³Is selected from H or C_1-6An alkyl group.

In some embodiments, R¹³Is selected from H.

In some embodiments, R¹⁴Selected from phenyl.

In some embodiments, R¹Is a bicyclic or tricyclic hydrocarbon bridge containing 0-3 optional O, N, S heteroatoms optionally substituted with C_1-6Alkyl, halogen, -OH, -CN, R¹⁵、-NO₂Substituted with the substituent(s);

provided that R is¹Does not comprise

In some embodiments, R¹⁵And R⁹Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T。

In some embodiments, s is selected from 0, 1,2, 3, or 4. In some embodiments, s is selected from 0. In some embodiments, s is selected from 1. In some embodiments, s is selected from 2. In some embodiments, s is selected from 3. In some embodiments, s is selected from 4.

In some embodiments, k is selected from 0, 1,2, 3, or 4. In some embodiments, k is selected from 0. In some embodiments, k is selected from 1. In some embodiments, k is selected from 2. In some embodiments, k is selected from 3. In some embodiments, k is selected from 4.

In some embodiments, P is absent or selected from-O-, -S-, -SO-, -SO-₂-、-CO-、-NR¹⁰CH＝CH、-N(R¹⁰)SO₂-、-N(R¹⁰)COO-、-N(R¹⁰)C(O)-、-SO₂N(R¹⁰)-、-CO(O)N(R¹⁰) -or-C (O) N (R)¹⁰)-。

In some embodiments, P is absent or selected from-CO-.

In some embodiments, P is absent.

In some embodiments, T is selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl, aryl, heteroaryl, said alkyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by a halogen atom, hydroxy, oxo, -SH, -NO₂、-CN、-CON(R¹⁰)₂、-NH₂、 -NHCOR¹⁰、-CO₂R¹⁰、C_1-6Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent of alkoxy.

In some embodiments, T is selected from H, C_1-6Alkyl or aryl.

In some embodiments, T is selected from H or C_1-6An alkyl group.

In some embodiments, T is selected from H, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, or tert-butyl.

In some embodiments, X^-Is a physiologically acceptable anion.

In some embodiments, R¹⁰Selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent of alkoxy.

In some embodiments, R¹⁰Selected from H, C_1-10Alkyl or C_1-6A haloalkyl group.

In some embodiments, R¹⁰Selected from H, methyl, ethyl, isopropyl or trifluoromethyl.

In some embodiments, R¹Is selected from

In some embodiments, R¹Is selected from

In some embodiments, R¹Is selected from

In some embodiments, R¹Is selected from

In some embodiments, R¹Is selected from

In some embodiments, wherein R¹¹And R^11’Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T。

p is absent or selected from-O-, -S-, -SO₂-、-CO-、-NR¹⁰CH＝CH、-N(R¹⁰)SO₂-、-N(R¹⁰)COO-、 -N(R¹⁰)C(O)-、-SO₂N(R¹⁰)-、-CO(O)N(R¹⁰) -or-C (O) N (R)¹⁰) -; in some embodiments, P is absent or selected from-CO-; in some embodiments, P is absent;

t is selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl, aryl, heteroaryl, said alkyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by a halogen atom, hydroxy, oxo, -SH, -NO₂、-CN、-CON(R¹⁰)₂、-NH₂、-NHCOR¹⁰、-CO₂R¹⁰、 C_1-6Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy; in some embodiments, T is selected from H, C_1-6Alkyl, aryl or heteroaryl; in some embodiments, T is selected from H, C_1-6An alkyl or aryl group; in some embodiments, T is selected from H or C_1-6An alkyl group; in some embodiments, T is selected from H, methyl, ethyl, propyl, isopropyl, isobutyl, or tert-butyl;

x-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy; in some embodiments, R¹⁰Selected from H, C_1-10Alkyl or C_1-6A haloalkyl group; in some embodiments, R¹⁰Selected from H, methyl, ethyl, isopropyl or trifluoromethyl.

In some embodiments, R¹Is selected from

In some embodiments, R¹Is selected from

In some embodiments, E is selected from

In some embodiments, Q₁、Q₂Each independently is absent, C_1-6Alkylene radical, C_3-8Heterocycloalkylene, said alkylene, heterocycloalkylene being optionally further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituents.

In some embodiments，Q₁、Q₂Each independently being absent, methylene, ethylene, propylene, butylene, pentylene, aziridinyl, azacyclobutyl, azacyclopentylene, azacyclohexylene, which radicals may optionally be further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituents.

In some embodiments, Q₁、Q₂Each independently is absent or C_1-6An alkylene group.

In some embodiments, Q₁、Q₂Each independently is absent, methylene, ethylene or propylene.

In some embodiments, B is selected from absent, arylene, heteroarylene, C_3-8Cycloalkylene or C_3-8Heterocycloalkylene, said heterocycloalkylene, arylene, cycloalkylene or heteroarylene optionally further substituted with a halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Is substituted with the substituent(s).

In some embodiments, B is selected from absent, phenylene, pyridyldiyl, pyrazinediyl, furandiyl, thiophenediyl, thiazolediyl, oxazolediyl, pyrazolediyl, cyclohexylene, pyridyldiyl, and thiadiazolediyl,

Or azacyclohexylene, which may optionally be further substituted by halogen atoms, C_1-6Alkyl or C_1-6Substituted by a substituent of a haloalkyl group.

In some embodiments, B is selected from absent, phenylene, pyrazinediyl, cyclohexylene, pyrazinediyl,

or azacyclohexylene.

-NR^wS(O)₂-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、

In some embodiments, C and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) -, -O-, -N (R)^w)-、 -NR^wC(O)-、

-NR^wS(O)₂-、-O-(CH₂)_t-O-C(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC (O) -or

In some embodiments, C and C' are each independently selected from-C (O) -, -O-C (O) -, or-NR^wC(O)-。

In some embodiments, D is selected from absent, arylene or heteroarylene, optionally further substituted with a halogen atom or C_1-6Alkoxy substituents.

In some embodiments, D is selected from arylene, optionally further substituted with a halogen atom or C_1-6Alkoxy substituents.

In some embodiments, D is selected from phenylene optionally further substituted with a halogen atom or C_1-6Alkoxy substituents.

M is selected from absent or-O-.

In some embodiments, M is selected from-O-.

R^wAnd R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radical, C_3-8heterocycloalkyl-C_1-6Alkyl, aryl or aryl-C_1-6Alkyl, said group optionally further substituted by 0 to 5C_1-6Alkyl radical, C_1-6Haloalkyl group, halogen atom, C_1-6Alkoxy radical, C_1-6A haloalkoxy group.

In some embodiments, R^wAnd R^w’Each independently selected from H or C_1-6An alkyl group.

In some embodiments, R^wAnd R^w’Each independently selected from H, methyl, ethyl, propyl, isopropyl or isobutyl.

In some embodiments, R^wAnd R^w’Each independently selected from H or methyl.

In some embodiments, R is optionally substituted with one or more substituents selected from the group consisting of^wAnd R^w’May form a ring with the atoms to which they are attached.

In some embodiments, R is optionally substituted with one or more substituents selected from the group consisting of^wAnd R^w’May form a four-, five-or six-membered ring with the atoms to which they are attached.

In some embodiments, R⁷、R⁸Each independently selected from H or C_1-6An alkyl group.

In some embodiments, R⁷、R⁸Each independently selected from H or methyl.

p is selected from 0, 1,2, 3 or 4. In some embodiments, p is selected from 0. In some embodiments, p is selected from 1. In some embodiments, p is selected from 2. In some embodiments, p is selected from 3. In some embodiments, p is selected from 4.

q is selected from 0, 1,2, 3 or 4. In some embodiments, q is selected from 0. In some embodiments, q is selected from 1. In some embodiments, q is selected from 2. In some embodiments, q is selected from 3. In some embodiments, q is selected from 4.

t is selected from 0, 1,2, 3 or 4. In some embodiments, t is selected from 0. In some embodiments, t is selected from 1. In some embodiments, t is selected from 2. In some embodiments, t is selected from 3. In some embodiments, t is selected from 4.

In some embodiments, E is selected from

In some embodiments, y is selected from 0, 1,2, 3, 4, or 5. In some embodiments, y is selected from 0. In some embodiments, y is selected from 1. In some embodiments, y is selected from 2. In some embodiments, y is selected from 3. In some embodiments, y is selected from 4. In some embodiments, y is selected from 5. In some embodiments, R^w"is independently selected from H, halogen atom or C_1-6An alkoxy group;

in some embodiments, R^w"is independently selected from H, F, Cl or methoxy.

In some embodiments, R^wIndependently selected from H, C_1-6Alkyl or C_3-6cycloalkyl-C_1-6An alkylene group.

In some embodiments, R^wEach independently selected from H, methyl, ethyl, isopropyl or cyclohexyl-methyl.

The invention also relates to a compound shown in the general formula (I) or (I-1) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof:

in some embodiments, E is selected from

In some embodiments, Q₁、Q₂Each independently being absent, methylene, ethylene, propylene, butylene, pentylene, aziridinyl, azacyclobutyl, azacyclopentylene, azacyclohexylene, which radicals may optionally be further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituents.

In some embodiments, B is selected from absent, arylene, C_3-8Cycloalkylene, heteroarylene or C_3-8Heterocycloalkylene, said heterocycloalkylene, arylene, cycloalkylene or heteroarylene optionally further substituted with a halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocyclic ringAlkyl, heteroaryl or-NR⁷R⁸Is substituted with the substituent(s).

Or azacyclohexylene, which may optionally be further substituted by halogen atoms, C_1-6Alkyl or C_1-6Substituted with a haloalkyl.

In some embodiments, B is selected from absent, phenylene or azacyclohexylene, which groups may optionally be further substituted by halogen atoms, C_1-6Alkyl or C_1-6Substituted with a haloalkyl.

or azacyclohexylene.

In some embodiments, B is selected from absent.

In some embodiments, B is selected from phenylene.

In some embodiments, B is selected from azacyclohexylene.

In some embodiments, C and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) O-, -C (OO) -, -S-, -S (O) -, -S (O)₂-、-OS(O)₂-、-N(R^w)-、-NR^wC(O)-、-OC(O)NR^w-、-NR^wC(O)O-、 -NR^wC(O)NR^w’-、-NR^wS(O)₂-、-NR^wS(O)₂NR^w-、-(CH₂)_t-OC(O)-、-O-C(O)-(CH₂)_t-O-C(O)-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、-NR^w-(CH₂)_t-OC(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、-NR^wC(O)NR^w’-、-NR^wS(O)₂-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、-NR^wS(O)₂-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、-O-(CH₂)_t-NR^wC(O)-、

In some embodiments, C and C' are each independently selected from absent, -O-, -C (O) -, -O-C (O) -, -N (R)^w)-、-NR^wC(O)-、-O-(CH₂)_t-NR^wC (O) -or

In some embodiments, C and C' are each independentlySelected from the group consisting of absent, -O-, -C (O) -, -O-C (O) -, -NR^wC(O)-、-O-(CH₂)_t-NR^wC(O)-。

In some embodiments, C and C' are each independently selected from-NR^wC(O)-。

In some embodiments, D is selected from arylene, which is optionally further substituted with F, Cl or a methoxy substituent.

In some embodiments, D is selected from phenylene, which is optionally further substituted with F, Cl or a methoxy substituent. In some embodiments, M is selected from absent or selected from-O-.

In some embodiments, M is selected from-O-.

In some embodiments, R^wAnd R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radical, C_3-8heterocycloalkyl-C_1-6Alkyl, aryl, heteroaryl, aryl-C_1-6Alkyl, heteroaryl-C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, said radical optionally being further substituted by 0 to 5C_1-6Alkyl radical, C_1-6Haloalkyl group, halogen atom, C_1-6Alkoxy radical, C_1-6A haloalkoxy group.

In some embodiments of the present invention, the substrate is,R^wand R^w’Each independently selected from H or methyl.

Alternatively, R^wAnd R^w’May form a ring with the atoms to which they are attached.

In some embodiments, R⁷、R⁸Each independently selected from H or methyl.

In some embodiments, R¹¹And R^11’Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T。

In some embodiments, p is selected from 0, 1,2, 3, or 4. In some embodiments, p is selected from 0. In some embodiments, p is selected from 1. In some embodiments, p is selected from 2. In some embodiments, p is selected from 3. In some embodiments, p is selected from 4.

In some embodiments, q is selected from 0, 1,2, 3, or 4. In some embodiments, q is selected from 0. In some embodiments, q is selected from 1. In some embodiments, q is selected from 2. In some embodiments, q is selected from 3. In some embodiments, q is selected from 4.

In some embodiments, t is selected from 0, 1,2, 3, or 4. In some embodiments, t is selected from 0. In some embodiments, t is selected from 1. In some embodiments, t is selected from 2. In some embodiments, t is selected from 3. In some embodiments, t is selected from 4.

In some embodiments, P is absent or selected from-CO-.

In some embodiments, P is absent.

In some embodiments, T is selected from H, C_1-6Alkyl or heteroaryl.

In some embodiments, T is selected from H or C_1-6An alkyl group.

In some embodiments, T is selected from H, methyl, ethyl, propyl, isopropyl, or isobutyl.

X^-Is a physiologically acceptable anion.

In some embodiments, E is selected from

In some embodiments, y is selected from 0, 1,2, 3, 4, or 5. In some embodiments, y is selected from 0. In some embodiments, y is selected from 1. In some embodiments, y is selected from 2. In some embodiments, y is selected from 3. In some embodiments, y is selected from 4. In some embodiments, y is selected from 5.

In some embodiments, R^w”Independently selected from H, halogen atoms or C_1-6An alkoxy group.

In some embodiments, R^w”Independently selected from H, F, Cl or methoxy.

In some embodiments, R^wIndependently selected from H, methyl, ethyl, isopropyl or cyclohexylmethyl.

In some embodiments, E is selected from

In some embodiments, E is selected from

The invention also relates to a compound shown in the general formula (II) or (II-1) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof, wherein

The linker is selected from

Or

Q₁、Q₂Each independently is absent, C_1-6Alkylene radical, C_3-8Heterocycloalkylene, said alkylene, heterocycloalkylene being optionally further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituent substitution; in some embodiments, Q₁、Q₂Each independently being absent, methylene, ethylene, propylene, butylene, pentylene, aziridinyl, azacyclobutyl, azacyclopentylene, azacyclohexylene, which radicals may optionally be further substituted by C_1-6Alkyl, aryl-C_1-6Alkyl or heteroaryl-C_1-6Alkyl substituent substitution; in some embodiments, Q₁、Q₂Each independently is absent, methylene, ethylene, propylene, butylene, pentylene, aziridinyl, azacyclobutyl, azacyclopentyleneA cyclohexyl group;

b is selected from absent, C_1-6Alkylene radical, C_3-8Cycloalkylene radical, C_3-8Heterocycloalkylene, arylene or heteroarylene, said alkylene, heterocycloalkylene, arylene or heteroarylene being optionally further substituted by halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s); in some embodiments, B is selected from absent, methylene, ethylene, propylene, butylene, pentylene, phenylene, pyridylene, furanylene, thiophenylene, thiazolylene, oxazolylene, pyrazolylene, which may optionally be further substituted with a halogen atom, C_1-6Alkyl or C_1-6Haloalkyl;

c and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) -, -NR^wC(＝O)-、-O-(CH₂)_t-NR^wC(O)-、 -O-(CH₂)_t-O-C(O)-、

R^w、R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl radical, C_3-6heterocycloalkyl-C_1-6Alkylene radical, C_1-6Alkoxycarbonyl group, C_1-6Alkylcarbonyl, aryl or aryl-C_1-6Alkyl, said radical being further substituted by halogen atoms, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy substitution; in some embodiments, R^wEach independently selected from H, methyl, ethyl, propyl, isopropyl, isobutyl, phenyl, cyclopropylmethyl, cyclohexylmethyl, cyclohexyl, benzyl, halobenzyl, methoxyethyl, methoxybenzyl, methylbenzyl, epoxyPropyl, oxacyclohexane, azacyclohexyl, acetyl, cyclohexylmethyl, cyclopentylmethyl, oxacyclohexylmethyl or trifluoromethylbenzyl;

R⁷、R⁸each independently selected from H or C_1-6An alkyl group; in some embodiments, R⁷、R⁸Each independently selected from H or methyl, ethyl or isopropyl;

X^-is a physiologically acceptable anion;

R¹¹and R^11’Each independently selected from H or C_1-6An alkyl group; in some embodiments, R¹¹And R^11’Each independently selected from H, methyl, ethyl or isopropyl.

The present invention relates to a compound selected from the group consisting of:

the ditrifluoroacetate salt of the compound of the embodiment of the present invention can be prepared by dissolving it in polar organic solvent (such as mixed solvent of methanol and dichloromethane (v/v. 1/90), adjusting pH to basicity by adding basic reagent (such as saturated sodium bicarbonate solution or saturated sodium carbonate solution), stirring, and adding organic solventExtracting with solvent (such as dichloromethane, ethyl acetate, etc.), and concentrating the organic phase under reduced pressure to obtain the corresponding compound in free base form. The invention also relates to a compound of general formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof, wherein the salt is selected from sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, 2, 6-dimethylpyridine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylammonium salt, hydrochloride salt, hydrobromide salt, sulfate salt, nitrate salt, phosphate salt, formate salt, trifluoroacetate salt, acetate salt, maleate salt, tartrate salt, citrate salt, succinate salt, mandelate salt, fumarate salt, malonate salt, malate salt, 2-hydroxypropionate salt, oxalate salt, glycolate salt, Salicylate, glucuronate, galacturonate, citrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof. The invention also relates to a pharmaceutical composition, which comprises an effective dose of the compound shown in the general formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention may be administered as the only active agent.

The invention also relates to a pharmaceutical composition, which comprises an effective dose of the compound shown in the general formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof, and one or more other active ingredients.

The present invention relates to compositions wherein the other therapeutic agents include: β 2-agonists, antimuscarinics, mitogen-activated protein kinase (P38MAP kinase) inhibitors, nuclear factor κ -B kinase subunit β (IKK2) inhibitors, Human Neutrophil Elastase (HNE) inhibitors, phosphodiesterase 4(PDE4) inhibitors, leukotriene modulators, nonsteroidal anti-inflammatory drugs (NSAIDs), antitussives, mucus regulators, mucolytics, expectorants/mucus activators, peptide mucolytics, antibiotics, JAK inhibitors, SYK inhibitors, PI3K or PI3K γ inhibitors, corticosteroids, and M3-antagonists/PDE 4-inhibitors (MAPIs described herein.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a β 2-agonist selected from carmoterol, vilanterol, indacaterol, mevalonate, arformoterol tartrate, formoterol fumarate, salmeterol xinafoate, salbutamol, levalbuterol, d-salbutamol, terbutaline, tulobuterol, olodaterol (olodaterol), LAS-100977, AZD-8871, CHF-6366, berradoline (KUR-1246), GSK961081, bambuterol, isoproterenol, procaterol, clenbuterol, reproterol, fenoterol, bitolterol and salts thereof.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, with an antimuscarinic agent selected from aclidinium, tiotropium bromide, glycopyrrolate, solifenacin, darifenacin, imidafenacin, TRN-157, benzcyclamine, JRP-878, ipratropium bromide, trospium chloride, glycopyrrolate, metaterol, GSK233705, LAS35201, QAT370, oxytropin and salts thereof.

The invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a PDE4 inhibitor selected from AN-2898, simperidone, cilomilast, roflumilast, doxofylline, theophylline, apremilast (apremilast), CHF-6001, tipelukast, ensientrine, AN-6415, CC-11050, omikast, tetomilast and salts thereof.

This invention also provides a combination of a compound of this invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, with a P38MAP kinase inhibitor selected from acumapimod, samimod (Semapimod), pirfenidone, PH-797804, minokine, lopinimod and salts thereof.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, with an HNE inhibitor selected from POL-6014, alvelestat, CHF-6333, DSP-1363, ADC-7828 and salts thereof.

The invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a leukotriene modulator selected from montelukast, ibudilast, marelukast, tipelukast, tolelukast (tomelukast), pobilukast (postilukast), zafirlukast, pranlukast, and salts thereof.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and an NSAID selected from ibuprofen, ketoprofen and salts thereof.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and an antitussive selected from codeine, dextro-morphinan (dexramorphan) and salts thereof.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a mucolytic selected from N-acetylcysteine, fudosteine and salts thereof.

The present invention also provides a combination of a compound of the invention or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof with an expectorant/mucus actuation modulator selected from ambroxol, a hypertonic solution (e.g. saline or mannitol), a surfactant.

The invention also provides a combination of a compound of the invention or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a peptide mucolytic selected from recombinant human deoxyribonuclease I (alfa-streptoase and rhDNase), spirodiclodin.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and an antibiotic selected from azithromycin, tobramycin, aztreonam and salts thereof.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, with a mucus regulating agent selected from INS-37217, diquafosol, siberian, CS-003, talnetant, DNK-333, MSI-1956, gefitinib and salts thereof.

The invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, with a JAK inhibitor selected from tofacitinib, AZD-0449, VR-588, CPL-409-057, WHI-P97 and salts thereof.

The invention also provides a combination of a compound of the invention or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof with a SYK inhibitor selected from fostamitinib, FF-10102-01, R-343, AVE-0950, R-280 and salts thereof.

The present invention also provides a combination of a compound of the invention, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a corticosteroid selected from dexamethasone, fluticasone furoate, fluticasone propionate, prednisolone, methylprednisolone, betamethasone, budesonide, mometasone furoate, triamcinolone acetonide, ciclesonide, beclomethasone dipropionate, beclomethasone propionate, prednisone, deflazacort, hydrocortisone, QAE-397, flunisolide, vamorolone, AZD-5423, TPI-1020, and salts thereof.

The invention provides application of a compound shown in a general formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof in preparation of medicaments.

The invention also relates to the use of a compound of formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof or a composition comprising a compound of formula (I), (I-1), (II-1) or (III) for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD).

The invention also relates to the use of a compound of formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a composition comprising a compound of formula (I), (I-1), (II-1) or (III) in the manufacture of a medicament for the treatment of an obstructive airways disease, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD).

The present invention also provides a method for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD), which comprises administering to a subject in need thereof a therapeutically effective dose of a compound of formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof.

The present invention also provides a method for the prevention and/or treatment of an airway obstructive disease, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD), which comprises administering to a subject in need thereof a therapeutically effective dose of a compound of formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof.

The invention also provides a pharmaceutical composition suitable for administration by inhalation comprising a compound of formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof.

Inhalable formulations including inhalable powders, propellant-containing dose aerosols or propellant-free inhalable formulations are prepared from each of the above-described pharmaceutical compositions together with one or more pharmaceutically acceptable carriers.

The invention also relates to a device which may be a single or multi dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer (soft mist nebulizer) comprising a compound of formula (I), (I-1), (II-1) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof.

The invention also relates to kits comprising compositions and devices of the compounds of formula (I), (I-1), (II-1) or (III) of the invention, or stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, alone or in combination or in admixture with one or more pharmaceutically acceptable carriers and/or excipients, which devices may be single or dry powder inhalers, metered dose inhalers or soft mist nebulizers comprising a compound of formula (I), (I-1), (II-1) or (III), or stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, multi-doses co-crystals or prodrugs thereof.

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" refers to straight and branched chain monovalent saturated hydrocarbon groups, 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; the alkyl group may be optionally further substituted with a substituent.

"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; the alkylene group may be optionally further substituted with a substituent.

"alkoxy" refers to a monovalent radical of-O-alkyl, where alkyl is as defined herein, and examples of alkoxy 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-carbon double bonds, and the main chain includes 2 to 10 carbon atoms, further preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms in the main chain, and 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-pentenylA base, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; said alkenyl may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃、-OCH₂F、-OCHF₂、-OCF₃Hydroxy, -SR¹⁹Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_k-C(＝O)-R¹⁹、 -(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹or-NR¹⁹R^19aSubstituted with the substituent(s). Alkenyl as used herein, is defined as above.

"alkenylene" refers to a divalent alkenyl group in which the alkenyl group is as defined 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 alkynyl may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃、-OCH₂F、-OCHF₂、-OCF₃Hydroxy, -SR¹⁹Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_k-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹or-NR¹⁹R^19aSubstituted with the substituent(s). Alkynyl, as found herein, is defined as above.

"alkynylene" refers to a divalent alkynyl group in which the alkynyl group is as defined above.

"cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically of 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. The cycloalkyl group may be optionally further substituted with various substituents.

"cycloalkylene" refers to a divalent cycloalkyl group, wherein cycloalkyl is as defined above.

"alkoxy" means an-O-alkyl group, wherein alkyl is as defined herein above. Alkoxy groups may be substituted or unsubstituted, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and the like.

"heterocycloalkyl" means a substituted or unsubstituted, saturated or unsaturated, non-aromatic ring containing at least 1 heteroatom selected from N, O or S, which may be a 3-to 10-membered monocyclic ring, a 4-to 20-membered spirocyclic, fused or bridged ring, and optionally substituted N, S in the heterocycloalkyl ring can be oxidized to various oxidation states. Non-limiting examples include oxacyclopropane, oxetanyl, oxocyclopentyl, oxocyclohexyl, oxooctyl, aziridinyl, azetidinyl, azacyclohexyl, aziridinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxacyclohexyl, 1, 3-dithiocyclohexyl, azepinyl, pyranyl, morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, dihydropyran, 1, 4-dioxacyclohexadienyl, oxacyclohexadienyl, oxacyclohexenyl, azacyclopentyl, azepinyl, 1, 3-dioxacyclopentyl, 1, 3-dioxacyclohexyl, 1,

And the like.

"Heterocycloalkylene" refers to a divalent heterocycloalkyl group, wherein heterocycloalkyl is as defined above.

"aryl" refers to substituted or unsubstituted 6 to 14 membered cyclic aromatic groups, including monocyclic aromatic groups and fused ring aromatic groups. Non-limiting examples thereof include phenyl, naphthyl, anthryl, phenanthryl, and the like. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

"arylene" is a divalent aromatic radical which, when fused, can be located on different rings, for example:

wherein aryl is as defined above.

"heteroaryl" refers to a substituted or unsubstituted aromatic ring containing at least 1 aromatic ring selected from N, O or S (═ O)_nA heteroatom or a group. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include

"heteroarylene" refers to a divalent heteroaryl group, which when fused, may be on different rings, such as

Wherein heteroaryl is as defined above.

"β -adrenoceptor binding group" refers to a group capable of binding to the β -adrenoceptor, such as described in the review article "β -adrenoceptors in Comprehensive Medicinal Chemistry, 1990, B.E.Main, p187(Pergamon Press)". the above groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627 non-limiting examples include

R²、R³、R⁴、R⁵Each independently selected from H, hydroxy, halogen atom, C_1-6Alkyl radical, C_1-6Haloalkyl or C_1-6Alkoxy radical, R⁶Selected from H or C_1-6Alkyl, A is selected from

Wherein R is¹²Selected from H, halogen atom or amino group, r is selected from 0, 1,2 or 3.

"hydroxy protecting group" means a group for protecting a hydroxy group that is suitable for protecting the hydroxy group from chemical reaction, but does so in other parts of the moleculeThis group is then easily removed. Non-limiting examples include, but are not limited to, trialkylsilyl (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), benzyl, C_1-6Alkanoyl (e.g. formyl, acetyl, propionyl, etc.) or C_6-10Arylacyl groups, and the like.

"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.

"independently selected" means that a group is independently selected at will among the candidate groups, and that the same R substituents in the same structure are not affected by each other.

Substituents of the invention which are optionally further substituted, when composed of two or more types of chemical groups, the last group expressed is a linking group, e.g. "aryl-C_1-6Alkyl "means that the aryl group is linked to an alkyl group, which is linked to other groups.

As a site for linkage of the group. When a group contains 2 or more than 2 such linking points, the linking site is included to link to any linking site of other groups. Such as

Means that 2 chemical linking sites may be optionally included with other groups such as methyl and ethyl groups

Two molecules.

When used as a chemical bond, it means that the bond is one of cis or trans structures, e.g. chemical structure

Indicates that the structure is

Or

"pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt thereof with other ingredients, wherein the other ingredients comprise a physiologically/pharmaceutically acceptable carrier or excipient.

"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.

"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 causes physiological or medical translation in a tissue, system, or subject that is sought, including an amount of the compound that is sufficient to prevent, or alleviate to some extent, one or more symptoms of the condition or disorder being treated when administered to a subject.

"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.

“IC₅₀"half inhibitory concentration" means the concentration at which half of the maximum inhibitory effect is achieved.

The synthesis method of the compound comprises the following steps:

to accomplish the objects of the present invention, the compounds of the present invention can be prepared by the following scheme:

the first scheme is as follows:

the compound of the general formula (I-A) is reacted with the compound of the general formula (I-B) to generate a compound of the general formula (I-C); the compound of the general formula (I-C) is subjected to Boc removal protection under an acidic condition to obtain a compound of the general formula (I-D); reacting the compound of formula (I-D) with triphosgene to form a compound of formula (I-E); carrying out addition reaction on the compound with the general formula (I-E) and the compound (I-F) to obtain a compound with the general formula (I-G); hydrolyzing the compound of the general formula (I-G) under alkaline conditions to generate a compound of the general formula (I-H); carrying out condensation reaction on the compound with the general formula (I-H) and the compound with the general formula (I-I) to obtain a compound with the general formula (I-J); the compound of the general formula (I-J) is deacetalized and protected under the acidic condition to form the compound of the general formula (I-K); carrying out reductive amination on the compound with the general formula (I-K) and the compound with the general formula (I-L) to obtain a compound with the general formula (I-M); the TBS and Boc protection of the compounds of general formula (I-M) under acidic conditions gives compounds of general formula (Ib).

Scheme II:

reacting the compound of the general formula (II-A) with benzyl bromide to generate a compound of a general formula (II-B); reacting the compound of the general formula (II-B) with hydroxylamine hydrochloride to obtain a compound of the general formula (II-C); reducing the compound of the general formula (II-C) by zinc powder to form a compound of the general formula (II-D); reacting the compound of formula (II-D) with triphosgene to form a compound of formula (II-E); carrying out addition reaction on the compound with the general formula (II-E) and the compound (I-F) to obtain a compound with the general formula (II-F); reacting the compound of the general formula (II-F) with 1, 4-cyclohexadiene in the presence of palladium on carbon to produce a compound of the general formula (II-G); reacting the compound of the general formula (II-G) with the compound of the general formula (II-H) to obtain a compound of the general formula (II-I); hydrolyzing the compound of the general formula (II-I) in a lithium hydroxide solution to form a compound of the general formula (II-J); carrying out condensation reaction on the compound with the general formula (II-J) and the compound with the general formula (II-K) to obtain a compound with the general formula (II-L); the compound of the general formula (II-L) is deacetalized to form the compound of the general formula (II-M) under the acidic condition; carrying out reductive amination on the compound of the general formula (II-M) and the compound of the general formula (II-N) to form a compound of the general formula (II-O); and (5) removing TBS and Boc protecting groups from the compound of the general formula (II-O) under acidic conditions to obtain the compound of the general formula (Ia).

Wherein Q is₁' selected from C_1-5Alkyl, X' is selected from heteroatom N or heteroatom O, Y is selected from NR^wOr the heteroatom O, B, D, R^w、Q₁P and q are as defined for formula (I) or (II) or (III).

The quaternary ammonium salt is further obtained by addition reaction of the general formula (Ia) and (Ib) and a bromo compound.

The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures, or by using other information readily available to those skilled in the art. While specific embodiments of the invention have been shown or described herein, it will be recognized by those skilled in the art that all embodiments or aspects of the invention may be made using the methods described herein or by using other methods, reagents, and starting materials well known to those skilled in the art. It is also understood that if typical or preferred process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressures, etc.) are specified, other process conditions may also be used unless otherwise specified. Although optimum reaction conditions may vary depending on the particular reactants or solvents used, such conditions are readily determined by one skilled in the art by routine optimization methods.

Detailed Description

The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS).

NMR shift () at 10^-6The units in (ppm) are given.

NMR was measured using a (Bruker ADVANCE III 400) nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS), 1HNMR information is tabulated in the following format: chemical shift (multiplet (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), number of protons).

MS was measured (Agilent 6120B (ESI)).

HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18100 x 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.

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 2L.

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

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, the starting materials/reagents used are commercially available, unless otherwise specified.

Intermediate 1: 4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a)

4-[[3-[[(7-tert-butoxycarbonyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)oxycarbonylamino]-phenyl -methyl]phenoxy]methyl]benzoic acid

4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-b)

The first step is as follows: 4- [ [3- [ amino (phenyl) methyl ] phenoxy ] methyl ] benzoic acid methyl ester (1B)

Methyl 4-[[3-[amino(phenyl)methyl]phenoxy]methyl]benzoate

Methyl 4- [ [3- [ (tert-butoxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoate (1A, preparation reference WO2014086924) (12.5g, 27.9mmol) was dissolved in 100ml of a 4mol/L ethyl acetate hydrochloride solution and stirred at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure, 200 ml of methylene chloride was added, the pH was adjusted to 9-10 with a saturated aqueous solution of sodium hydrogencarbonate, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to give methyl 4- [ [3- [ amino (phenyl) methyl ] phenoxy ] methyl ] benzoate (1B) (8.0g, yield: 82%).

¹H NMR(400MHz,CDCl₃)8.05–8.01(m,2H),7.47(d,2H),7.37–7.33(m,2H),7.32–7.27(m,2H),7.25–7.20(m,2H),7.04–7.02(m,1H),6.98(d,1H),6.85–6.81(m,1H),5.19(s,1H),5.09(s,2H),3.92(s,3H),2.42(b,2H).

LCMS m/z＝331.2[M-16]⁺.

The second step is that: 4- [ [3- [ isocyanato (phenyl) methyl ] phenoxy ] methyl ] benzoic acid methyl ester (1C)

Methyl 4-[[3-[isocyanato(phenyl)methyl]phenoxy]methyl]benzoate

Methyl 4- [ [3- [ amino (phenyl) methyl ] phenoxy ] methyl ] benzoate (1B) (6.40g, 18.4mmol) was dissolved in 100ml dichloromethane, 100ml water was added, solid sodium bicarbonate (4.64g, 55.2mmol) was added, cooling was performed on an ice bath to 0 ℃,20 ml of a solution of triphosgene (1.80g, 6.08mmol) in dichloromethane was slowly added dropwise, and the reaction was continued at 0 ℃ for 20 minutes. The reaction solution is kept stand for liquid separation, an organic layer is dried by anhydrous sodium sulfate, and the organic layer is concentrated under reduced pressure to obtain a crude product of methyl 4- [ [3- [ isocyanato (phenyl) methyl ] phenoxy ] methyl ] benzoate (1C), which is directly used in the next step.

The third step: 9- [ [ [3- [ (4-methoxycarbonylphenyl) methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1D-a)

Tert-butyl 9-[[[3-[(4-methoxycarbonylphenyl)methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicy clo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ (4-methoxycarbonylphenyl) methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1D-b)

The crude methyl 4- [ [3- [ isocyanato (phenyl) methyl ] phenoxy ] methyl ] benzoate (1C) obtained in the previous step was dissolved in 100ml of 1, 4-dioxane, and 7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3,3,1] nonan-9-ol (4.93g, 20.3mmol) and DBU (2.80g, 18.4mmol) were added, and the reaction was stirred at 100 ℃ for 1 hour after the addition. The reaction solution was concentrated under reduced pressure, the crude product was dissolved in 100ml of ethyl acetate, 20ml of water was added, liquid separation was carried out, the organic layer was washed with 20ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100:0-3:1), to give 9- [ [ [3- [ (4-methoxycarbonylphenyl) methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1D-a) (3.70g, yield: 32.6%) and 9- [ [ [3- [ (4-methoxycarbonylphenyl) methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane- 7-Carboxylic acid tert-butyl ester (1D-b) as two pure products (2.50g, yield: 22.0%).

1D-a (developing solvent: petroleum ether/ethyl acetate 7/3, Rf value: 0.3)

¹H NMR(400MHz,DMSO-d₆)8.30(d,1H),7.97(d,2H),7.56(d,2H),7.30(t,4H),7.27– 7.19(m,2H),7.02(s,1H),6.95-6.85(m,2H),5.83(d,1H),5.17(s,2H),4.81(t,1H),4.05–3.98(m, 1H),3.96–3.87(m,3H),3.86(s,3H),3.61(t,2H),3.33(d,1H),3.20(d,1H),1.79(s,2H),1.38(s, 9H).

LCMS m/z＝639.3[M+23]⁺,517.3[M-100+1]⁺。

1D-b (developing solvent: petroleum ether/ethyl acetate 7/3, Rf value: 0.4)

¹H NMR(400MHz,DMSO-d₆)8.33(d,1H),7.96(d,2H),7.56(d,2H),7.30(t,4H),7.27– 7.19(m,2H),7.02(s,1H),6.98–6.86(m,2H),5.84(d,1H),5.17(s,2H),4.76(t,1H),4.29(d,1H), 4.18(d,1H),4.00-3.90(m,2H),3.86(s,3H),3.73-3.65(m,2H),3.15(d,1H),3.00(d,1H),1.70(s, 2H),1.38(s,9H).

LCMS m/z＝639.3[M+23]⁺,517.3[M-100+1]⁺。

The fourth step: 4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a)

Tert-butyl 9- [ [ [3- [ (4-methoxycarbonylphenyl) methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (1D-a) (2.20g, 3.57mmol) was dissolved in 20ml of tetrahydrofuran, 4 ml of water was added, solid lithium hydroxide (0.854g, 35.7mmol) was added, and after completion of the addition, the reaction was stirred at 60 ℃ for 1 hour. Cooled to room temperature, adjusted the pH to 5-6 with 1mol/L dilute hydrochloric acid, added with 50ml of ethyl acetate, separated, and the organic layer was washed once with 10ml of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a) (2.10g, yield: 97.7%).

¹H NMR(400MHz,CD₃OD)7.99(d,2H),7.49(d,2H),7.32–7.20(m,6H),6.94–6.82(m, 3H),5.87(s,1H),5.14(s,2H),4.90(s,1H),4.15–4.01(m,4H),3.76–3.66(m,2H),3.44(d,1H), 3.33(d,1H),1.90–1.82(m,2H),1.44(s,9H).

LCMS m/z＝626.3[M+23]⁺,503.2[M-100+1]⁺。

The intermediate 1-b is obtained by using 1D-b as a starting material according to the synthesis method of the fourth step of the intermediate 1-a.

Intermediate 2: 9- [ [ (3-hydroxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (intermediate 2-a)

Tert-butyl 9-[[(3-hydroxyphenyl)-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylat e

The first step is as follows: (3-Benzyloxyphenyl) -phenyl-methanone (2B)

(3-Benzyloxyphenyl)-phenyl-methanone

(3-hydroxyphenyl) -phenyl-methanone (2A) (20.0g, 101mmol) was dissolved in 200 mL of DMF, and benzyl bromide (25.9g, 150mmol) and potassium carbonate (27.9g, 202mmol) were added sequentially, followed by reaction at room temperature overnight. 300 ml of water and 200 ml of ethyl acetate were added, the layers were separated, and washed twice with 150 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, added with 200 ml of petroleum ether, stirred for 30 minutes to precipitate a white solid, and filtered to obtain (3-benzyloxyphenyl) -phenyl-methanone (2B) (24.1g, yield: 83%).

The second step is that: (3-Benzyloxyphenyl) -phenyl-methanoxime (2C)

(3-Benzyloxyphenyl)-phenyl-methanone oxime

(3-benzyloxyphenyl) -phenyl-methanone (2B) (4.5g, 15.6mmol) was dissolved in 20ml of methanol, hydroxylamine hydrochloride (1.6g, 23.4mmol) and sodium acetate (2.6g, 31.2mmol) were added, and the reaction was allowed to proceed at 65 ℃ overnight. Cooled to room temperature, concentrated, added with 50ml of ethyl acetate, washed with 150 ml of saturated sodium chloride, dried, and concentrated to give (3-benzyloxyphenyl) -phenyl-methanoxime (2C) (4.7g, yield: 99%).

LCMS m/z＝304.3[M+1]⁺。

The third step: (3-benzyloxyphenyl) -phenyl-methylamine (2D)

(3-Benzyloxyphenyl)-phenyl-methanamine

(3-benzyloxyphenyl) -phenyl-ketoxime (2C) (4.3g, 14mmol) was dissolved in 60 ml of ethanol, and zinc powder (4.6g, 71mmol) and ammonium acetate (1.1g, 14mmol) were added to the solution, followed by refluxing at elevated temperature for 2 hours. Filtering with celite, washing with ethanol, concentrating under reduced pressure to remove the solvent, adding 100ml of ethyl acetate, washing with 150 ml of saturated sodium chloride, drying, and concentrating to obtain (3-benzyloxyphenyl) -phenyl-methylamine (2D) (4.2g, yield: 99%).

The fourth step: 1-benzyloxy-3- [ isocyanato (phenyl) methyl ] benzene (2E)

1-Benzyloxy-3-[isocyanato(phenyl)methyl]benzene

Triphosgene (1.8g, 6.2mmol) was dissolved in 50ml of dichloromethane, cooled to zero, then (3-benzyloxyphenyl) -phenyl-methylamine (2D) (3.6g, 12.4mmol) was dissolved in 10ml of dichloromethane and added dropwise to the reaction mixture, and triethylamine (1.9g, 18.7mmol) was added dropwise, after which the reaction was continued at 0 ℃ for 20 minutes. 30ml of water was added to the reaction mixture, followed by liquid separation, drying of the organic layer over anhydrous sodium sulfate, and concentration under reduced pressure to give a crude product of 1-benzyloxy-3- [ isocyanato (phenyl) methyl ] benzene (2E), which was used directly in the next step.

The fifth step: 9- [ [ (3-benzyloxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (2F-a)

Tert-butyl 9-[[(3-benzyloxyphenyl)-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxy late

9- [ [ (3-benzyloxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (2F-b)

The crude 1-benzyloxy-3- [ isocyanato (phenyl) methyl ] benzene (2E) obtained in the previous step was dissolved in 50ml of 1, 4-dioxane, and 7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3,3,1] nonan-9-ol (3.1g, 12.7mmol) and triethylamine (1.8g, 18.4mmol) were added thereto, followed by stirring at 100 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in 100ml of ethyl acetate, 120 ml of water was added, liquid separation was carried out, the organic layer was washed with 120 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100:0-3:1), to give two pure products, i.e., tert-butyl 9- [ [ (3-benzyloxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (2F-a) (3.0g, yield: 40%) and tert-butyl 9- [ [ (3-benzyloxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (2F-b) (2.50g, yield: 33%).

2F-a (developing solvent: petroleum ether/ethyl acetate 3/1, Rf value: 0.45)

¹HNMR(400MHz,CDCl₃)7.42–7.22(m,11H),6.87(t,3H),5.88(d,1H),5.43(s,1H),5.02(s,2H),4.88(t,1H),4.50(d,1H),4.31(d,1H),4.15–3.90(m,2H),3.88-3.70(m,2H),3.16(d, 1H),3.05(d,1H),1.77(s,2H),1.46(s,9H).

LCMS m/z＝459.3[M-100+1]⁺。

2F-b (developing solvent: petroleum ether/ethyl acetate 3/1, Rf value: 0.42)

¹HNMR(400MHz,CDCl₃)7.42–7.22(m,11H),6.87(t,3H),5.83(d,1H),5.42(s,1H),5.04(d,2H),4.94(t,1H),4.30-3.95(m,4H),3.70(s,2H),3.29–2.83(m,2H),1.84(s,2H),1.46(s, 9H).

LCMS m/z＝459.3[M-100+1]⁺。

And a sixth step: 9- [ [ (3-hydroxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (intermediate 2-a)

Tert-butyl 9- [ [ (3-benzyloxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (2F-a) (1.3g, 2.3mmol) was dissolved in 30mL of methanol, 10% palladium on carbon (0.26g) was added, and the mixture was stirred under a hydrogen balloon for 3 hours. Filtration through celite and concentration under reduced pressure gave 9- [ [ (3-hydroxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (intermediate 2-a) (0.8g, yield: 70%).

¹HNMR(400MHz,CDCl₃)7.88(br,1H),7.33–7.13(m,6H),6.91(dd,1H),6.78(dd,2H), 6.54(s,1H),5.96(d,1H),5.10(s,1H),4.51(t,1H),4.35(dd,1H),4.20(dd,1H),4.07–3.62(m, 3H),3.20(d,1H),3.10(d,1H),1.80(t,2H),1.22(dd,9H).

LCMS m/z＝491.3[M+23]⁺。

Intermediate 3: n- (3-aminopropyl) -N- [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] carbamic acid tert-butyl ester (intermediate 3)

Tert-butyl N-(3-aminopropyl)-N-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo- 1H-quinolin-5-yl)ethyl]carbamate

The first step is as follows: 8-benzyloxy-5- [ (1R) -2-bromo-1- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -1H-quinolin-2-one (3B)

8-Benzyloxy-5-[(1R)-2-bromo-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-1H-quinolin-2-one

(R) -8- (benzyloxy) -5- (2-bromo-1-hydroxyethyl) -1H-quinolin-2-one (3A) (15.0g, 40.09mmol) was suspended in 150 ml of dichloromethane, cooled to 0 ℃ under nitrogen, 2, 6-lutidine (12.89g, 120.3mmol) was added, tert-butyldimethylsilyl trifluoromethanesulfonate (31.79g, 120.3mmol) was slowly added dropwise, and after completion of the addition, the reaction was allowed to stand at room temperature overnight. 20mL of water was added, the layers were separated, and the organic layer was successively washed with 1mol/L hydrochloric acid (10 mL. times.2) and 10mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8-benzyloxy-5- [ (1R) -2-bromo-1- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -1H-quinolin-2-one (3B) (11.0g, yield: 56.2%).

¹H NMR(400MHz,CDCl₃)9.36(s,1H),8.25(d,1H),7.47–7.36(m,5H),7.17(d,1H),7.03(d,1H),6.72(d,1H),5.21–5.15(m,3H),3.59(dd,1H),3.49(dd,1H),0.88(s,9H),0.13(s, 3H),-0.12(s,3H).

The second step is that: benzyl N- [3- [ [ (2R) -2- (8-benzyloxy-2-oxo-1H-quinolin-5-yl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] amino ] propyl ] carbamate (3C)

Benzyl N-[3-[[(2R)-2-(8-benzyloxy-2-oxo-1H-quinolin-5-yl)-2-[tert-butyl(dimethyl)silyl]oxy- ethyl]amino]propyl]carbamate

8-benzyloxy-5- [ (1R) -2-bromo-1- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -1H-quinolin-2-one (3B) (11.0g, 22.5mmol) was dissolved in 50ml of N, N-dimethylformamide, benzyl N- (3-aminopropyl) carbamate (7.03g, 33.8mmol) and triethylamine (3.42g, 33.8mmol) were added, and after the completion of the addition, the reaction was carried out at 90 ℃ for 5 hours. After cooling to room temperature, 100ml of water and 100ml of ethyl acetate were added, the mixture was separated, the organic layer was washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0:1-1:9) to give benzyl N- [3- [ [ (2R) -2- (8-benzyloxy-2-oxo-1H-quinolin-5-yl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] amino ] propyl ] carbamate (3C) (10.8g, yield: 77.9%).

¹H NMR(400MHz,DMSO-d₆)8.27(d,1H),7.60–7.54(m,2H),7.44–7.26(m,10H),7.19 (d,2H),7.11(d,1H),6.54(d,1H),5.27(s,2H),5.14–5.10(m,1H),5.00(s,2H),3.04–2.98(m, 2H),2.74(dd,1H),2.62(dd,1H),2.55–2.50(m,2H),1.53–1.45(m,2H),0.82(s,9H),0.04(s, 3H),-0.18(d,3H).

LCMS m/z＝616.3[M+1]⁺。

The third step: n- [3- (benzyloxycarbonylamino) propyl ] -N- [ (2R) -2- (8-benzyloxy-2-oxo-1H-quinolin-5-yl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] carbamic acid tert-butyl ester (3D)

Tert-butyl N-[3-(benzyloxycarbonylamino)propyl]-N-[(2R)-2-(8-benzyloxy-2-oxo-1H-quinolin -5-yl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]carbamate

Benzyl N- [3- [ [ (2R) -2- (8-benzyloxy-2-oxo-1H-quinolin-5-yl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] amino ] propyl ] carbamate (3C) (10.8g, 17.54mmol) was dissolved in 50mL of dichloromethane, di-tert-butyl dicarbonate (7.65g, 35.08mmol) was added, and the reaction was stirred at room temperature overnight. 100ml of water was added thereto, the mixture was separated, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 0:1-2:3) to give tert-butyl N- [3- (benzyloxycarbonylamino) propyl ] -N- [ (2R) -2- (8-benzyloxy-2-oxo-1H-quinolin-5-yl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] carbamate (3D) (6.50g, yield: 51.8%).

¹H NMR(400MHz,CD₃OD)8.72(s,1H),7.51(d,2H),7.39(t,2H),7.35–7.24(m,6H),7.20(d,2H),6.67(dd,1H),5.32(s,2H),5.04(d,2H),3.44(d,1H),3.40–3.35(m,2H),3.29–3.12 (m,2H),3.06(t,2H),1.70–1.60(m,2H),1.40(d,9H),0.88(s,9H),0.05(s,3H),-0.16(s,3H).

The fourth step: n- (3-aminopropyl) -N- [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] carbamic acid tert-butyl ester (intermediate 3)

Tert-butyl N-(3-aminopropyl)-N-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H -quinolin-5-yl)ethyl]carbamate

N- [3- (benzyloxycarbonylamino) propyl ] -N- [ (2R) -2- (8-benzyloxy-2-oxo-1H-quinolin-5-yl) -2- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] carbamic acid tert-butyl ester (3D) (2.10g, 2.93mmol) was dissolved in 30ml of anhydrous ethanol, 600 mg of 10% palladium on charcoal was added, 1-methyl-1, 4-cyclohexadiene (1.38g,14.7mmol) was added, and after completion of the addition, the reaction was refluxed at 90 ℃ for 1 hour. After cooling to room temperature, palladium on carbon was removed by filtration and the filtrate was concentrated, the crude product was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1:20-1:5) to give N- (3-aminopropyl) -N- [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] carbamic acid tert-butyl ester (intermediate 3) (1.40g, yield: 97.1%).

¹H NMR(400MHz,DMSO-d₆)8.28(s,1H),7.05(s,1H),7.0–6.8(m,2H),6.53(d,1H),6.45(d,1H),6.08(b,2H),5.36(s,1H),3.30(d,2H),3.24–3.05(m,2H),2.54–2.48(m,2H),1.57 –1.48(m,2H),1.40(d,9H),0.82(s,9H),0.01(s,3H),-0.18(s,3H).

LCMS m/z＝492.3[M+1]⁺。

Intermediate 4: n- (2-aminoethyl) -N- [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] carbamic acid tert-butyl ester (intermediate 4)

Tert-butyl-N-(2-aminoethyl)-N-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H- quinolin-5-yl)ethyl]carbamate

The intermediate 4 is obtained by using N-carbobenzoxy-1, 2-diaminoethane hydrochloride as a starting material according to the synthesis methods from the first step to the fourth step of the intermediate 3.

LCMS m/z＝378.3[M-100+1]⁺。

Example 1:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 1)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-q uinolin-5-yl)ethyl]amino]propylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

The first step is as follows: 9- [ [ [3- [ [4- (3, 3-diethoxypropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1a)

Tert-butyl 9-[[[3-[[4-(3,3-diethoxypropylcarbamoyl)phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3- oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a) (0.580g, 0.962mmol) was dissolved in 10mL of DMF and 1-amino-3, 3-diethoxypropane (0.213g, 1.44mmol), triethylamine (0.341g, 3.37mmol), 1-hydroxybenzotriazole (0.260g, 1.92mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.369g, 1.92mmol) were added in this order and reacted at room temperature overnight after the addition. 20ml of water and 50ml of ethyl acetate were added, liquid separation was performed, the organic layer was washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4:1-1:4) to give 9- [ [ [3- [ [4- (3, 3-diethoxypropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1a) (0.528g, yield: 75%).

¹H NMR(400MHz,DMSO-d₆)8.40(t,1H),8.30(d,1H),7.82(d,2H),7.49(d,2H),7.35– 7.25(m,4H),7.25–7.20(m,2H),7.01(s,1H),6.95–6.85(m,2H),5.82(d,1H),5.12(s,2H),4.80 (t,1H),4.56(t,1H),4.05–3.97(m,1H),3.96-3.84(m,3H),3.65–3.53(m,4H),3.50–3.40(m, 2H),3.35–3.25(m,3H),3.22–3.16(m,1H),1.84–1.76(m,4H),1.38(s,9H),1.11(t,,6H).

The second step is that: 9- [ [ [3- [ [4- (3-oxopropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1b)

Tert-butyl 9-[[[3-[[4-(3-oxopropylcarbamoyl)phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7- azabicyclo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- (3, 3-diethoxypropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1a) (0.528g, 0.721mmol) was dissolved in 8 ml of tetrahydrofuran, and 4 ml of 4mol/L aqueous hydrochloric acid was added and stirred at room temperature for 30 minutes. After completion of the reaction, the pH was adjusted to 9-10 with a saturated sodium bicarbonate solution, extracted with 20ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 9- [ [ [3- [ [4- (3-oxopropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (1b) (0.475g, yield: 99%).

LCMS m/z＝558.3[M-100+1]⁺。

The third step: 9- [ [ [3- [ [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1c)

Tert-butyl 9-[[[3-[[4-[3-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]propylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3. 3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- (3-oxopropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1b) (0.470g, 0.715mmol) was dissolved in 10ml of anhydrous methanol, (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (0.650g, 1.43mmol) was added, 0.5 ml of triethylamine was added, stirring was carried out at room temperature for 2 hours, glacial acetic acid (0.064g, 1.07mmol) was added, followed by sodium triacetoxyborohydride (0.454g, 2.14mmol), and the reaction was continued for 2 hours. Saturated sodium bicarbonate solution was added dropwise to adjust pH to 9-10, followed by extraction with 20ml of dichloromethane, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:0-10:1) to give 9- [ [ [3- [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1c) (0.100g, yield: 14.3%).

¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),8.42(t,1H),8.30(d,1H),8.24(d,1H),7.82(d, 2H),7.48(d,2H),7.35–7.25(m,4H),7.24–7.16(m,2H),7.02(d,2H),6.97–6.84(m,3H),6.49 (d,1H),5.82(d,1H),5.15–5.07(m,3H),4.80(t,1H),4.01(d,1H),3.95–3.83(m,3H),3.59(d, 2H),3.39–3.23(m,5H),3.24–3.16(m,1H),2.86–2.77(m,1H),2.69–2.63(m,1H),2.61(t,2H), 1.79(s,2H),1.69–1.57(m,2H),1.37(s,9H),0.82(s,9H),0.03(s,3H),-0.18(s,3H).

LCMS m/z＝438.8[(M-100)/2+1]⁺。

The fourth step: 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 1)

To 9- [ [ [3- [ [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (1c) (0.100g, 0.102mmol) was added 10ml of a 4mol/L solution of ethyl acetate hydrochloride, and 2 ml of anhydrous methanol was added and stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model SunfireC18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min), and lyophilized to give 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 1) (0.040g, yield: 39%).

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.84(d,2H),7.51(d,2H),7.34–7.20(m,7H),7.03(d,1H),6.96–6.85(m,3H),6.66(d,1H),5.89(s,1H),5.45(t,1H),5.13(s,2H),5.02(t,1H), 4.19(d,2H),3.85(d,2H),3.60–3.49(m,4H),3.44(d,2H),3.25(d,2H),3.15(t,2H),2.18(s,2H), 2.10–2.00(m,2H).

¹⁹F NMR(376MHz,CD₃OD)-74.84.

LCMS m/z＝762.3[M+1]⁺。

Example 2:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 2)

Compound 2 was obtained according to the synthesis procedures from the first step to the fourth step of example 1 starting from intermediate 1-b.

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.84(d,2H),7.51(d,2H),7.36–7.20(m,7H),7.03(d,1H),6.95–6.85(m,3H),6.66(d,1H),5.89(s,1H),5.48–5.42(m,1H),5.12(s,2H),4.99 (s,1H),4.16(d,2H),3.95(d,2H),3.67(d,2H),3.58–3.49(m,2H),3.44(d,2H),3.26(d,2H),3.15 (t,2H),2.11(s,2H),2.06–2.00(m,2H).

¹⁹F NMR(376MHz,CD₃OD)-74.84.

LCMS m/z＝762.4[M+1]⁺。

Example 3:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 3)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[4-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-q uinolin-5-yl)ethyl]amino]butylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

The first step is as follows: 2- (3- (1, 3-Dioxolan-2-yl) propyl) isoindoline-1, 3-dione (3b)

2-(3-(1,3-Dioxolan-2-yl)propyl)isoindoline-1,3-dione

2- (3-chloropropyl) -1, 3-dioxolane (3.00g, 19.9mmol) was dissolved in 15ml of DMF, and phthalimide potassium salt (4.40g, 29.9mmol) was added, and after the addition, the reaction was stirred at 80 ℃ for 16 hours. After cooling to room temperature, 30ml of water and 50ml of ethyl acetate were added, liquid separation was performed, the aqueous layer was extracted with 20ml of ethyl acetate again, and the organic layers were combined, washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100:0-3:2) to give 2- (3- (1, 3-dioxolan-2-yl) propyl) isoindoline-1, 3-dione (3b) (5.0g, yield: 96%).

The second step is that: 3- (1, 3-Dioxolan-2-yl) propan-1-amine (3c)

3-(1,3-Dioxolan-2-yl)propan-1-amine

2- (3- (1, 3-Dioxolan-2-yl) propyl) isoindoline-1, 3-dione (3b) (5.0g, 19.1mmol) was dissolved in 100ml of isopropanol, and 2.0 ml of hydrazine hydrate was added to react at 80 ℃ overnight. Cooled to room temperature, 20ml of absolute ethanol was added, filtered, and the filtrate was concentrated to give 3- (1, 3-dioxolan-2-yl) propan-1-amine (3c) (1.40g, yield: 56%).

LCMS m/z＝132.2[M+1]⁺。

The third step: 9- [ [ [3- [ [4- [3- (1, 3-dioxolan-2-yl) propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3d)

Tert-butyl 9-[[[3-[[4-[3-(1,3-dioxolan-2-yl)propylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoy loxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a) (0.500g, 0.830mmol) was dissolved in 10mL of DMF, 3- (1, 3-dioxolan-2-yl) propan-1-amine (3c) (0.163g, 1.24mmol), triethylamine (0.294g, 2.90mmol), 1-hydroxybenzotriazole (0.224g, 1.66mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.318g, 1.66mmol) were added, and after completion of the addition, the reaction was allowed to proceed at room temperature overnight. 20ml of water and 50ml of ethyl acetate were added, and the organic layer was washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5:1-1:4) to give 9- [ [ [3- [ [4- [3- (1, 3-dioxolan-2-yl) propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3d) (0.460g, yield: 77.5%).

¹H NMR(400MHz,DMSO-d₆)8.44(t,1H),8.30(d,1H),7.83(d,2H),7.49(d,2H),7.35– 7.27(m,4H),7.26–7.20(m,2H),7.01(s,1H),6.95–6.85(m,2H),5.82(d,1H),5.12(s,2H),4.81 (s,2H),4.06–3.96(m,1H),3.96–3.83(m,5H),3.80–3.73(m,2H),3.61(t,2H),3.39–3.23(m, 3H),3.20(d,1H),1.79(s,2H),1.66–1.56(m,4H),1.38(s,9H).

LCMS m/z＝616.3[M-100+1]⁺。

The fourth step: 9- [ [ [3- [ [4- (4-oxobutylcarbamoylamino) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3e)

Tert-butyl 9-[[[3-[[4-(4-oxobutylcarbamoyl)phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-az abicyclo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- [3- (1, 3-dioxolan-2-yl) propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3d) (0.450g, 0.629mmol) was dissolved in 10ml of tetrahydrofuran, 6 ml of 4mol/L aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 9-10 with a saturated sodium bicarbonate solution, extracted with 20ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 9- [ [ [3- [ [4- (4-oxobutylcarbamoylamino) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (3e) (0.422g, yield: 99%).

LCMS m/z＝572.3[M-100+1]⁺。

The fifth step: 9- [ [ [3- [ [ [4- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3f)

Tert-butyl 9-[[[3-[[4-[4-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]butylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3. 1]nonane-7-carboxylate

9- [ [ [3- [ [4- (4-oxobutylcarbamoylamino) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3e) (0.400g, 0.595mmol) was dissolved in 10ml of anhydrous methanol, (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (0.541g, 1.19mmol) was added, 0.5 ml of triethylamine was added, stirring was performed at room temperature for 2 hours, glacial acetic acid (0.053g, 0.892mmol) was added, followed by sodium triacetoxyborohydride (0.379g, 1.79mmol) and the reaction was continued for 2 hours. Saturated sodium bicarbonate solution was added dropwise to adjust pH to 9-10, followed by extraction with 20ml of dichloromethane, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:0-10:1) to give 9- [ [ [3- [ [4- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3f) (0.120g, yield: 20.4%).

¹H NMR(400MHz,DMSO-d₆)10.29(s,1H),8.42(t,1H),8.30(d,1H),8.24(d,1H),7.82(d, 2H),7.48(d,2H),7.36–7.28(m,4H),7.26–7.18(m,2H),7.02(d,2H),6.95–6.85(m,3H),6.49 (d,1H),5.83(d,1H),5.15–5.08(m,3H),4.81(t,1H),4.01(d,1H),3.95–3.83(m,3H),3.61(t, 2H),3.42–3.14(m,6H),2.85–2.77(m,1H),2.65(dd,1H),2.57(t,2H),1.79(s,2H),1.55–1.47 (m,2H),1.47–1.32(m,11H),0.81(s,9H),0.03(s,3H),-0.19(s,3H).

LCMS m/z＝445.9[(M-100)/2+1]⁺。

And a sixth step: 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 3)

To 9- [ [ [3- [ [ [4- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (3f) (0.120g, 0.121mmol) was added 20ml of a 4mol/L solution of ethyl acetate hydrochloride, and 2 ml of anhydrous methanol was added and stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model SunfireC18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min), and lyophilized to give 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 3) (0.043g, yield: 35.3%).

¹H NMR(400MHz,CD₃OD)8.35(d,1H),7.80(d,2H),7.48(d,2H),7.35–7.21(m,7H),7.03(d,1H),6.94–6.86(m,3H),6.66(d,1H),5.89(s,1H),5.39(t,1H),5.12(s,2H),5.02(t,1H), 4.17(d,2H),3.85(d,2H),3.55–3.41(m,6H),3.24(d,2H),3.16(t,2H),2.19(s,2H),1.87–1.68 (m,4H).

¹⁹F NMR(376MHz,CD₃OD)-74.94.

LCMS m/z＝388.7[M/2+1]⁺。

Example 4:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 4)

Compound 4 was obtained according to the synthesis methods of the third step to the sixth step of example 3, starting from intermediate 1-b.

¹H NMR(400MHz,CD₃OD)8.35(d,1H),7.80(d,2H),7.48(d,2H),7.35–7.21(m,7H),7.02(d,1H),6.90(d,3H),6.66(d,1H),5.89(s,1H),5.39(t,1H),5.12(s,2H),5.00(s,1H),4.16(d, 2H),3.95(d,2H),3.67(d,2H),3.48–3.40(t,4H),3.24(d,2H),3.16(t,2H),2.11(s,2H),1.85– 1.77(m,2H),1.77–1.69(m,2H).

¹⁹F NMR(376MHz,CD₃OD)-75.03.

LCMS m/z＝388.8[M/2+1]⁺。

Example 5:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [5- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] pentylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 5)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[5-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-q uinolin-5-yl)ethyl]amino]pentylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

The first step is as follows: 2- (4- (1, 3-Dioxolan-2-yl) butyl) isoindoline-1, 3-dione (5b)

2-(4-(1,3-Dioxolan-2-yl)butyl)isoindoline-1,3-dione

2- (4-bromobutyl) -1, 3-dioxolane (5a) (2.78g, 13.3mmol) was dissolved in 15ml of DMF, and the potassium phthalimide salt (3.90g, 27mmol) was added and reacted at 80 ℃ for 16 hours. After cooling to room temperature, 30ml of water, 40ml of toluene and 10ml of ethyl acetate were added, liquid separation was performed, the aqueous layer was extracted with a mixed solvent of 40ml of toluene and 10ml of ethyl acetate, the organic layers were combined, washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100:0-3:2) to give 2- (4- (1, 3-dioxolan-2-yl) butyl) isoindoline-1, 3-dione (5b) (2.3g, yield: 63%).

The second step is that: 4- (1, 3-Dioxolan-2-yl) but-1-amine (5c)

4-(1,3-Dioxolan-2-yl)butan-1-amine

2- (4- (1, 3-Dioxolan-2-yl) butyl) isoindoline-1, 3-dione (5b) (2.3g, 8.36mmol) was dissolved in 50ml of isopropanol, and 1.25 ml of hydrazine hydrate was added to react at 80 ℃ overnight. Cooled to room temperature, 10ml of ethanol was added, filtered, and the filtrate was concentrated to give 4- (1, 3-dioxolan-2-yl) butan-1-amine (5c) (1.00g, yield: 83%).

LCMS m/z＝146.2[M+1]⁺。

The third step: 9- [ [ [3- [ [4- [4- (1, 3-dioxolan-2-yl) butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5d)

Tert-butyl 9-[[[3-[[4-[4-(1,3-dioxolan-2-yl)butylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyl oxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a) (0.500g, 0.830mmol) was dissolved in 10ml of DMF, and 4- (1, 3-dioxolan-2-yl) butan-1-amine (5c) (0.181g, 1.24mmol), triethylamine (0.294g, 2.90mmol), 1-hydroxybenzotriazole (0.224g, 1.66mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.318g, 1.66mmol) were added, followed by reaction at room temperature for 2 hours. 20ml of water and 50ml of ethyl acetate were added, and the organic layer was separated, washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4:1-1:4) to give 9- [ [ [3- [ [4- [4- (1, 3-dioxolan-2-yl) butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5d) (0.350g, yield: 58%).

¹H NMR(400MHz,CD₃OD)7.79(d,2H),7.47(d,2H),7.34–7.19(m,6H),6.99–6.84(m, 3H),5.88(s,1H),5.12(s,2H),4.91(s,1H),4.83(t,1H),4.16–3.98(m,4H),3.95–3.89(m,2H), 3.84–3.79(m,2H),3.77–3.65(m,2H),3.47–3.41(m,1H),3.40–3.32(m,3H),1.84(s,2H), 1.72–1.62(m,4H),1.59–1.47(m,2H),1.44(s,9H).

LCMS m/z＝752.3[M+23]⁺

The fourth step: 9- [ [ [3- [ [4- (5-oxapentylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5e)

Tert-butyl 9-[[[3-[[4-(5-oxopentylcarbamoyl)phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-a zabicyclo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- [4- (1, 3-dioxolan-2-yl) butylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5d) (0.350g, 0.629mmol) was dissolved in 10ml of tetrahydrofuran, 10ml of 4mol/L aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 9-10 with a saturated sodium bicarbonate solution, extracted with 20ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 9- [ [ [3- [ [4- (5-oxapentylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (5e) (0.329g, yield: 99%).

LCMS m/z＝586.3[M-100+1]⁺

The fifth step: 9- [ [ [3- [ [ [4- [5- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] pentylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5f)

Tert-butyl 9-[[[3-[[4-[5-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]pentylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3. 1]nonane-7-carboxylate

9- [ [ [3- [ [4- (5-oxapentylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5e) (0.300g, 0.437mmol) was dissolved in 10ml of anhydrous methanol, (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxo) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (0.398g, 0.875mmol) was added, 0.5 ml of triethylamine was added, stirring was carried out at room temperature for 2 hours, glacial acetic acid (0.039g, 0.655mmol) was added, followed by sodium triacetoxyborohydride (0.278g, 1.31mmol) and reaction continued for 2 hours. Saturated sodium bicarbonate solution was added dropwise to adjust pH to 9-10, followed by extraction with 20ml of dichloromethane, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:0-10:1) to give 9- [ [ [3- [ [4- [5- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] pentylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5f) (0.084g, yield: 19.1%).

¹H NMR(400MHz,DMSO-d₆)10.28(s,1H),8.39(s,1H),8.30(d,1H),8.24(d,1H),7.83(d, 2H),7.48(d,2H),7.35–7.27(m,4H),7.26–7.20(m,2H),7.02(d,2H),6.95–6.84(m,3H),6.50 (d,1H),5.82(d,1H),5.12(s,3H),4.80(s,1H),4.01(d,1H),3.95–3.85(m,3H),3.65–3.55(m, 2H),3.37–3.33(m,1H),3.27–3.15(m,5H),2.85–2.77(m,1H),2.68–2.62(m,1H),2.60–2.52 (m,2H),1.79(s,2H),1.58–1.47(m,2H),1.46–1.27(m,13H),0.81(s,9H),0.02(s,3H),-0.19(s, 3H).

LCMS m/z＝452.9[(M-100)/2+1]⁺

And a sixth step: 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [5- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] pentylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 5)

To 9- [ [ [3- [ [ [4- [5- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] pentylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (5f) (0.084g, 0.0836mmol) was added 10ml of a 4mol/L ethyl acetate hydrochloride solution, and 2 ml of anhydrous methanol was added and stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model SunfireC18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min), and lyophilized to give 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [5- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] pentylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 5) (0.016g, yield: 24.2%).

¹H NMR(400MHz,CD₃OD)8.36(d,1H),7.80(d,2H),7.48(d,2H),7.35–7.21(m,7H),7.01(d,1H),6.93–6.87(m,3H),6.66(d,1H),5.88(s,1H),5.38–5.34(m,1H),5.12(s,2H),5.01 (t,1H),4.19(d,2H),3.85(d,2H),3.49(d,2H),3.43–3.36(m,4H),3.18–3.11(m,2H),3.00(t, 2H),2.13(s,2H),1.81–1.64(m,4H),1.53–1.45(m,2H).

LCMS m/z＝395.9[M/2+1]⁺

Example 6:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [5- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] pentylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 6)

Compound 6 was obtained from intermediate 1-b as the starting material according to the synthesis methods of the third to sixth steps of example 5.

¹H NMR(400MHz,CD₃OD)8.36(d,1H),7.80(d,2H),7.48(d,2H),7.36–7.21(m,7H),7.03(d,1H),6.96–3.86(m,3H),6.67(d,1H),5.89(s,1H),5.40(t,1H),5.11(s,2H),4.99(s,1H), 4.16(d,2H),3.95(d,2H),3.67(d,2H),3.47–3.37(m,4H),3.24(d,2H),3.10(t,2H),2.11(s,2H), 1.85–1.75(m,2H),1.73–1.65(m,2H),1.53–1.45(m,2H).

¹⁹F NMR(376MHz,CD₃OD)-74.86.

LCMS m/z＝395.8[M/2+1]⁺

Example 7:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 7)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-q uinolin-5-yl)ethyl]amino]propyl-methyl-carbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbam ate ditrifluoroacetate

The first step is as follows: 9- [ [ [3- [ [ [4- [2- (1, 3-dioxolan-2-yl) ethyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7a)

Tert-butyl 9-[[[3-[[4-[2-(1,3-dioxolan-2-yl)ethyl-methyl-carbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]ca rbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a) (0.500g, 0.830mmol) was dissolved in 10mL of DMF, and 2- (1, 3-dioxolan-2-yl) -N-methylethylamine (0.163g, 1.24mmol), triethylamine (0.294g, 2.90mmol), 1-hydroxybenzotriazole (0.224g, 1.66mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.318g, 1.66mmol) were added, followed by reaction at room temperature for 2 hours after completion of the addition. 20ml of water and 50ml of ethyl acetate were added, liquid separation was performed, the organic layer was washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4:1-1:4) to give 9- [ [ [3- [ [4- [2- (1, 3-dioxolan-2-yl) ethyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7a) (0.260g, yield: 43.8%).

¹H NMR(400MHz,DMSO-d₆)8.31(d,1H),7.47(d,2H),7.40–7.30(m,6H),7.24(t,2H), 7.02(s,1H),6.98–6.86(m,2H),5.83(d,1H),5.10(s,2H),4.92–4.62(m,2H),4.08–3.96(m, 1H),3.96–3.84(m,4H),3.82–3.74(m,3H),3.61(t,2H),3.38–3.26(m,3H),3.24–3.16(m,1H), 2.90(d,3H),1.94–1.76(m,4H),1.38(s,9H).

LCMS m/z＝716.3[M+1]⁺

The second step is that: 9- [ [ [3- [ [4- [ methyl (3-oxopropyl) carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7b)

Tert-butyl 9-[[[3-[[4-[methyl(3-oxopropyl)carbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]- 3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- [2- (1, 3-dioxolan-2-yl) ethyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7a) (0.350g, 0.489mmol) was dissolved in 10ml of tetrahydrofuran, 10ml of 4mol/L aqueous hydrochloric acid was added, and the mixture was stirred at room temperature for 60 minutes. After completion of the reaction, the pH was adjusted to 9-10 with a saturated sodium bicarbonate solution, extracted with 20ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 9- [ [ [3- [ [4- [ methyl (3-oxopropyl) carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (7b) (0.328g, yield: 99%).

LCMS m/z＝672.3[M+1]⁺

The third step: 9- [ [ [3- [ [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7c)

Tert-butyl 9-[[[3-[[4-[3-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]propyl-methyl-carbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabi cyclo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- [ methyl (3-oxopropyl) carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7b) (0.200g, 0.298mmol) was dissolved in 10ml of anhydrous methanol, (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (0.271g, 0.595mmol) was added, 0.5 ml of triethylamine was added, and the mixture was stirred at room temperature for 2 hours, glacial acetic acid (0.027g, 0.447 mmol) was added, followed by sodium triacetoxyborohydride (0.189g, 0.893mmol), and the reaction was continued for 2 hours. Saturated sodium bicarbonate solution was added dropwise to adjust pH to 9-10, extraction was performed with 20ml of dichloromethane, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:0-10:1) to give 9- [ [ [3- [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7c) (0.050g, yield: 17%).

LCMS m/z＝445.8[(M-100)/2+1]⁺

The fourth step: 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 7)

To 9- [ [ [3- [ [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (7c) (0.050g, 0.050mmol) was added 10ml of a 4mol/L solution of ethyl acetate hydrochloride, followed by addition of 2 ml of anhydrous methanol and stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model Sunfire C18, 5 μm, inner diameter. length. about.30 mm. about.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min), and lyophilized to give 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 7) (0.022g, yield: 43%).

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.55–7.43(m,4H),7.35–7.21(m,7H),7.03(d, 1H),6.95–6.87(m,3H),6.62(d,1H),5.89(s,1H),5.46(t,1H),5.12(s,2H),5.02(t,1H),4.19(d, 2H),3.89–3.71(m,3H),3.70–3.62(m,1H),3.58–3.38(m,4H),3.29–3.24(m,2H),3.20–3.10 (m,2H),3.03(s,3H),2.22–2.10(m,4H).

¹⁹F NMR(376MHz,CD₃OD)-74.94.

LCMS m/z＝776.3[M+1]⁺

Example 8:

7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 8)

7-Methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2- oxo-1H-quinolin-5-yl)ethyl]amino]propylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carba mate ditrifluoroacetate

The first step is as follows: 4- [ [3- [ (3-oxa-7-azabicyclo [3.3.1] nonan-9-yloxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoic acid methyl ester hydrochloride (8a)

Methyl 4-[[3-[(3-oxa-7-azabicyclo[3.3.1]nonan-9-yloxycarbonylamino)-phenyl-methyl]phenoxy]methyl]ben zoate hydrochlorate

To tert-butyl 9- [ [ [3- [ (4-methoxycarbonylphenyl) methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (1D-a) (1.40g, 2.27mmol) was added 20ml of a 4mol/L ethyl acetate hydrochloride solution and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give methyl 4- [ [3- [ (3-oxa-7-azabicyclo [3.3.1] nonan-9-yloxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoate hydrochloride (8a) (1.26g, yield: 99%).

LCMS m/z＝517.3[M+1]⁺

The second step is that: 4- [ [3- [ [ (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid methyl ester (8b)

Methyl 4-[[3-[[(7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)oxycarbonylamino]-phenyl-methyl]phenoxy]methyl]benzoate

Methyl 4- [ [3- [ (3-oxa-7-azabicyclo [3.3.1] nonan-9-yloxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoate hydrochloride (8a) (1.10g, 2.13mmol) was dissolved in 20ml of 1, 2-dichloroethane, glacial acetic acid (0.256g, 4.26mmol) was added, 5ml of formalin was added, stirring was carried out at room temperature for 1 hour, sodium triacetoxyborohydride (0.903g, 4.26mmol) was added, and after completion of the addition, the reaction was carried out at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust pH to 9-10, 50ml of dichloromethane was added, liquid separation was performed, the organic layer was dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:0-10:1) to give methyl 4- [ [3- [ [ (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoate (8b) (1.10g, yield: 97%).

¹H NMR(400MHz,DMSO-d₆)8.24(d,1H),7.96(d,2H),7.56(d,2H),7.30(t,4H),7.28– 7.20(m,2H),7.02(s,1H),6.97–6.86(m,2H),5.83(d,1H),5.17(s,2H),4.70(t,1H),3.87(d,2H), 3.86(s,3H),3.63(d,2H),2.74(d,2H),2.56(d,2H),1.90(s,3H),1.82(s,2H).

LCMS m/z＝531.3[M+1]⁺

The third step: 4- [ [3- [ [ (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (8c)

4-[[3-[[(7-Methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)oxycarbonylamino]-phenyl-methyl]phe noxy]methyl]benzoic acid

Methyl 4- [ [3- [ [ (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoate (8b) (1.10g, 2.07mmol) was dissolved in 16 ml of tetrahydrofuran, 4 ml of water was added, solid lithium hydroxide (0.745g, 31.1mmol) was added, and after completion of the addition, the reaction was carried out at 60 ℃ for 1 hour. Cooled to room temperature, adjusted pH to 5-6 with 1mol/L dilute hydrochloric acid, added with 50ml ethyl acetate, separated, washed the organic layer once with 10ml saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 4- [ [3- [ [ (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (8c) (0.900g, yield: 84%).

LCMS m/z＝517.3[M+1]⁺

The fourth step: (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- (3, 3-diethoxypropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8d)

(7-Methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)-N-[[3-[[4-(3,3-diethoxypropylcarbamoyl)phen yl]methoxy]phenyl]-phenyl-methyl]carbamate

4- [ [3- [ [ (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (8c) (1.0g, 1.94mmol) was dissolved in 10ml of DMF and 1-amino-3, 3-diethoxypropane (0.427g, 2.90mmol), triethylamine (0.686g, 6.78mmol), 1-hydroxybenzotriazole (0.523g, 3.87mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.742g, 3.87mmol) were added and the mixture was reacted at room temperature overnight. 20ml of water and 50ml of ethyl acetate were added, and the organic layer was washed with 30ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:0-10:1) to give (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- (3, 3-diethoxypropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8d) (0.930g, yield 74.4%).

¹H NMR(400MHz,DMSO-d₆)8.40(t,1H),8.24(d,1H),7.83(d,2H),7.49(d,2H),7.35– 7.27(m,4H),7.26–7.20(m,2H),7.02(s,1H),6.92(d,1H),6.89(dd,1H),5.83(d,1H),5.13(s, 2H),4.69(t,1H),4.56(t,1H),3.87(d,2H),3.67–3.54(m,4H),3.50-3.40(m,2H),3.34–3.25(m, 2H),2.71(d,2H),2.54(d,2H),2.12(s,3H),1.84–1.74(m,4H),1.12(t,6H).

LCMS m/z＝646.4[M+1]⁺

The fifth step: (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- (3-oxopropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8e)

(7-Methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)-N-[[3-[[4-(3-oxopropylcarbamoyl)phenyl]met hoxy]phenyl]-phenyl-methyl]carbamate

(7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- (3-oxopropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8d) (0.800g,1.24mmol) was dissolved in 10ml of tetrahydrofuran, and 6 ml of a 4mol/L aqueous hydrochloric acid solution was added and stirred at room temperature for 30 minutes. After completion of the reaction, the pH was adjusted to 9-10 with a saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL. times.3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- (3-oxopropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8e) (0.708g, yield: 99%).

LCMS m/z＝572.3[M+1]⁺

And a sixth step: (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8f)

(7-Methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)-N-[[3-[[4-[3-[[(2R)-2-[tert-butyl(dimethyl)sily l]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]propylcarbamoyl]phenyl]methoxy]phenyl]- phenyl-methyl]carbamate

(7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- (3-oxopropylcarbamoyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8e) (0.700g, 1.22mmol) was dissolved in 15ml of anhydrous methanol, (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (1.11g, 2.45 mmol) was added, 0.5 ml of triethylamine was added, stirring was carried out at room temperature for 2 hours, glacial acetic acid (0.109g, 1.83mmol) was added, followed by sodium triacetoxyborohydride (0.799g, 3.67mmol) and the reaction was continued for 2 hours. Saturated sodium bicarbonate solution was added dropwise to adjust pH to 9-10, extraction was performed with 20ml of dichloromethane, drying was performed with anhydrous sodium sulfate, concentration was performed under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:0-20:1) to give (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy ] 2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8f) (0.090g, yield: 8.3%).

LCMS m/z＝445.8[M/2+1]⁺

The seventh step: 7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 8)

To (7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) -N- [ [3- [ [4- [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (8f) (0.090g, 0.10mmol) was added 10ml of a 4mol/L solution of ethyl acetate hydrochloride, 2 ml of anhydrous methanol was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model Sunfire C18, 5 μm, inner diameter. length. about.30 mm. about.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min), lyophilized to give 7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 8) (0.054g, yield: 54%).

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.84(d,2H),7.51(d,2H),7.40–7.21(m,7H),7.03(d,1H),6.97–6.85(m,3H),6.65(d,1H),5.88(s,1H),5.45(t,1H),5.13(s,2H),4.99(s,1H), 4.16(t,2H),3.82(d,2H),3.62(d,2H),3.58–3.49(m,2H),3.42(d,2H),3.25(d,2H),3.15(t,2H), 2.83(s,3H),2.24(s,2H),2.10–1.99(m,2H).

¹⁹F NMR(376MHz,CD₃OD)-74.87.

LCMS m/z＝388.8[M/2+1]⁺

Example 9:

[3- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methyl-4- [ [3- [ (3-oxa-7-azabicyclo [3.3.1] nonan-9-yloxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoate ditrifluoroacetate (Compound 9)

[3-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]methyl -4-[[3-[(3-oxa-7-azabicyclo[3.3.1]nonan-9-yloxycarbonylamino)-phenyl-methyl]phenoxy]methyl]be nzoate ditrifluoroacetate

The first step is as follows: 3- (1, 3-Dioxolan-2-yl) benzoic acid methyl ester (9b)

Methyl 3-(1,3-dioxolan-2-yl)benzoate

Methyl 3-formaldehyde benzoate (9a) (5.0g, 30.5mmol), ethylene glycol (8.4 mL, 151mmol), p-toluenesulfonic acid monohydrate (0.58g, 3.0mmol) and 120 mL of toluene were added in this order to a 250 mL reaction flask, and after the addition, the reaction was refluxed and dehydrated for 4 h. After the reaction was completed, the reaction flask was diluted with 200 ml of ethyl acetate, followed by saturated NaHCO in turn₃The solution (100mL × 1) and saturated brine (100mL × 1) were washed, and the organic phase after separation was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give methyl 3- (1, 3-dioxolan-2-yl) benzoate (9b) (6.34g, yield: 99%).

LCMS m/z＝209.1[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)8.05–7.96(m,2H),7.71(dt,1H),7.56(t,1H),5.82(s,1H), 4.09–3.95(m,4H),3.87(s,3H).

The second step is that: [3- (1, 3-Dioxolan-2-yl) phenyl ] methanol (9c)

[3-(1,3-Dioxolan-2-yl)phenyl]methanol

In a 100ml reaction flask, methyl 3- (1, 3-dioxolan-2-yl) benzoate (9b) (2.08g,10mmol) was dissolved in 40ml of tetrahydrofuran, the reaction was cooled to-78 ℃ in a dry ice bath, 15ml of a solution of lithium aluminum hydride (1.14g, 30mmol) in tetrahydrofuran was added in portions, and after the addition, the temperature was naturally raised to room temperature and the reaction was stirred for 4 hours. The reaction was quenched after completion of the reaction by LCMS, and 0.3mL of water, 0.3mL of 2mol/L sodium hydroxide solution, water (0.3mL × 3) were slowly added dropwise to the reaction solution, followed by addition of 70 mL of ethyl acetate and 50g of anhydrous magnesium sulfate, and stirring was carried out at room temperature for 1 hour. Suction filtration, concentration of the filtrate under reduced pressure, and separation and purification of the resulting crude product by column chromatography gave [3- (1, 3-dioxolan-2-yl) phenyl ] methanol (9c) (1.3g, yield: 72%).

LCMS m/z＝181.1[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)7.45–7.23(m,4H),5.71(s,1H),5.19(t,1H),4.51(d,2H), 4.11–3.80(m,4H).

The third step: 9- [ [ [3- [ [4- [ [3- (1, 3-dioxolan-2-yl) phenyl ] methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyl ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (9d)

Tert-butyl 9-[[[3-[[4-[[3-(1,3-dioxolan-2-yl)phenyl]methoxycarbonyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

In a 50ml reaction flask were added 4- [ [3- [ [ (7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl) oxycarbonylamino ] -phenyl-methyl ] phenoxy ] methyl ] benzoic acid (intermediate 1-a) (0.44g, 0.73mmol), 1-hydroxybenzotriazole (0.2g, 1.46mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.42g, 2.2mmol), triethylamine (0.223g, 2.2mmol) and 20ml of dichloromethane in this order, followed by addition of [3- (1, 3-dioxolan-2-yl) phenyl ] methanol (0.2g, 1.1mmol), and after completion of the addition, the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:2) to give tert-butyl 9- [ [ [3- [ [4- [ [3- (1, 3-dioxolan-2-yl) phenyl ] methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyl ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (9d) (0.426 g, yield: 76%).

The fourth step: 9- [ [ [3- [ [4- [ (3-formylphenyl) methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (9e)

Tert-butyl 9-[[[3-[[4-[(3-formylphenyl)methoxycarbonyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoylox y]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

In a 50ml reaction flask, tert-butyl 9- [ [ [3- [ [4- [ [3- (1, 3-dioxolan-2-yl) phenyl ] methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyl ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (9d) (426mg, 0.56 mmol) was dissolved in 10ml tetrahydrofuran, followed by addition of 25 ml of 4mol/L dilute hydrochloric acid and reaction at room temperature for 1 hour after completion of the addition. To the reaction mixture was added 25 ml of ethyl acetate, followed by liquid separation, drying of the organic phase over anhydrous sodium sulfate, suction filtration, and concentration of the filtrate under reduced pressure to give tert-butyl 9- [ [ [3- [ [4- [ (3-formylphenyl) methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (9e) (277mg, 69% yield).

LCMS m/z＝621.3[M-100+1]⁺

The fifth step: 9- [ [ [3- [ [ [4- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (9f)

Tert-butyl 9-[[[3-[[4-[[3-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]a mino]methyl]phenyl]methoxycarbonyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-ox a-7-azabicyclo[3.3.1]nonane-7-carboxylate

In a 50ml reaction flask was added 9- [ [ [3- [ [ [4- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (9f) (280mg, 0.39mmol), (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxo) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (268mg, 0.59mmol), acetic acid (35mg, 0.59mmol) and 10ml of a mixed solvent of dichloromethane/methanol (v/v ═ 1/4), and after the addition was completed, the reaction was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (521mg, 2.46mmol) was added and the reaction was stirred overnight after the addition was completed. The reaction solution was suction-filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give tert-butyl 9- [ [ [3- [ [4- [ [3- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (9f) (400mg, yield: 99%).

And a sixth step: [3- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methyl-4- [ [3- [ (3-oxa-7-azabicyclo [3.3.1] nonan-9-yloxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoate ditrifluoroacetate (Compound 9)

In a 50ml reaction flask, 9- [ [ [3- [ [4- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methoxycarbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (9f) (93mg, 0.09mmol) was dissolved in 25 ml of a 4mol/L ethyl acetate hydrochloride solution, and after completion of addition, the reaction was stirred at room temperature for 2 hours to give a pale yellow solid precipitate, 2.5 ml of methanol was added to dissolve the solid clear, the reaction was then continued stirring at room temperature for 1 hour and LCMS monitored the progress of the reaction. The reaction was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (instrument and preparative column: a liquid phase was prepared using glison gx-281, preparative column model Sunfire C18, 5 μm, inner diameter x length 30mm x 150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min) and lyophilized to give [3- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methyl-4- [ [3- [ (3-oxa-7-azabicyclo [3.3.1] nonan-9-yloxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoate bistrifluoroacetate (compound 9) (35mg, yield: 37%).

LCMS m/z＝413.3[M/2+1]⁺

¹HNMR(400MHz,CD₃OD)8.20(d,1H),7.98(d,2H),7.63(s,1H),7.61–7.55(m,1H),7.55–7.43(m,4H),7.35–7.18(m,7H),7.00(d,1H),6.96–6.85(m,3H),6.60(d,1H),5.88(s,1H),5.45–5.33(m,3H),5.14(s,2H),5.01(t,1H),4.34(s,2H),4.19(d,2H),3.84(d,2H),3.58– 3.37(m,4H),3.25–3.17(m,2H),2.18(s,2H).

Example 10:

[3- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] methyl ] phenyl ] methyl-4- [ [3- [ (3-oxa-7-azabicyclo [3.3.1] nonan-9-yloxycarbonylamino) -phenyl-methyl ] phenoxy ] methyl ] benzoate ditrifluoroacetate (Compound 10)

Compound 10 was obtained according to the synthesis methods of the third step to the sixth step of example 9, starting from intermediate 1-b.

¹HNMR(400MHz,CD₃OD)8.20(d,1H),7.96(dd,2H),7.79–7.42(m,6H),7.35–7.17(m, 7H),6.98–6.83(m,3H),6.61(d,1H),5.88(s,1H),5.52–5.32(m,3H),5.13(s,2H),4.99(s,1H), 4.68–4.40(m,1H),4.34(s,1H),4.16(d,2H),3.95(d,2H),3.67(d,3H),3.43(d,3H),3.22(d,1H), 1.95(s,1H),1.61(s,1H).

LCMS m/z＝413.3[M/2+1]⁺

Example 11:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] piperidine-1-carbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 11)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[4-[[2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinoli n-5-yl)ethyl]amino]piperidine-1-carbonyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

The first step is as follows: 1- [4- (chloromethyl) benzoyl ] piperidin-4-one (11b)

1-[4-(Chloromethyl)benzoyl]piperidin-4-one.

Piperidin-4-one hydrochloride (1.49g,15.0mmol) was dissolved in 20mL DCM, triethylamine (4.56g,45.1 mmol) was added, the temperature was decreased to 0 deg.C, 4- (chloromethyl) benzoyl chloride (2.84g,15.0mmol) was slowly added dropwise, after addition, the temperature was raised to room temperature and stirred for 0.5 h. The reaction mixture was washed with a saturated aqueous citric acid solution (20mLx 1), a saturated aqueous sodium carbonate solution (20mL x 1) and a saturated common salt solution (20mLx 1), and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 100:1-20:1) to give 1- [4- (chloromethyl) benzoyl ] piperidin-4-one (11b) (2.6g, yield: 69%).

LCMS m/z＝252.1[M+1]⁺

¹HNMR(400MHz,CDCl₃)7.47(s,4H),4.61(s,2H),3.87(brs,4H),2.50(brs,4H).

The second step is that: n- [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamic acid tert-butyl ester (11c)

Tert-butyl

N-[[3-[[4-(4-oxopiperidine-1-carbonyl)phenyl]methoxy]phenyl]-phenyl-methyl]carbamate

1- [4- (chloromethyl) benzoyl ] piperidin-4-one (11b) (2.5g,9.9mmol) and tert-butyl ((3-hydroxyphenyl) phenyl) methyl) carbamate (3.3g,11mmol) were dissolved in 20ml of DMF, and potassium carbonate (2.7g,20mmol) and sodium iodide (0.3g,2.0mmol) were added in this order, and after completion of the addition, the mixture was heated to 90 ℃ and stirred for 2 hours. After cooling to room temperature, 30mL of water and 30mL of ethyl acetate were added, liquid separation was performed, the organic layer was washed with saturated brine (30mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1:3-1:0) to give tert-butyl N- [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (11c) (2g, yield: 39%).

LCMS m/z＝537.3[M+23]⁺

¹H NMR(400MHz,CDCl₃)7.48(s,4H),7.35–7.29(m,2H),7.28–7.22(m,4H),6.90–6.83(m,3H),5.87(s,1H),5.15(br,1H),5.05(s,2H),3.89(br,4H),2.50(br,4H),1.44(s,9H).

The third step: 1- [4- [ [3- [ amino (phenyl) methyl ] phenoxy ] methyl ] benzoyl ] piperidin-4-one hydrochloride (11d)

1-[4-[[3-[amino(phenyl)methyl]phenoxy]methyl]benzoyl]piperidin-4-onehydrochlorate

To tert-butyl N- [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (11c) (1.90g,3.69mmol) was added 20ml of a 4mol/L ethyl acetate hydrochloride solution, and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave 1- [4- [ [3- [ amino (phenyl) methyl ] phenoxy ] methyl ] benzoyl ] piperidin-4-one hydrochloride (11d) (1.6g, yield: 99%).

The fourth step: 9- [ [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (11e-a)

Tert-butyl 9-[[[3-[[4-(4-oxopiperidine-1-carbonyl)phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-ox a-7-azabicyclo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (11e-b)

1- [4- [ [3- [ amino (phenyl) methyl ] phenoxy ] methyl ] benzoyl ] piperidin-4-one hydrochloride (11d) (1.55g,3.44 mmol) was dissolved in 20ml DCM, 20ml of an aqueous solution of sodium bicarbonate (1.44g,17.2mmol) was added, 5ml of a solution of triphosgene (0.35g,1.17mmol) in DCM was added dropwise under ice bath, after completion of the addition, the mixture was stirred under ice bath for 10min, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, 20ml of 1, 4-dioxane, 7-tert-butoxycarbonyl-3-oxa-7-azabicyclo [3,3,1] nonan-9-ol (0.92g,3.78mmol) and DBU (0.52g,3.44mmol) were added to the residue in this order, and stirred at 80 ℃ for 10 min. Cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/dichloromethane (v/v) ═ 1:1) to give tert-butyl 9- [ [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (11e-a) (0.27g, yield: 11%) and tert-butyl 9- [ [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (11e-b) (0.22g, yield: 9%) of two pure products.

11e-a (developing solvent: ethyl acetate/dichloromethane: 1/1, Rf: 0.45)

¹H NMR(400MHz,CDCl₃)7.48(s,4H),7.37–7.24(m,6H),6.93–6.84(m,3H),5.98–5.70(m,1H),5.57–5.46(m,1H),5.06(s,2H),4.94(t,1H),4.15-3.63(m,10H),3.35(d,1H),3.25 (d,1H),2.50(s,4H),1.94–1.68(m,2H),1.46(s,9H).

LCMS m/z＝584.3[M-100+1]⁺

11e-b (developing solvent: ethyl acetate/dichloromethane: 1/1, Rf: 0.5)

¹H NMR(400MHz,CDCl₃)7.48(s,4H),7.38–7.25(m,6H),6.93–6.84(m,3H),5.98–5.72(m,1H),5.52–5.33(m,1H),5.06(s,2H),4.89(t,1H),4.50(d,1H),4.30(d,1H),4.07–3.60 (m,8H),3.17(d,1H),3.05(d,1H),2.50(s,4H),1.82–1.74(m,2H),1.45(s,9H).

LCMS m/z＝584.3[M-100+1]⁺

The fifth step: 9- [ [ [3- [ [ [4- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] piperidine-1-carbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (11f)

Tert-butyl 9-[[[3-[[4-[4-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]piperidine-1-carbonyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicycl o[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [4- (4-oxopiperidine-1-carbonyl) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (11e-a) (0.27g,0.39mmol) was dissolved in 10ml of methanol and (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxo) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (185mg, 0.47mmol) and 2 drops of acetic acid were added at room temperature followed by sodium triacetoxyborohydride (0.16g,0.75mmol) and stirring for 6H. The solvent was removed under reduced pressure, 20ml of ethyl acetate and 20ml of an aqueous sodium bicarbonate solution were added, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 50:1-20:1) to give 9- [ [ [3- [ [4- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] piperidine-1-carbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (11f) (0.16g, yield: 40%).

LCMS m/z＝1002.5[M+1]⁺.

And a sixth step: 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] piperidine-1-carbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 11)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[4-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-q uinolin-5-yl)ethyl]amino]piperidine-1-carbonyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

To 9- [ [ [3- [ [ [4- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] piperidine-1-carbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (11f) (0.15g, 0.15mmol) was added 10ml of a 4mol/L solution of ethyl acetate hydrochloride, followed by addition of 5ml of anhydrous methanol and stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model SunfireC18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min), and lyophilized to give 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] piperidine-1-carbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 11) (20mg, yield: 13%).

¹H NMR(400MHz,CD₃OD)8.38(d,1H),7.51(d,2H),7.42(d,2H),7.37–7.20(m,7H),7.04(d,1H),6.91(d,3H),6.68(d,1H),5.89(s,1H),5.43(t,1H),5.11(s,2H),5.02(s,1H),4.19(d, 2H),3.84(d,3H),3.62–3.38(m,4H),3.31–3.17(m,4H),3.17–2.70(m,2H),2.35–1.93(m,4H), 1.67(br,2H).

¹⁹F NMR(376MHz,CD₃OD)-74.73

LCMS m/z＝788.4[M+1]⁺

Example 12:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] piperidine-1-carbonyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 12)

Compound 12 was obtained according to the synthesis methods of the fifth step to the sixth step of example 11, starting from 11 e-b.

¹H NMR(400MHz,CD₃OD)8.38(d,1H),7.50(d,2H),7.41(d,2H),7.36–7.19(m,7H),7.04(d,1H),6.90(d,3H),6.68(d,1H),5.89(s,1H),5.43(t,1H),5.10(s,2H),4.99(s,1H),4.16(d, 2H),3.95(d,2H),3.84(br,1H),3.67(d,2H),3.60–3.36(m,4H),3.30–3.23(m,2H),3.20–2.80 (m,2H),2.35–1.95(m,4H),1.68(br,2H).

¹⁹F NMR(376MHz,CD₃OD)-74.71.

LCMS m/z＝788.4[M+1]⁺

Example 13:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [3- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 13)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[3-[4-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-q uinolin-5-yl)ethyl]amino]butoxy]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

The first step is as follows: [3- [3- (1, 3-Dioxolan-2-yl) propoxy ] phenyl ] methanol (13b)

[3-[3-(1,3-Dioxolan-2-yl)propoxy]phenyl]methanol

3- (hydroxymethyl) phenol (13a) (5.0g, 40.3mmol) was dissolved in 100mL of DMF, and 2- (3-chloropropyl) -1, 3-dioxolane (6.37g, 42.3mmol) and cesium carbonate (26.2g, 80.6mmol) were added, followed by heating to 80 ℃ for reaction overnight. After cooling to room temperature, 100ml of water and 100ml of ethyl acetate were added, liquid separation was performed, the organic layer was washed with 100ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:0-5:1) to give [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methanol (13b) (7.1g, yield: 74%).

¹H NMR(400MHz,DMSO-d₆)7.20(t,1H),6.86(d,2H),6.76(dd,1H),5.13(t,1H),4.85(t, 1H),4.46(d,2H),3.97(t,2H),3.91–3.86(m,2H),3.79–3.74(m,2H),1.83–1.75(m,2H),1.75– 1.68(m,2H).

The second step is that: n- [ [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamic acid tert-butyl ester (13c)

Tert-butyl

N-[[3-[[3-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate

[3- [3- (1, 3-Dioxolan-2-yl) propoxy ] phenyl ] methanol (13b) (2.0g, 8.4mmol) was dissolved in 30ml of tetrahydrofuran, N- [ (3-hydroxyphenyl) -phenyl-methyl ] carbamic acid tert-butyl ester (3.0g, 10mmol) and triphenylphosphine (2.6g, 10mmol) were added, the mixture was cooled to 0 ℃ under nitrogen protection, diisopropyl azodicarboxylate (2.0g, 10mmol) was slowly added dropwise, and after completion of the addition, the mixture was allowed to warm to room temperature naturally and reacted overnight. 20ml of water and 50ml of ethyl acetate were added, liquid separation was performed, the organic layer was washed with 20ml of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:0-5:1) to give tert-butyl N- [ [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (13c) (4.4g, yield: 99%).

The third step: [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methylamine (13d)

[3-[[3-[3-(1,3-Dioxolan-2-yl)propoxy]phenyl]methoxy]phenyl]-phenyl-methanamine

Tert-butyl N- [ [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate (13c) (1.80g, 3.46mmol) was dissolved in 10ml of dichloromethane, and 10ml of a 4mol/L dioxane solution of hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. After removing most of hydrochloric acid gas by concentration under reduced pressure, the pH was adjusted to 9 to 10 with a saturated sodium bicarbonate solution, extracted with 30ml of dichloromethane, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (dichloromethane/methanol (v/v) ═ 1:0 to 1:50) to give [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methylamine (13d) (0.700g, yield: 44.3%).

LCMS m/z＝403.2[M-16]⁺

The fourth step: 9- [ [ [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13e-a)

Tert-butyl 9-[[[3-[[3-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3- oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13e-b)

Tert-butyl 9-[[[3-[[3-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]methoxy]phenyl]-phenyl -methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate

7-tert-Butoxycarbonyl-3-oxa-7-azabicyclo [3,3,1] nonan-9-ol (0.500g, 2.06mmol) is dissolved in 5ml of tetrahydrofuran, cooled to 0 ℃ under nitrogen, diisopropylethylamine (0.664g, 5.14mmol) is added, triphosgene (0.305g, 1.03mmol) is added and stirring is continued for 30 minutes after the addition is complete. [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methylamine (13d) (0.862g, 2.06mmol) was dissolved in 10ml of pyridine, and the reaction mixture was added dropwise in an ice bath, and then naturally warmed to room temperature to react for 1 hour. Adding 20ml of water and 20ml of ethyl acetate, separating, drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying the crude product by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:0-1:2) to obtain 9- [ [ [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13e-a) (0.150g, yield: 11%) and 9- [ [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3- Oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13e-b) (0.070g) as two pure products.

13e-a (developing solvent: petroleum ether/ethyl acetate 7/3, Rf 0.6)

¹H NMR(400MHz,CDCl₃)7.38–7.30(m,2H),7.29–7.19(m,5H),6.98–6.91(m,2H),6.91–6.80(m,4H),5.91(s,1H),5.49(s,1H),4.98(s,2H),4.93(t,1H),4.88(t,1H),4.49(d,1H), 4.31(d,1H),4.05–3.92(m,5H),3.89–3.73(m,3H),3.70–3.40(m,1H),3.16(d,1H),3.05(d, 1H),1.97–1.81(m,4H),1.77(s,2H),1.45(s,9H).

LCMS m/z＝711.3[M+23]⁺

13e-b (developing solvent: petroleum ether/ethyl acetate 7/3, Rf 0.5)

The fifth step: 9- [ [ [3- [ [3- (4-oxobutoxy) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13f)

Tert-butyl 9-[[[3-[[3-(4-oxobutoxy)phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo [3.3.1]nonane-7-carboxylate

9- [ [ [3- [ [3- [3- (1, 3-dioxolan-2-yl) propoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13e-a) (0.150g, 0.218mmol) was dissolved in 2.5 ml of tetrahydrofuran, 10ml of 4mol/L aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 9 to 10 with a saturated sodium bicarbonate solution, extracted with 20ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 9- [ [ [3- [ [3- (4-oxobutoxy) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (13f) (0.130g, yield: 92.6%).

LCMS m/z＝667.3[M+23]⁺

And a sixth step: 9- [ [ [3- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] butoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13g)

Tert-butyl 9-[[[3-[[3-[4-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]butoxy]phenyl]methoxy]phenyl]-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane -7-carboxylate

Tert-butyl 9- [ [ [3- [ [3- (4-oxobutoxy) phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (13f) (0.130g, 0.202mmol) was dissolved in 15ml of anhydrous methanol, (R) -5- (2-amino-1- ((tert-butyl (dimethyl) silyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one acetate (0.183g, 0.403 mmol) was added, 0.5 ml of triethylamine was added, and the mixture was stirred at room temperature for 2 hours, glacial acetic acid (0.018g, 0.303mmol) was added, followed by sodium triacetoxyborohydride (0.128g, 0.605mmol), and the reaction was continued for 2 hours. Saturated sodium bicarbonate solution was added dropwise to adjust pH to 9-10, extraction was performed with 20ml of dichloromethane, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was separated and purified by column chromatography (dichloromethane/methanol (v/v) ═ 1:0-1:5) to give 9- [ [ [3- [ [3- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] butoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13g) (0.030g, yield: 15%).

LCMS m/z＝432.4[(M-100)/2+1]⁺

The seventh step: 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [3- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 13)

To 9- [ [ [3- [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] butoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (13g) (0.030g, 0.035mmol) was added 4 ml of a 4mol/L solution of ethyl acetate hydrochloride, 2 ml of anhydrous methanol was added and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model Sunfire C18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min), and lyophilized to give 3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [3- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 13) (0.010g, yield: 29%).

¹H NMR(400MHz,CD₃OD)8.35(d,1H),7.34–7.21(m,9H),7.03(d,1H),6.96(d,2H),6.95–6.85(m,4H),6.67(d,1H),5.88(s,1H),5.39(t,1H),5.01(s,3H),4.16(d,2H),4.04(t,2H), 3.95(d,2H),3.67(d,2H),3.43(d,2H),3.25(d,2H),3.21–3.14(m,2H),2.11(s,2H),1.99–1.84 (m,4H).

¹⁹F NMR(376MHz,CD₃OD)-74.94.

LCMS m/z＝375.3[M/2+1]⁺

Example 14:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [3- [4- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxa-1H-quinolin-5-yl) ethyl ] amino ] butoxy ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 14)

Compound 14 was obtained by the synthesis procedures of the fifth step to the seventh step of example 13, starting from crude product 13 e-b.

¹H NMR(400MHz,CD₃OD)8.35(d,1H),7.36–7.19(m,9H),7.03(d,1H),6.96(d,2H),6.92–6.84(m,4H),6.66(d,1H),5.88(s,1H),5.40(t,1H),5.05–4.98(m,3H),4.19(d,2H),4.04 (t,2H),3.84(d,2H),3.55–3.40(m,4H),3.25(d,2H),3.21–3.13(m,2H),2.17(s,2H),2.02–1.82 (m,4H).

¹⁹F NMR(376MHz,CD₃OD)-74.86.

LCMS m/z＝375.2[M/2+1]⁺

Example 15

7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 15)

Compound 15 was obtained by the synthesis methods of the first step to the seventh step of example 8 starting from intermediate 1-b.

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.84(d,2H),7.51(d,2H),7.35–7.20(m,7H),7.03(d,1H),6.95–6.87(m,3H),6.66(d,1H),5.89(s,1H),5.45(t,1H),5.12(s,2H),5.01(s,1H), 4.15(d,2H),3.95(d,2H),3.81(d,2H),3.61–3.48(m,2H),3.45(d,2H),3.26(d,2H),3.15(t,2H), 2.84(s,3H),2.15(s,2H),2.10–1.99(m,2H).

¹⁹F NMR(376MHz,CD₃OD)-74.91.

LCMS m/z＝388.8[M/2+1]⁺.

Example 16

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propyl-methyl-carbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 16)

Compound 16 was obtained by the synthesis method of the first step to the fourth step of example 7 starting from intermediate 1-b.

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.55–7.45(m,4H),7.35–7.20(m,7H),7.03(d, 1H),6.94–6.87(m,3H),6.63(d,1H),5.89(s,1H),5.46(t,1H),5.12(s,2H),5.00(s,1H),4.16(d, 2H),3.95(d,2H),3.81–3.60(m,4H),3.44(d,2H),3.29(d,2H),3.25–3.13(m,2H),3.03(s,3H), 2.20–2.05(m,3H),2.05–1.90(m,1H).

¹⁹F NMR(376MHz,CD₃OD)-74.87.

LCMS m/z＝388.8[M/2+1]⁺.

Example 17:

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 17a)

3-oxa-7-azabicyclo [3.3.1] nonan-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 17b)

The first step is as follows: preparation of Compounds 1D-b-a and 1D-b-b

1D-b is separated by high performance liquid chromatography to obtain 1D-b-a and 1D-b-b. The preparation conditions were as follows:

instrument and preparative column: the liquid phase was prepared using Glison GX-281, column type

OZ-H,5 μm, inner diameter 20mm 250mm long.

The preparation method comprises the following steps: the crude product was dissolved in ethanol and filtered through a 0.45 μm filter to prepare a sample solution.

Mobile phase system: n-hexane/ethanol, isocratic elution: and (3) eluting with n-hexane/ethanol (85/15) for 120 min.

The second step is that: preparation of Compounds 17a and 17b

Starting from 1D-b-a, the carboxylic acid form of intermediate 1-b-a was obtained according to the synthesis method of the fourth step of intermediate 1-b, and continuing the synthesis methods of the first to fourth steps of reference example 1 gave compound 17 a.

Starting from 1D-b-b, the carboxylic acid form of intermediate 1-b-b was obtained according to the synthesis method of the fourth step of intermediate 1-b, and continuing the synthesis methods of the first to fourth steps of reference example 1 gave compound 17 b.

1D-b-a and 1D-b-b analysis methods:

a chromatographic column: daluosite CHIRALCEL OZ-H

Specification: 4.6mm × 250mm, 5 μm

Mobile phase A: n-hexane (0.1% diethylamine)

Mobile phase B: ethanol

Column temperature: 35 deg.C

Flow rate: 1.0mL/min

Wavelength: 210nm

Elution procedure: and (5) when the mobile phase A and the mobile phase B are 85:15, and isocratic elution is carried out for 40 min.

1D-b-a retention time: 23.784 min;

1D-b-b Retention time: 27.822 min.

Example 18

3-oxa-7-azabicyclo [3.3.1] non-9-yl-N- [ [3- [ [ 2-fluoro-4- [ [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] methyl ] carbamate bistrifluoroacetate (Compound 18)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[2-fluoro-4-[[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2- oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]propylcarbamoyl]phenyl]methoxy]phenyl]phenyl]methyl]carbamateditrifluoroacetate

The first step is as follows: 9- [ [ [ [3- [ [ 2-fluoro-4- (methoxy-carbonyl) benzyl ] oxy ] phenyl ] methyl ] carbamoyl ] oxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (18a)

Tert-butyl 9-[[[[3-[[2-fluoro-4-(methoxy-carbonyl)benzyl]oxy]phenyl]phenyl]methyl]carbamoyl]oxy]-3-oxa-7- azabicyclo[3.3.1]nonane-7-carboxylate

Tert-butyl 9- [ [ (3-hydroxyphenyl) -phenyl-methyl ] carbamoyloxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (intermediate 2-a) (0.205g,0.438mmol) was dissolved in 10ml of DMF and methyl 4- (bromomethyl) -3-fluorobenzoate (0.163g,0.656mmol) and potassium carbonate (0.182g,1.31mmol) were added in that order and the reaction was stirred at room temperature overnight. DMF was removed by concentration under reduced pressure, the residue was dissolved in 20mL of ethyl acetate, 20mL of water was added and stirred, the mixture was allowed to stand for separation, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined and washed successively with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v): 8:1-4:1) to give tert-butyl 9- [ [ [ [3- [ [ 2-fluoro-4- (methoxy-carbonyl) benzyl ] oxy ] phenyl ] methyl ] carbamoyl ] oxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (18a) (0.243g, yield: 88%).

The second step is that: 4- [ [3- [ [ [ [ [ [ (tert-butoxycarbonyl) -3-oxa-7-azabicyclo [3.3.1] non-9-yl ] -oxy ] carbonyl ] amino ] phenyl ] methyl ] phenoxy ] methyl ] -3-fluorobenzoic acid (18b)

4-[[3-[[[[[(tert-butoxycarbonyl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)-oxy]carbonyl]amino]phe nyl]methyl]phenoxy]methyl]-3-fluorobenzoic acid

Tert-butyl 9- [ [ [ [3- [ [ 2-fluoro-4- (methoxy-carbonyl) benzyl ] oxy ] phenyl ] methyl ] carbamoyl ] oxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (18a) (0.243g,0.383mmol) was dissolved in 12 ml of tetrahydrofuran and 8 ml of water, and lithium hydroxide monohydrate (0.161g, 3.83mmol) was added and heated to 90 ℃ for 2 hours. Adding 1N diluted hydrochloric acid to adjust pH to 5-6, adding 20mL ethyl acetate for extraction, extracting the water phase with ethyl acetate (20mLx 2), combining the organic phases, washing with saturated saline (30mL), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude 4- [ [3- [ [ [ [ [ [ (tert-butoxycarbonyl) -3-oxa-7-azabicyclo [3.3.1] non-9-yl ] -oxy ] carbonyl ] amino ] phenyl ] methyl ] phenoxy ] methyl ] -3-fluorobenzoic acid (18b) (0.22 g).

The third step: 9- [ [ [ [3- [ [4- [ [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl ] amino ] propyl ] carbamoyl ] -2-fluorobenzyl ] oxy ] phenyl ] methyl ] carbamoyl ] oxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (18c)

Tert-butyl 9-[[[[3-[[4-[[3-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl]amino]propyl]carbamoyl]-2-fluorobenzyl]oxy]phenyl]phenyl]methyl]carbamoyl]oxy]-3-oxa-7- azabicyclo[3.3.1]nonane-7-carboxylate

4- [ [ [ [ [ 7-tert-Butoxycarbonyl-3-oxa-7-azabicyclo [3.3.1] non-9-yl ] -oxy ] carbonyl ] amino ] phenyl ] methyl ] phenoxy ] methyl ] -3-fluorobenzoic acid (18b) (0.22g) was dissolved in 10ml of DMF and 1-hydroxybenzotriazole (0.1 g,0.708mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (140mg,0.708mmol), N-diisopropylethylamine (0.14g,1.1mmol) and N- (3-aminopropyl) -N- [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] were added in this order Tert-butyl formate (intermediate 3) (210mg,0.57mmol), and reacted at room temperature overnight. Concentrating under reduced pressure to remove DMF, dissolving the residue with 20mL ethyl acetate, adding 30mL water, stirring, standing for layering, extracting the aqueous phase with ethyl acetate (20mLx 2), combining organic phases, washing with saturated saline (30mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, separating and purifying the crude product with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:1 to dichloromethane/methanol (v/v) ═ 25/1) to obtain 9- [ [ [ [3- [ [4- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy ] 2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl ] amino ] propyl ] carbamoyl ] -2-fluorobenzyl ] oxy ] phenyl ] methyl ] carbamoyl ] 9- [ [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy ] 2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin Oxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (18c) (0.144g, yield: 41%).

The fourth step: 3-oxa-7-azabicyclo [3.3.1] non-9-yl-N- [ [3- [ [ 2-fluoro-4- [ [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] methyl ] carbamate bistrifluoroacetate (Compound 18)

To 9- [ [ [ [3- [ [4- [ [3- [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl ] amino ] propyl ] carbamoyl ] -2-fluorobenzyl ] oxy ] phenyl ] methyl ] carbamoyl ] oxy ] -3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester (18c) (0.144g, 0.144mmol) was added 20ml of a saturated 1, 4-dioxane solution of hydrochloric acid, 2 ml of anhydrous methanol was added, and the mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure and the crude product was subjected to Pre-HPLC (Instrument and preparative column: liquid phase was prepared using Glison GX-281, preparative column model Sunfire C18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with 5% gradient 60% (elution time 15min) and lyophilized to give 3-oxa-7-azabicyclo [3.3.1] non-9-yl-N- [ [3- [ [ 2-fluoro-4- [ [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] methyl ] carbamate bistrifluoroacetate (compound 18) (0.074 g).

¹H NMR(400MHz,CD₃OD)8.38(d,1H),7.69–7.55(m,3H),7.37–7.19(m,7H),7.03(d, 1H),7.00–6.87(m,3H),6.66(d,1H),5.90(s,1H),5.45(t,1H),5.16(s,2H),5.00(s,1H),4.16(d, 2H),3.95(d,2H),3.67(d,2H),3.56–3.50(m,2H),3.44(d,2H),3.26(d,2H),3.16(t,2H),2.15– 2.00(m,4H).

LCMS m/z＝780.3[M+1]⁺

Example 19

3-oxa-7-azabicyclo [3.3.1] non-9-yl-N- [ [3- [ [ 2-chloro-4- [ [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 19)

3-Oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[2-chloro-4-[[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2- oxo-1H-quinolin-5-yl)ethyl]amino]propylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carba mate ditrifluoroacetate

Compound 19 was obtained according to the synthesis methods of the first to fourth steps of example 18, starting from methyl 4- (bromomethyl) -3-chlorobenzoate.

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.94–7.90(m,1H),7.80–7.75(m,1H),7.67–7.61(m,1H),7.35–7.21(m,7H),7.03(d,1H),6.96–6.88(m,3H),6.67(d,1H),5.90(s,1H),5.45 (t,1H),5.19(s,2H),5.00(s,1H),4.17(d,2H),3.95(d,2H),3.67(d,2H),3.57–3.49(m,2H),3.44 (d,2H),3.26(d,2H),3.15(t,2H),2.16–1.99(m,4H).

LCMS m/z＝398.8[M/2+1]⁺

Example 20

3-oxa-7-azabicyclo [3.3.1] non-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] ethylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 20)

3-oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-qu inolin-5-yl)ethyl]amino]ethylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

Compound 20 was obtained according to the synthesis methods of the third step to the fourth step in example 18, starting from intermediates 1-b and intermediate 4.

¹H NMR(400MHz,CD₃OD)8.38(d,1H),7.86(d,2H),7.51(d,2H),7.36–7.20(m,7H),7.03(d,1H),6.96–6.86(m,3H),6.64(d,1H),5.89(s,1H),5.44(dd,1H),5.12(s,2H),5.00(s,1H), 4.16(d,2H),3.95(d,2H),3.79–3.72(m,2H),3.67(d,2H),3.43(d,2H),3.40–3.32(m,4H),2.15 –1.83(m,2H).

LCMS m/z＝374.8[M/2+1]⁺

Example 21

3-oxa-7-azabicyclo [3.3.1] non-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] ethylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 21)

Compound 21 was obtained according to the synthesis methods of the third step to the fourth step in example 18, starting from intermediate 1-a and intermediate 4.

¹H NMR(400MHz,CD₃OD)8.38(d,1H),7.87(d,2H),7.52(d,2H),7.36–7.21(m,7H),7.03(d,1H),6.97–6.87(m,3H),6.65(d,1H),5.92–5.87(m,1H),5.43(dd,1H),5.13(s,2H),5.02 (t,1H),4.24–4.10(m,2H),3.85(d,2H),3.78–3.72(m,2H),3.58–3.27(m,8H),2.26–1.84(m, 2H).

LCMS m/z＝374.6[M/2+1]⁺

Example 22

Trans-3-oxa-7-azabicyclo [3.3.1] non-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] cyclohexyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate salt (Compound 22)

Trans-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1H-quinolin-5-yl)ethyl]amino]propylcarbamoyl]cyclohexyl]methoxy]phenyl]-phenyl-methyl]carbam ate ditrifluoroacetate

Compound 22 was obtained according to the synthesis procedures of the first to fourth steps of example 18, starting from trans-4- ((tosyloxy) methyl) cyclohexanecarboxylate.

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.38–7.18(m,7H),7.04(d,1H),6.93–6.77(m, 3H),6.68(d,1H),5.89(s,1H),5.44(t,1H),5.00(s,1H),4.17(d,2H),3.95(d,2H),3.75(d,2H), 3.67(d,2H),3.44(d,2H),3.36–3.26(m,2H),3.24–3.18(m,2H),3.06(t,2H),2.25–2.15(m, 1H),2.11(s,2H),1.99–1.83(m,6H),1.82–1.68(m,1H),1.57–1.42(m,2H),1.20–1.08(m, 2H).

LCMS m/z＝384.8[M/2+1]⁺

Example 23

3, 7-diazabicyclo [3.3.1] non-9-yl-N- [ [3- [ [4- [3- [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] propylcarbamoyl ] phenyl ] methoxy ] phenyl ] -phenyl-methyl ] carbamate bistrifluoroacetate (Compound 23)

3,7-diazabicyclo[3.3.1]nonan-9-yl-N-[[3-[[4-[3-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quin olin-5-yl)ethyl]amino]propylcarbamoyl]phenyl]methoxy]phenyl]-phenyl-methyl]carbamate ditrifluoroacetate

Compound 23 was obtained from 9-hydroxy-3, 7-diazabicyclo [3.3.1] nonane-3, 7-dicarbonate di-tert-butyl ester as the starting material according to the synthesis methods of the third to fourth steps of intermediate 1 and the third to fourth steps of example 18.

¹H NMR(400MHz,CD₃OD)8.39(d,1H),7.84(d,2H),7.51(d,2H),7.36–7.21(m,7H),7.03(d,1H),6.97–6.86(m,3H),6.66(d,1H),5.89(s,1H),5.45(t,1H),5.13(s,2H),4.95(s,1H), 3.61–3.47(m,6H),3.46–3.38(m,2H),3.38–3.32(m,2H),3.25(d,2H),3.15(t,2H),2.37(s,2H), 2.10–2.00(m,2H).

LCMS m/z＝381.2[M/2+1]⁺

Biological assay

1. Inhibitory Activity on human muscarinic M3 receptor

CHO cells (PerkinElmer, ES-212-AF) 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(sigmaG5013) and 250. mu.g/mL Zeocin (Invitrogen ant-zn-5p) at37 ℃ with 5% CO₂Culturing under the condition of 90-100% fusion, washing with PBS/5Mm EDTA to separate cells, centrifuging, collecting, re-suspending and counting the cells with 0.1% BSA (BOVOGEN BSAS 100) phenol-free red Ham's F12 medium (Invitrogen 11039-⁶cells/mL, 15mL of cell suspension was added to a 50mL centrifuge tube, Coelenterazine-h (Promega S2011) was added to a final concentration of 5 μ M, wrapped with tinfoil in the dark, incubated for 4 hours at 20 ℃ on a rotary shaker, and the cells were diluted with 0.1% BSA/phenol-free Red Ham' S F12 medium to a final concentration of 5.0 × 10⁵cells/mL, cells were placed on a rotary shaker and spun at low speed and incubated at room temperature for at least 1 hour. The compounds of the examples were formulated in DMSO as 10mM stock solution, 0.1% BSA/phenol red free Ham's F12 medium diluted in gradient (log (M): 7, -8, -9, -10, -11), 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), 50. mu.L of acetylcholine chloride (SigmaA6625) solution at a concentration of 112.92nM (hM3) was added to each well with a microplate reader applicator, luminescence was recorded for 20 seconds, and IC was calculated and analyzed using origin 7.5₅₀. 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

Example numbering	hM3 receptor IC₅₀(nM)
		Compound 1	1.43
Compound 2	0.56
		Compound 3	7.01
Compound 4	1.03
		Compound 6	4.2
Compound 7	1.7
		Compound 15	1.08
Compound 16	0.99
		Compound 17a	0.13
Compound 17b	0.91
		Compound 18	0.28
Chemical combinationObject 19	0.72
		Compound 20	0.86
Compound 21	0.71
		Compound 22	0.87
Compound 23	1.33

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

2. Agonistic activity at the human adrenergic beta 2 receptor

Example agonistic activity of the compounds on human adrenergic receptors was determined by LANCE Ultra cAMPAssay.

CHO cells (PerkinElmer, ES-034-CF) stably expressing human adrenergic receptor (h β 2) were cultured in MEM-alpha medium (Invitrogen 12561-056) containing 10% Fetal Bovine Serum (FBS) (Gibico 10099-141) and 250. mu.g/mL Zeocin (Invivogen ant-zn-5p) at37 ℃ with 5% CO₂Culturing under conditions to achieve 90-100% fusion and detecting cAMP agonism of the examples using the LANCE Ultra cAMPAssay kit (PerkinElmer TRF0263) cells were separated with PBS/5mM EDTA, harvested by centrifugation, resuspended in Stimulation Buffer (1 × HBSS,5mM HEPES,0.5mM IBMX, 0.1% BSA, pH 7.4), and adjusted to 6 × 10 cell concentration⁵cells/mL. the compounds of the examples were made up in DMSO as 10mM stock solutions, diluted in a Ststimulation Buffer gradient and added to 384 well plates at 5. mu.L per well, 5. mu.L of cell suspension (3000 cells/well) per well was added, and after incubation for 30 minutes at room temperature, 5. mu.L of 4 × Eu-cAMPtracer working solution was added per well, followed by 5. mu.L of 4 × Ulight-anti-cAMP working solution per wellAnd incubated 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 origin 7.5₅₀. The agonistic activity of the compounds of the present invention at the human adrenergic receptor was determined by the above experiment, and the EC50 values were measured as 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 β 2 adrenergic receptor.

3. Inhibition of methacholine-induced bronchoconstriction in guinea pigs

The 8-week-old male guinea pigs were purchased in the Witonglihua and the experiment was started after 3 days of acclimation. The positive compound optical isomer compound 15, the compound 16 and the compound to be tested are prepared into 2mM stock solution by 83% absolute ethyl alcohol and 17% Tween 80. It is diluted 500 times with water before administration. Prior to dosing, animals were anesthetized with 5% isoflurane using a small animal anesthesia machine (Matrx: VME2) for 1.5-2 minutes. After anesthetizing the guinea pigs, the guinea pigs were mounted on a tracheal intubation operating platform and administered intratracheally using a rat liquid aerosol dosing kit (pen-centre; MSA-250-R) in a volume of 250. mu.L per guinea pig. After administration, values of the guinea pig enhanced breathing pause (enhancedpause: PenH) were measured at 4 hours using a full-volume spectrometer (DSI: GS220A 12-R7B). Methacholine (Mch) was administered at 3mg/mL by nebulization for 36 seconds and recorded for 7 minutes. The PenH mean was calculated. (reference J Pharmacol Exp Ther 345: 260-270). The results are shown in Table 3.

PenH formula: PenH PEP/PIP Pause; pause ═ Te-Tr/Tr

Te: expiratory phase time(s)

Tr: relaxation phase time(s)

PEP: expiratory peak flow rate (ml/s)

PIP: inspiratory peak flow rate (ml/s)

TABLE 3 inhibition of acetylcholine-induced bronchoconstriction in guinea pigs

Compound a is reported as compound 52 in patent WO2014086924a1 (structure shown below), compound B is an enantiomer of reported compound 52 (structure shown below), and both compounds are prepared by the method disclosed in WO2014086924a 1.

And (4) conclusion: the compound of the invention has better inhibition effect on acetylcholine-induced bronchoconstriction of guinea pigs than positive control.

4. Histamine-induced bronchoconstriction inhibition in guinea pigs

The 8-week-old male guinea pigs were purchased in the Witonglihua and the experiment was started after 3 days of acclimation. The positive compound optical isomer compound 15, the compound 16 and the compound to be tested are prepared into 2mM stock solution by 83% absolute ethyl alcohol and 17% Tween 80. It is diluted 500 times with water before administration. Before administration, animals were anesthetized with 5% isoflurane using a small animal anesthesia machine for 1.5-2 minutes. After anesthetizing the guinea pigs, the guinea pigs were mounted on a tracheal intubation operating platform and administered intratracheally using a rat liquid aerosol dosing kit (pen-centre; MSA-250-R) in a volume of 250. mu.L per guinea pig. After the administration, the PenH values of the guinea pigs were measured at 4 hours using a full volume spectrometer (DSI: GS220A 12-R7B). Histamine (His) was administered at 0.8mg/mL by nebulization for 1 minute and the time recorded for 5 minutes. The PenH mean was calculated. The results are shown in Table 4.

PenH formula: PenH PEP/PIP Pause; pause ═ Te-Tr/Tr

Te: expiratory phase time(s)

Tr: relaxation phase time(s)

PEP: expiratory peak flow rate (ml/s)

PIP: inspiratory peak flow rate (ml/s)

TABLE 4 results of inhibitory Effect of Compounds on Histamine-induced bronchoconstriction in Guinea pigs

And (4) conclusion: the compound has obvious inhibiting effect on histamine-induced bronchoconstriction of guinea pigs.

Claims

1. A compound of formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

wherein:

is β -adrenoceptor binding group;

e is selected from

b is selected from absent, C_3-8Cycloalkylene radical, C_1-6Alkylene radical, C_3-8Heterocycloalkylene, arylene or heteroarylene, said cycloalkylene, alkylene, heterocycloalkyleneAryl or heteroarylene optionally further substituted by halogen atom, cyano, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s);

c and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) O-, -C (OO) -, -S-, -S (O) -, -S (O)₂-、-OS(O)₂-、-N(R^w)-、-NR^wC(O)-、-OC(O)NR^w-、-NR^wC(O)-(CH₂)_t-、-NR^wC(O)NR^w’-、-NR^wS(O)₂-、-NR^wS(O)₂NR^w-、-(CH₂)_t-OC(O)-、-O-C(O)-(CH₂)_t-O-C(O)-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、-NR^w-(CH₂)_t-OC(O)-、

m is selected from absent or selected from-O-, -NR^w-, -OC (O) -or-S-;

f is selected from arylene or heteroarylene, said arylene or heteroarylene being optionally further substituted by halogen, hydroxy, oxo, mercapto, nitro, amino, cyano, -CON (R)^w)₂、-NHCOR^w、-CO₂R^w、C_1-6Alkylsulfanyl group, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkyl, aryl, haloaryl, heteroaryl or C_1-6Substituted by a substituent of alkoxy;

g is selected from-O-or-NR¹³；

R⁷、R⁸each independently selected from H or C_1-6An alkyl group;

R¹⁵and R⁹Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

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

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

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

p is absent or selected from-O-, -S-, -SO₂-、-CO-、-NR¹⁰CH＝CH-、-N(R¹⁰)SO₂-、-N(R¹⁰)COO-、-N(R¹⁰)C(O)-、-SO₂N(R¹⁰)-、-CO(O)N(R¹⁰) -or-C (O) N (R)¹⁰)-；

T is selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl, aryl, heteroaryl, said alkyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by a halogen atom, hydroxy, oxo, -SH, -NO₂、-CN、-CON(R¹⁰)₂、-NH₂、-NHCOR¹⁰、-CO₂R¹⁰、C_1-6Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent substitution of alkoxy;

X^-is a physiologically acceptable anion;

2. A compound of formula (III) according to claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

a is selected from

R⁶selected from H or C_1-6An alkyl group;

R¹²selected from H, halogen atom or amino;

r is selected from 0, 1,2 or 3.

3. A compound of formula (III) according to claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

a is selected from

4. A compound of formula (III) according to claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R¹⁴selected from phenyl.

5. A compound of formula (III) according to claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R¹is a bicyclic or tricyclic hydrocarbon bridge ring containing 0 to 3 optional ring membersO, N, S heteroatom of (A), optionally substituted by C_1-6Alkyl, halogen, -OH, -CN, R¹⁵、-NO₂Substituted with the substituent(s);

provided that it does not contain

R¹⁵And R⁹Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

p is absent or selected from-O-, -S-, -SO₂-、-CO-、-NR¹⁰CH＝CH、-N(R¹⁰)SO₂-、-N(R¹⁰)COO-、-N(R¹⁰)C(O)-、-SO₂N(R¹⁰)-、-CO(O)N(R¹⁰) -or-C (O) N (R)¹⁰)-；

x-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent of alkoxy.

6. A compound of formula (III) according to claim 5, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R¹is selected from

Wherein

R¹¹And R^11’Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

X^-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radicalAryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms, -OH, -SH, -NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent of alkoxy.

7. A compound of formula (III) according to claim 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R¹is selected from

8. A compound of formula (III) according to claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

e is selected from

-NR^wS(O)₂-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、

m is selected from absent or-O-;

R⁷、R⁸each independently selected from H or C_1-6An alkyl group;

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

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

t is selected from 0, 1,2, 3 or 4.

9. A compound of formula (III) according to claim 8, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

e is selected from

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

R^w”independently selected from H, halogen atoms or C_1-6An alkoxy group;

R^windependently selected from H, C_1-6Alkyl or C_3-6cycloalkyl-C_1-6An alkylene group.

10. A compound of formula (I) or (I-1) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

e is selected from

b is selected from absent, arylene, C_3-8Cycloalkylene, heteroarylene or C_3-8Heterocycloalkylene, said heterocycloalkylene, arylene, cycloalkylene or heteroarylene being optionally substituted withOne step by halogen atom, cyano group, amino group, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, aryl-C_1-6Alkyl, heterocycloalkyl, heteroaryl or-NR⁷R⁸Substituted with the substituent(s);

c and C' are each independently selected from the group consisting of absent, -O-, -C (O) -, -O-C (O) O-, -C (OO) -, -S-, -S (O) -, -S (O)₂-、-OS(O)₂-、-N(R^w)-、-NR^wC(O)-、-OC(O)NR^w-、-NR^wC(O)NR^w’-、-NR^wS(O)₂-、-NR^wS(O)₂NR^w-、-(CH₂)_t-OC(O)-、-O-C(O)-(CH₂)_t-O-C(O)-、-O-(CH₂)_t-NR^wC(O)-、-O-(CH₂)_t-O-C(O)-、-NR^w-(CH₂)_t-OC(O)-、

m is selected from absent or-O-;

R^wand R^w’Each independently selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl radical, C_3-8heterocycloalkyl-C_1-6Alkyl, aryl, heteroaryl, aryl-C_1-6Alkyl, heteroaryl-C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, said radical optionally being further substituted by 0 to 5C_1-6Alkyl radical, C_1-6A halogenated alkyl group,Halogen atom, C_1-6Alkoxy radical, C_1-6Substituted with a substituent of haloalkoxy;

R⁷、R⁸each independently selected from H or C_1-6An alkyl group;

R¹¹and R^11’Each independently selected from- (CH)₂)_s-P-(CH₂)_k-T；

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

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

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

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

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

X^-is a physiologically acceptable anion;

R¹⁰selected from H, C_1-10Alkyl radical, C_1-6Haloalkyl, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, aryl or heteroaryl, said alkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl being optionally further substituted by halogen atoms、-OH、-SH、-NO₂、-CN、-CONH₂、-COOH、C_1-10Alkoxycarbonyl, C_1-10Alkylsulfanyl group, C_1-10Alkylsulfinyl radical, C_1-10Alkylsulfonyl radical, C_1-10Alkyl or C_1-10Substituent of alkoxy.

11. The compound of formula (I) or (I-1) according to claim 10, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

e is selected from

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

R^w”independently selected from H, halogen atoms or C_1-6An alkoxy group;

12. The compound of formula (I) or (I-1) according to claim 11, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein

E is selected from

13. The compound according to claim 1 or 10, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein compound is selected from:

14. a compound according to any one of claims 1 to 13, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the salt is selected from the group consisting of sodium, potassium, calcium, magnesium, barium, ammonium, trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylammonium, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, trifluoroacetate, acetate, maleate, tartrate, citrate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, salts, Citrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof.

15. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 14, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, together with a pharmaceutically acceptable carrier or excipient.

16. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 14, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, together with one or more other active ingredients.

17. The composition of claim 16, wherein the additional therapeutic agent comprises: β 2-agonists, antimuscarinics, mitogen-activated protein kinase (P38MAP kinase) inhibitors, nuclear factor κ -B kinase subunit β (IKK2) inhibitors, Human Neutrophil Elastase (HNE) inhibitors, phosphodiesterase 4(PDE4) inhibitors, leukotriene modulators, nonsteroidal anti-inflammatory drugs (NSAIDs), antitussives, mucus regulators, mucolytics, expectorant/mucus driver modulators, peptide mucolytics, antibiotics, JAK inhibitors, SYK inhibitors, PI3K or PI3K γ inhibitors, corticosteroids, and M3-antagonists/PDE 4-inhibitors (MAPIs).

18. Use of a compound according to any one of claims 1 to 14 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a composition according to any one of claims 15 to 17, in the manufacture of a medicament for use in the treatment of an obstructive disease of the airways, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD).

19. A pharmaceutical composition according to claims 15-17 for administration by inhalation, such as an inhalable powder, a propellant-containing metered dose aerosol or a propellant-free inhalable formulation.

20. A device comprising a pharmaceutical composition according to claim 19, which may be a single-or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer.