TW202112770A - Heterocyclic derivatives with β2 receptor agonist and m receptor antagonistic activities and medical use thereof - Google Patents

Abstract

The present invention relates to a heterocyclic derivative with β2 receptor agonist and M receptor antagonistic activity and medical use thereof. Specifically, the present invention relates to a compound of general formula (I) or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, the preparatiom method thereof, the pharmaceutical composition comprising the same, as well as the use thereof in the preparation of medicaments for the treatment of obstructive airways diseases. The definitions of each groups in general formula (I) is the same as defined in the description.

Description

Heterocyclic derivative with β2 receptor agonistic and M receptor antagonistic activity and its medical use

The present invention belongs to the technical field of medicine, and specifically relates to a heterocyclic compound, a preparation method thereof, and a pharmaceutical composition containing it, and its use as a muscarinic receptor antagonist and β -adrenergic receptor agonist in treatment and/or The use of preventing diseases related to the activity of muscarinic receptors and β -adrenergic receptors, especially the use of treating and/or preventing asthma, chronic obstructive pulmonary disease, bronchitis, emphysema and other diseases.

Bronchodilators play an important role in the treatment of chronic obstructive pulmonary disease (COPD) and asthma and other respiratory diseases. Bronchodilators widely used in clinical practice include β2 -adrenergic receptor agonists and muscarinic receptor antagonists. Beta 2-adrenergic receptor agonists currently used in the inhalation route include salbutamol, aformoterol, formoterol, indacaterol, odacaterol, and salmeterol. These drugs mainly dilate the bronchi by stimulating the adrenergic receptors of the airway smooth muscle, and reverse the contraction response of the bronchi to acetylcholine and other mediators. Currently used inhaled muscarinic receptor antagonists include oxitropium bromide, ipratropium bromide, aclitropium bromide, glycopyrrolate, tiotropium bromide and umeclidinium bromide. These drugs play the role of bronchiectasis mainly by reducing the vagus nerve cholinergic level of airway smooth muscle. These drugs can not only improve the function of the lungs, but also improve the quality of life of patients and reduce the deterioration of the disease. As more clinical studies have found, it is proved that the combined use of muscarinic receptor antagonists and β2 -adrenergic receptor agonists is more effective than using one of the therapeutic agents alone. At present, muscarinic receptors are clinically antagonized And β 2-adrenergic receptor agonists to prepare compound preparations. Such compound preparations mainly include indacaterol/glycopyrrolate, odacaterol/tiotropium bromide, umeclidinium bromide/vilan Terrol, aclidinium bromide/formoterol, glycopyrrolate/formoterol, etc. Although the compound preparation has a better therapeutic effect than the single preparation, it has higher requirements on the preparation of the preparation.

Therefore, people hope to develop drugs that have both muscarinic receptor antagonism and β2 -adrenergic receptor agonism. Compared with the compound preparation of the two drugs, this dual-energy drug has a combination of two components. Advantages, while having a single molecular pharmacokinetics. These compounds are administered as a single therapeutic agent and can have two different and possibly synergistic modes of action to provide bronchodilation. Further, compounds having muscarinic receptor antagonist and β 2- adrenergic receptor agonistic dual function (MABA) in the formulation also has associated advantages, it is easier to therapy in combination with other drugs, for example with a corticosteroid (ICS ) Anti-inflammatory drug combination to form two therapeutic agents (MABA/ICS) to provide triple-action therapeutic effects (Expert Opin. Investig. Drugs (2014) 23(4): 453-456).

Therefore, it is necessary to develop novel drugs with dual activities of β 2-adrenergic receptor agonism and muscarinic receptor antagonism to provide more effective single therapeutic doses or compound preparations, and provide more for patients with respiratory diseases The choice of clinical medication.

After painstaking research, the inventors designed and synthesized a series of heterocyclic compounds, which showed dual activities of muscarinic receptor antagonists and β -adrenergic receptor agonists, and could be developed for treatment and/or prevention and Drugs for diseases related to the activity of muscarinic receptors and β-adrenergic receptors.

Therefore, an object of the present invention is to provide a compound represented by general formula (I):

Or its mesosome, racemate, enantiomer, diastereomer, or mixture form thereof, or its prodrug, or its pharmaceutically acceptable salt,

among them,

； R ¹ is

；

R ^1a and R ^1b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or (CH _{2) p} R ^a, the alkyl, alkenyl Group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group optionally further selected from halogen, amine group, nitro group, cyano group, pendant oxy group, hydroxyl group, mercapto group, carboxyl group, ester group, alkane group Group, haloalkyl, OR ^a , SR ^a , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, one of -OC(O)R ^b or -C(O)R ^b Or multiple groups are substituted, provided that R ^1a and R ^{1b are} not hydrogen at the same time;

R ^{1c is} selected from hydrogen, hydroxyl, cyano, amino, alkyl, OR ^a , SR ^a or -C(O)NR ^b R ^c ;

R ² and R ³ are each independently selected from hydrogen or alkyl;

B is selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are further selected from halogen, hydroxy, amino, nitro, Cyano group, pendant oxy group, mercapto group, carboxyl group, ester group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, -(CH ₂ ) _p OR ^a , -C(O)OR ^a , -C(O )R ^b , -NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , -NR ^b S(O) ₂ NR ^b R ^c , -S(O) ₂ NR ^b R ^c ,- OC(O)R ^b or -NR ^b (CH ₂ ) _p R ^c is substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is further selected from halogen, Amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl One or more groups are substituted;

A ¹ and A ² are each independently selected from an alkylene group, an alkenylene group or an alkynylene group; the alkylene group, an alkenylene group or an alkynylene group is further selected from halogen, a hydroxyl group, an amino group, a carboxyl group, and a cyano group as necessary. , Nitro, alkyl, haloalkyl, OR ^a , SR ^a , -OC(O)R ^b , -C(O)R ^b , cycloalkyl, heterocyclyl, aryl or heteroaryl one or Multiple group substitutions;

L ^{1 is} selected from a single bond, -NR ^b -or -O-;

L ^{2 is} selected from single bond, -O-, -NR ^b -, -S(O) _m -, -NR ^b C(O)-, -C(O)NR ^b -, -NR ^b C(O)( CH ₂ ) _p O-, -O(CH ₂ ) _p C(O)NR ^b -, -NR ^b (CH ₂ ) _p O-, -O(CH ₂ ) _p NR ^b -, -NR ^b C(O )NR ^c -, -C(O)-, -C(O)O-, -OC(O)-, -S(O) _m NR ^b -, -NR ^b S(O) _m -, -NR ^b S(O) _m NR ^c -, -NR ^b S(O) _m (CH ₂ ) _p S-, -S(CH ₂ ) _p S(O) _m NR ^b -, -NR ^b (CH ₂ ) _p S -, -S(CH ₂ ) _p NR ^b -, -C(O)NR ^b S(O) _m -or -S(O) _m NR ^b C(O)-;

Ring C is selected from cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is further selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, pendant oxy, alkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^a ,- C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O) ) (R ^b ) ₂ is substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are further selected from halogen, amine group, nitro group as required One or more of group, cyano group, pendant oxy group, hydroxyl group, mercapto group, carboxyl group, ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Group substitution

不為

、

、

、 requirement is,

Not for

,

,

,

Among them, ˙ represents the site connected to O; ^* represents the site connected to A ^1;

G is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl may be further selected from hydrogen, halogen, amine, nitro, cyano if necessary Group, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O )R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ are substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group If necessary, the group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic group. One or more groups of aryl, aryl, and heteroaryl;

The condition is that when G is a phenyl group, L ^{2 is} not directly connected to it with a -O-, -NHC(O)-, -C(O)NH- or -NHC(O)O- group;

R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;

R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro , Cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl one or more groups Group replacement

Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups;

m is 0, 1 or 2;

p is an integer from 0 to 6.

In a preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

Ring C is selected from cycloalkyl or heterocyclic group, preferably 5-12 membered spirocycloalkyl, 6-12 membered bridged cycloalkyl, 5-12 membered spiroheterocyclic group, 6-12 membered bridged heterocyclic group, Wherein the cycloalkyl or heterocyclic group is further selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclic group if necessary , Aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC One or more of (O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ Group substitution, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted with one or more selected from halogen, amine group, nitro group, cyano group, pendant oxy group , Hydroxy, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups;

R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;

R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups;

Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups;

m is 0, 1, or 2.

In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention is a compound represented by general formula (II),

among them,

Ring D is selected from heterocyclic group, preferably 5-12 membered spiro heterocyclic group and 6-12 membered bridged heterocyclic group, wherein the heterocyclic group is further selected from hydrogen, halogen, amine, nitro, cyano Group, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O )R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ are substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group If necessary, the group is further selected from one or more halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl groups. , One or more groups of heterocyclic group, aryl group, heteroaryl group;

R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;

R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups;

Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups;

m is 0, 1 or 2;

A ¹ , A ² , R ¹ , R ² , R ³ , L ¹ , L ² , G and B are as defined in the general formula (I).

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

、

和

； B is selected from

,

with

；

among them:

R ⁴ a each is independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, ^{alkoxy, -C (O) OR a,} -C (O) R b, - NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , -NR ^b S(O) ₂ NR ^b R ^c , -OC(O)R ^b , or -NR ^b (CH ₂ ) _p R ^c ; wherein the alkyl group and alkoxy group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group as necessary , Substituted by one or more groups of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R ⁵ is independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, ^{alkoxy, -C (O) OR a,} -C (O) R b, - NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , NR ^b S(O) ₂ NR ^b R ^c , -OC(O)R ^b , or -NR ^b (CH ₂ ) _p R ^c ; Wherein the alkyl group and alkoxy group are optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, One or more group substitutions of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^{6 is} selected from hydrogen, halogen, hydroxyl, amino, carboxy, cyano, nitro, alkyl, alkoxy, -C(O)OR ^a , -C(O)R ^b , -NR ^b C(O ) R ^c , -NR ^b S(O) ₂ R ^c , NR ^b S(O) ₂ NR ^b R ^c , -OC(O)R ^b , or -NR ^b (CH ₂ ) _p R ^c ; wherein the alkane The group and alkoxy group are optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkane Substitution of one or more groups of group, heterocyclic group, aryl group, heteroaryl group;

M is selected from -C(R ^d )=C(R ^e ), -CR ^d R ^e CR ^d R ^e , -O-, -S-, -OCR ^d R ^e -, -CR ^d R ^e O-,- SCR ^d R ^e - and -CR ^d R ^e S-, wherein, R ^d and R ^e are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, oxo, mercapto, carboxyl, ester Group, alkyl, alkoxy, cycloalkyl, heterocyclyl, -(CH ₂ ) _p OR ^a , -C(O)OR ^a , -C(O)R ^b , -NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , -NR ^b S(O) ₂ NR ^b R ^c , -S(O) ₂ NR ^b R ^c , -OC(O)R ^b or -NR ^b (CH ₂ ) _p R ^c , wherein the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxygen One or more group substitutions of group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;

R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups;

Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups;

n is an integer from 0 to 4;

q is an integer from 0 to 4.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

； B is selected from

；

R ⁶ is independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, ^{alkoxy, -C (O) OR a,} -C (O) R b, -NR b C(O)R ^c , -NR ^b S(O) ₂ R ^c , NR ^b S(O) ₂ NR ^b R ^c , -OC(O)R ^b , or -NR ^b (CH ₂ ) _p R ^c ; Wherein the alkyl group and alkoxy group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, and alkynyl group as necessary. , Cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more groups;

M is selected from -C(R ^d )=C(R ^e ), -CR ^d R ^e CR ^d R ^e , -O-, -S-, -OCR ^d R ^e -, -CR ^d R ^e O-,- SCR ^d R ^e - and -CR ^d R ^e S-, wherein, R ^d and R ^e are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, oxo, mercapto, carboxyl, ester Group, alkyl, alkoxy, cycloalkyl, heterocyclyl, -(CH ₂ ) _p OR ^a , -C(O)OR ^a , -C(O)R ^b , -NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , -NR ^b S(O) ₂ NR ^b R ^c , -S(O) ₂ NR ^b R ^c , -OC(O)R ^b or -NR ^b (CH ₂ ) _p R ^c , wherein the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxygen One or more group substitutions of group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;

R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups;

Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

Wherein, each of R ⁴ , R ⁵ or R ^{6 is} independently selected from -C(O)OR ^a , -C(O)R ^b , -NR ^b C(O)R ^c or NR ^b S(O) ₂ NR ^b R ^c ;

R ^{a is} selected from hydrogen or alkyl;

R ^b and R ^c are each independently selected from hydrogen or alkyl.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

Wherein, each of R ⁴ , R ⁵ or R ^{6 is} independently selected from -NR ^b S(O) ₂ R ^c ;

R ^{b is} selected from hydrogen or alkyl;

R ^{c is} selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further selected from halogen, alkyl as required Or one or more of the alkoxy groups are substituted.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

Wherein, each of R ⁴ , R ⁵ or R ^{6 is} independently selected from -OC(O)R ^b ;

R ^{b is} selected from hydrogen, an amine group or an aryl group, and the amine group or aryl group is further substituted with one or more groups selected from an alkyl group or an alkoxy group as necessary.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

Wherein, each of R ⁴ , R ⁵ or R ^{6 is} independently selected from -NR ^b (CH ₂ ) _p R ^c ;

R ^{b is} selected from hydrogen or alkyl;

R ^{c is} selected from cycloalkyl, heterocyclic or aryl, and the cycloalkyl, heterocyclic or aryl is further substituted with one or more groups selected from halogen, alkyl or alkoxy as required;

p is an integer from 0 to 6.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

M is selected from -C(R ^d )=C(R ^e ), -CR ^d R ^e CR ^d R ^e , -O-, -S-, -OCR ^d R ^e -, -CR ^d R ^e O-,- SCR ^d R ^e -and -CR ^d R ^e S-, wherein R ^d and R ^e are each independently selected from hydrogen or alkyl.

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention, wherein:

、

、

、

、

、

、

、

、

、

和

，較佳

和

，更佳

。 B is selected from

,

,

,

,

,

,

,

,

,

with

, Better

with

, Better

.

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention, wherein:

R ^1a and R ^1b are each independently selected from hydrogen, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3 to 8-membered heterocyclyl, C _5-10 aryl, 3 To 10-membered heteroaryl, C _3-10 cycloalkyl-C _1-6 alkylene or 3 to 10-membered heterocyclyl-C _1-6 alkylene, preferably C _3-7 cycloalkyl, 3 To 6-membered heterocyclyl, C _5-6 aryl and 5 to 6-membered heteroaryl, more preferably 5 to 6-membered heteroaryl, the alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic group , Aryl and heteroaryl groups are optionally further selected from halogen, hydroxyl, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy , C _1-6 haloalkoxy, C _1-6 alkylthio, -OC(O)C _1-6 alkyl, -C(O)C _1-6 alkyl, or -C _3-6 cycloalkane One or more groups of oxy are substituted; provided that R ^1a and R ^{1b are} not hydrogen at the same time;

R ^{1c is} selected from hydrogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio or -C(O)NH ₂ , preferably hydroxyl.

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention, wherein:

、

、

、

、

和

，較佳

和

，更佳

。 R ^{1 is} selected from

,

,

,

,

with

, Better

with

, Better

.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

，其中，˙代表與A²相連接的位點，^*代表與L²相連接的位點， G is selected from C _5-10 aryl or 5-10 membered heteroaryl, preferably phenyl and 7-10 membered fused heteroaryl, more preferably phenyl and

, Where ˙ represents the site connected ^{to A 2 and *} represents the site connected to L ^2,

Wherein the aryl or heteroaryl group is optionally further selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, Aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC( O) R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ Group substitution, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, pendant oxy group, hydroxyl group, and mercapto group as required , Carboxyl group, ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;

X, Y and Z are each independently selected from -N-, -C-, -S-, -O- or -C(O)-, wherein Z is preferably N, and X is preferably N, O, C or S , Y is preferably N, C or -C(O)-;

R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;

R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups;

Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups;

m is 0, 1, or 2.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

和

； G is selected from

with

；

Among them, ˙ represents the site connected ^{to A 2 and *} represents the site connected to L ^2.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

L ^{1 is} selected from single bond, -NR ^b -and -O-, preferably single bond and -NR ^b -;

R ^{b is} selected from hydrogen, halogen, and alkyl, where the alkyl group is further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxy, ester, pendant oxy, alkyl, and alkoxy if necessary. One or more of the group is substituted by the group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

among them,

L ^{2 is} selected from single bond, -NR ^b -, -S-, -SO ₂ -, -C(O)-, -C(O)O-, -S(O) ₂ NR ^b -, -NR ^b S (O) ₂ -, -NR ^b C(O)(CH ₂ )O-, -O(CH ₂ )C(O)NR ^b -, -NR ^b C(O)NR ^c -and -C(O) NR ^b S(O) ₂ -; preferably single bond, -NH-, -S-, -SO ₂ -, -C(O)-, -NR ^b C(O)NR ^c -and -O(CH ₂ )(CO)NR ^b , preferably a single bond and -O(CH ₂ )(CO)NR ^b ;

Wherein, R ^b and R ^c are each independently selected from hydrogen, halogen, and alkyl group, wherein the alkyl group is further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, sulfhydryl group, carboxyl group, ester group, side One or more groups of oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted.

In another preferred embodiment of the present invention, according to the compound represented by the general formula (I) of the present invention,

Wherein, A ¹ and A ² are each independently selected from C _1-10 alkylene, preferably C _1-6 alkylene; if necessary, the alkylene is further selected from halogen, hydroxyl, amino, carboxy, cyano Group, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, -OC(O) C _1-6 alkyl, -C(O)C _1-6 alkyl, C _3-6 cycloalkoxy, C _5-6 aryl and C _3-7 cycloalkyl substituted by one or more groups .

Typical compounds of the present invention include but are not limited to:

Its meso, racemate, enantiomer, diastereomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof.

The present invention further provides a method for preparing the compound represented by the general formula (I) according to the present invention, which comprises the following steps:

When -L ¹ -A ¹ -is -CH ₂ -CH ₂ -CH ₂ -and A ² is -CH ₂ -,

Step 1: In the presence of a catalyst and a reducing agent, the compound Ie is reacted with the compound If to obtain the compound Ig, the catalyst is preferably anhydrous zinc chloride, and the reducing agent is preferably sodium cyanoborohydride;

Step 2: In the presence of a catalyst, the compound Ig is subjected to a deprotection reaction to obtain a compound of general formula (I), the protecting group is preferably TBS, and the catalyst is preferably triethylamine hydrofluoride;

Wherein R ¹ , R ² , R ³ , B, G, L ² and C are as defined in the general formula (I).

The present invention further provides a pharmaceutical composition, which contains the compound represented by the general formula (I) according to the present invention and a pharmaceutically acceptable carrier.

The present invention further provides the use of the compound represented by the general formula (I) according to the present invention, or a pharmaceutical composition containing it, in the preparation of muscarinic receptor antagonists and β -adrenergic receptor agonists .

The present invention further provides the compound represented by the general formula (I) according to the present invention, or a pharmaceutical composition containing it, for preparing prevention and/or treatment with muscarinic receptor and β -adrenergic receptor activity Use in medicine for related diseases.

The diseases related to the activity of muscarinic receptors and β -adrenergic receptors according to the present invention may be respiratory diseases, such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema and the like.

Another aspect of the present invention provides a compound represented by the general formula (I) according to the present invention, or a pharmaceutical composition containing it, in combination with another or more therapeutic agents, in preparation for the prevention and/or treatment of respiratory diseases such as Use in medicines for asthma, chronic obstructive pulmonary disease, bronchitis, and emphysema, wherein the other or more therapeutic agents are preferably selected from PDE4 inhibitors, muscarinic receptor antagonists, corticosteroids and β -adrenergics Receptor agonists.

According to conventional methods in the field of the present invention, the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid. The acid includes inorganic acid and organic acid, particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid , Trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

According to conventional methods in the field to which the present invention belongs, the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base. The base includes inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide and calcium hydroxide. , Potassium hydroxide, sodium carbonate and sodium hydroxide, etc.

In addition, the present invention also includes prodrugs of the compounds represented by the general formula (I) of the present invention. The prodrugs of the present invention are derivatives of the compound represented by the general formula (I). They may have weak activity or even no activity, but after administration, under physiological conditions (for example, by metabolism, solvent Decomposition or another way) is converted into the corresponding biologically active form.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing to the eye And delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone Or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time. For example, water-soluble taste-masking substances such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extended time substances such as ethyl cellulose, cellulose acetate butyrate can be used.

Hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin can also be used, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide oral preparations.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents, which can be natural Produced phospholipids such as lecithin, or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as seventeen-carbon vinyloxy cetyl Alcohol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitol monooleate, or ethylene oxide and ethylene oxide derived from fatty acids and hexitol anhydrides Condensation products of partial esters, such as polyethylene oxide sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, or alba Spatan.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. Oil suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient and a dispersing or wetting agent for mixing, suspending agent or one or more preservatives. suitable Dispersing or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide. , Such as polyethylene oxide sorbitol monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants. Syrups and elixirs formulated with sweetening agents such as glycerin, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. Then the oil solution is added to the mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.

The pharmaceutical composition of the present invention may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol. In addition, sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

The compounds of the present invention can be administered in the form of suppositories for rectal administration. It can be made by mixing the drug with a drug that is solid at normal temperature but liquid in the rectum, so that it will melt in the rectum and release the drug Suitable non-irritating excipients are mixed to prepare these pharmaceutical compositions. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

Those skilled in the art are well aware that the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient’s age, the patient’s weight, the patient’s health, the patient’s clothing, and the patient’s Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc. In addition, the best treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.

The present invention may contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions and the like. The compound of the present invention can be used as the sole active ingredient, and can also be used in combination with other therapeutic agents. Combination therapy is achieved by administering each treatment component simultaneously, separately or sequentially.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and the scope of the patent application have the following meanings.

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 An alkyl group of carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Benzylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be taken at any available point of attachment Instead, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro Group, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy, or carboxy Acid ester group.

The term "alkylene" refers to straight and branched divalent saturated hydrocarbon groups, including -(CH ₂ )v- (v is an integer from 1 to 10, preferably an integer from 1 to 6), examples of alkylene Including but not limited to methylene, ethylene, propylene and butylene, etc.; alkylene may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment , The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro , Cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy, or carboxylic acid Ester group. When the number of substituents in the alkylene group is greater than or equal to 2, the substituents may be fused together to form a cyclic structure.

The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

The term "alkenylene" refers to straight-chain and branched divalent alkenyl groups, wherein the definition of alkenyl is as described above.

The term "alkynyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like. Alkynyl can be substituted or non Substituted, when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, Mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynylene" refers to straight-chain and branched divalent alkynyl groups, wherein alkynyl is defined as described above.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "cycloalkyl" refers to a divalent cycloalkyl, wherein the definition of cycloalkyl is as described above.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings with 5 to 20 members. It may contain one or more double bonds, but none of the rings have complete conjugation. Π electron system. It is preferably 5 to 12 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl is classified into a single spirocycloalkyl, a dispirocycloalkyl, or a polyspirocycloalkyl, preferably a single spirocycloalkyl and a bispirocycloalkyl . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group consisting of 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-member, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected with the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 10 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 5 to 7 ring atoms, of which 1 ~2 or 1~3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1,2,5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, condensed, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _{Heteroatoms of m} (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 5 to 12 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 14 members, and any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 5 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

和

等。

with

Wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, Heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy, or carboxylate.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy, or carboxylate.

The term "arylene" refers to a divalent aryl group, wherein the definition of the aryl group is as described above.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, and thiazolyl , Pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; It is more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "heteroaryl" refers to a divalent heteroaryl group, wherein the definition of the heteroaryl group is as described above.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

The term "hydroxy" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "pendant oxy" refers to =O.

The term "carboxy" refers to -C(O)OH.

The term "mercapto" refers to -SH.

The term "ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

The term "acyl" refers to a compound containing a -C(O)R group, where R is an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group.

"As needed" or "as needed" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group substituted by an alkyl group as necessary" means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, more preferably 1 to 3 hydrogen atoms independently of each other and substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.

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

"Prodrug" refers to a compound that can be converted into a compound of the present invention with biological activity under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compounds of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound.

Synthetic method of the compound of the present invention

In order to accomplish the purpose of the present invention, the present invention adopts the following synthetic scheme to prepare the compound of general formula (I) of the present invention.

When -L ¹ -A ¹ -is -CH ₂ -CH ₂ -CH ₂ -and A ² is -CH ₂ -, the compound of general formula (I) is synthesized according to Scheme 1:

Step 1: Under basic conditions, compound Ia is reacted with compound Ih to obtain compound Ib. The basic conditions are preferably sodium methoxide, and the protecting group is preferably Boc;

Step 2: Under acidic conditions, the compound Ib is subjected to deprotection reaction to obtain compound Ic, and the acidic conditions are preferably trifluoroacetic acid and hydrochloric acid;

Step 3: Under basic conditions, compound Ic and compound Id are substituted to obtain compound Ie. The basic conditions are preferably DIPEA;

Step 4: In the presence of a catalyst and a reducing agent, the compound Ie is reacted with the compound If to obtain the compound Ig, the catalyst is preferably anhydrous zinc chloride, and the reducing agent is preferably sodium cyanoborohydride;

Step 5: In the presence of a catalyst, the compound Ig is subjected to a deprotection reaction to obtain a compound of the general formula (I), the protecting group is preferably TBS, and the catalyst is preferably triethylamine hydrofluoride;

Wherein R ¹ , R ² , R ³ , B, G, L ² and ring C are as defined in the general formula (I).

Further examples are used to understand the compounds of the present invention and their preparation. These examples illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.

The compound of the present invention is prepared by using convenient starting materials and general preparation procedures. The present invention provides typical or inclined reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. Optimal conditions may vary with the use of specific reactants or solvents, but under normal circumstances, reaction optimization steps and conditions can be determined.

In addition, some protecting groups may be used in the present invention to protect certain functional groups to avoid unnecessary reactions. The protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, T.W.Greene and G.M.Wuts's "Organic Preparation" "Protecting Groups" (3rd edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protective groups.

The separation and purification of compounds and intermediates should adopt appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high performance liquid chromatography or a combination of the above methods. . For the specific method of use, please refer to the examples described in the present invention. Of course, other similar separation and purification methods can also be used. It can be characterized using conventional methods including physical constants and spectral data.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts are given in units of ^{10 -6 (ppm).} NMR was measured with Brukerdps 300 nuclear magnetometer, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl Base Silane (TMS).

LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector) was used for MS measurement.

The lc6000 high-performance liquid chromatograph (manufacturer: Chuangxin Tongheng) was used for the preparative liquid chromatography. The chromatographic column is Daisogel C18 10 μm 100A (30mm×250mm), and the mobile phase: acetonitrile/water.

The thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.20mm~0.25mm, and the size of thin layer chromatography separation and purification products is 0.5mm.

Column chromatography generally uses Qingdao Marine Silicone 100~200 mesh, 200~300 mesh and 300~400 mesh silica as the carrier.

The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from the network store, Beijing coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Companies such as Anaiji Chemical, Shanghai Bide, etc.

There are no special instructions in the examples, and the reactions can all be carried out under a nitrogen atmosphere.

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

The reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), Chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. There is no special description in the examples, and the solution refers to an aqueous solution.

The chemical reaction described in the present invention is generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C under one atmosphere, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent system used in the reaction includes: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.

The eluent system of column chromatography and the developing agent system of thin layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is based on the compound It can be adjusted according to its polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.

Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equal to the content described can be applied to the method of the present invention.

Abbreviations

μL = microliter

μM=micromole

NMR=Nuclear Magnetic Resonance

Boc=Third butoxycarbonyl

br=broad peak

d = doublet

δ = chemical shift

℃=Celsius

dd=double doublet

DIPEA=Diisopropylethylamine

DMAP=4-Dimethylaminopyridine

DMF = N,N -Dimethylformamide

DMSO=Dimethyl sulfide

DCM=dichloromethane

EA=ethyl acetate

HPLC=high performance liquid phase

Hz=Hertz

IC ₅₀ = concentration that inhibits 50% of the activity

J=Coupling constant (Hz)

LC-MS = liquid chromatography-mass spectrometry

m = multiplet

M+H ⁺ = mass of parent compound + one proton

mg = milligrams

mL=ml

mmol=millimoles

mol=mole

Ms=Methanesulfonyl

MS = mass spectrum

MsCl=Methanesulfonyl chloride

m/z = mass-to-charge ratio

nM = nanomolar

PE=Petroleum Ether

ppm = parts per million

Pro=Protective group

R-CBS=(R)-2-methyl-CBS-oxazoborane

s=single peak

t = triplet

TBABr ₃ = tetrabutylammonium tribromide

TBS-=tertiary butyl dimethyl silyl

TEA=Triethylamine

TFA=Trifluoroacetic acid

THF=tetrahydrofuran.

Example 1: 8-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[ d ]thiazole-3( 2H )-yl)propyl)-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxyl Preparation of -2,2-bis(thiophen-2-yl)acetate (1)

Step 1: Preparation of 2-oxo-2,3-dihydrobenzo[ d ]thiazole-6-carbaldehyde ( 1a )

At room temperature, 6-bromobenzo[ d ]thiazole-2-(3 H )-one (1.00g, 4.35mmol) was dissolved in THF (20mL), and the temperature was lowered to -78°C under a nitrogen atmosphere. Methylmagnesium iodide (2.20 mL, 6.53 mmol) was added dropwise to the system, and after the addition was completed, the stirring was continued for 30 minutes. Add THF (30mL), control the temperature not higher than -50°C, then add n-BuLi (3.50mL, 8.69mmol) dropwise, continue stirring for 30 minutes, then add DMF (634mg, 8.69mmol) dropwise, after the addition is complete, It was naturally raised to room temperature and stirred for 1 hour. Saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench the reaction, and EA (20 mL) was added for extraction, the organic phase was washed with water (15 mL), saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was depressurized concentrate. The residue was slurried with PE (15 mL) and EA (5 mL), filtered, and the filter cake was dried to obtain 570 mg of the title compound as an off-white solid, with a yield of 73.2%.

LC-MS: m/z 180.00 [M+H] ⁺ .

Step 2: Preparation of 3-(3-hydroxypropyl)-2-oxo-2,3-dihydrobenzo[ d ]thiazole-6-carbaldehyde ( 1b)

At room temperature, add 2-oxo-2,3-dihydrobenzo[ d ]thiazole-6-carbaldehyde (2.00g, 11.2mmol), 3-bromo-1-propanol (1.86g, 13.4mmol), K ₂ CO ₃ (4.60 g, 33.5 mmol) and KI (926 mg, 5.58 mmol) were added to acetonitrile (15 mL), and the reaction solution was heated to 65° C. and stirred overnight. EA (30mL) was added to the reaction solution, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (extractant: EA/PE=1:5-1:1) to obtain 1.3 g of the title compound as a white solid, with a yield of 50.0%.

LC-MS: m/z 238.05 [M+H] ⁺ .

Step 3: Preparation of 3-(6-methanyl-2-oxobenzo[ d ]thiazole-3-(2 H )-yl) propyl methanesulfonate ( 1c )

At room temperature, 3-(3-hydroxypropyl)-2-oxo-2,3-dihydrobenzo[ d ]thiazole-6-carbaldehyde (150mg, 0.633mmol) was dissolved in DCM (10mL), Under a nitrogen atmosphere at 0°C, triethylamine (0.180 mL, 1.27 mmol) and methylsulfonyl chloride (0.0540 mL, 0.696 mmol) were sequentially added, and stirring was continued for 2 hours. The reaction solution was diluted with DCM (10mL), washed with saturated NaHCO ₃ (10mL), washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 160 mg of the title compound as an off-white solid , The yield is 80.2%.

LC-MS: m/z 316.02 [M+H] ⁺ .

Step 4: Preparation of 8-(benzyloxy)-5-(2-bromoacetoxy)quinoline-2-(1 H )-one ( 1d )

At room temperature, add 5-acetyl-8-(benzyloxy)quinoline-2-(1 H )-one (Shanghai Bi De) (10.0 g, 34.1 mmol) to THF (100 mL) and CH ₃ OH (70 mL). Tetrabutylammonium tribromide (28.0 g, 58.0 mmol) was dissolved in THF (30 mL), slowly added dropwise to the above solution under a nitrogen atmosphere, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, added EA (100 mL), filtered, the filter cake was washed with EA (20 mL), and dried to obtain 10 g of the title compound as an off-white solid with a yield of 78.8%.

LC-MS: m/z 372.02 [M+H] ⁺ .

Step 5: Preparation of (R )-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinoline-2-(1 H )-one ( 1e )

At room temperature, 8-(benzyloxy)-5-(2-bromoacetoxy)quinoline-2-(1 H )-one (12.0g, 32.3mmol) was dissolved in THF (200mL) and added R-CBS (35.5 mL, 35.5 mmol). Under a nitrogen atmosphere, borane dimethyl sulfide solution (21.0 mL, 41.9 mmol) was slowly added dropwise to the reaction solution at -20°C, and stirring was continued for 1 hour. The reaction was quenched with methanol (20mL), stirred at room temperature for 30 minutes, concentrated under reduced pressure, 1mol/L HCl (200mL) was added, stirred at room temperature overnight, filtered, the filter cake was washed twice with water, and dried to obtain an off-white solid The title compound was 10g, and the yield was 82.9%.

LC-MS: m/z 374.03 [M+H] ⁺ .

Step 6: ( R )-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinoline-2-(1 H )-Ketone ( 1f ) preparation

At room temperature, add ( R )-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinoline-2-(1 H )-one (5.30g, 14.2mmol), imidazole (1.45 g, 21.3 mmol) and DMAP (0.347 g, 2.84 mmol) were dissolved in DMF (100 mL), TBS-Cl (2.58 g, 17.1 mmol) was added, and the mixture was stirred at 50°C overnight. Add water (500mL) to dilute, EA extraction (200mL x 3), the combined organic phase was washed with saturated brine (100mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed with silica gel column. Method for separation and purification (extractant: EA/PE=1: 2), 4.2 g of the title compound was obtained as a white solid, with a yield of 60.7%.

LC-MS: m/z 488.12 [M+H] ⁺ .

Step 7: ( R )-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinoline-2-( Preparation of 1 H )-ketone ( 1g)

At room temperature, ( R )-8-(benzyloxy)-5-(2-bromo-1-((tertiary butyldimethylsilyl)oxy)ethyl)quinoline-2-( 1 H )-ketone (1.00 g, 2.05 mmol), KI (438 mg, 2.67 mmol) and NaN ₃ (182 mg, 2.67 mmol) were dissolved in DMF (18 mL) and water (2 mL), and stirred at 80°C for 30 hours. Add water (50mL) to dilute, EA extraction (20mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 580mg of the title compound as a brown solid. The yield was 62.8%.

Step 8: ( R )-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-hydroxyquinolin-2-(1 H )-one ( 1h ) Preparation

At room temperature, add ( R )-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinoline-2 -(1 H )-ketone (400 mg, 0.889 mmol) was dissolved in absolute ethanol (10 mL), 200 mg of Pd/C was added, and the reaction was carried out at 50° C. in a hydrogen atmosphere for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 254 mg of the title compound as a dark yellow solid with a yield of 85.5%.

LC-MS: m/z 335.17 [M+H] ⁺ .

Step 9: 3-(2-Hydroxy-2,2-bis(thiophen-2-yl)acetoxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester ( 1i ) Preparation

Combine methyl 2-hydroxy-2,2-bis(thiophen-2-yl)acetate (Shanghai Bide) (2.00g, 7.87mmol) and 3-hydroxy-8-azabicyclo[3.2.1]octane- Tert-butyl 8-carboxylate (Shanghai Bide) (1.97 g, 8.66 mmol) was dissolved in toluene (100 mL), sodium methoxide (170 mg, 3.15 mmol) was added, and the mixture was stirred at 90°C overnight. The reaction solution was concentrated under reduced pressure, EA (30 mL) and saturated NaCl solution (100 mL) were added for extraction, the organic phases were combined, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (extractant: EA/PE= 10:1), 1.2 g of the title compound was obtained as a pink solid with a yield of 33.9%.

LC-MS: m/z 450.13 [M+H] ⁺ .

Step 10: Preparation of 8-azabicyclo[3.2.1]oct-3-yl-2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 1j )

At room temperature, 3-(2-hydroxy-2,2-bis(thiophen-2-yl)acetoxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl The ester (1.20 g, 2.67 mmol) was dissolved in DCM (10 mL), 4 mol/L hydrochloric acid dioxane solution (20 mL) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. Adjust the pH to 8 with saturated NaHCO ₃ solution, extract with DCM (20 mL x 3), combine the organic phases, and concentrate under reduced pressure to obtain 890 mg of the title compound as a yellow solid with a yield of 95%.

LC-MS: m/z 350.08 [M+H] ⁺ .

Step 11: 8-(3-(6-Methanoyl-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl)-8-azabicyclo[3.2.1]octane- Preparation of 3-yl 2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 1k )

At room temperature, 8-azabicyclo[3.2.1]oct-3-yl 2-hydroxy-2,2-bis(thiophen-2-yl)acetate (660mg, 1.90mmol) and 3-(6 -Formyl-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl methanesulfonate (1c) (600mg, 1.90mmol) was dissolved in DMF (8mL), potassium iodide ( 788 mg, 4.75 mmol) and DIPEA (0.47 mL, 2.85 mmol). Stir at 60°C for 3 hours. Dilute with water (30mL), extract with EA (15mL x 3), and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (extractant: EA/PE=5:1-1:1) to obtain yellow The oily title compound was 800 mg, and the yield was 74.6%.

LC-MS: m/z 569.12 [M+H] ⁺ .

Step 12: 8-(3-(6-(((( R )-2-((tertiary butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1, 2-Dihydroquinolin-5-yl)ethyl)amino)methyl)-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl)-8-azabicyclo[ 3.2.1] Preparation of oct-3-yl 2-hydroxy-2,2-bis(thiophen-2-yl))acetate ( 11 )

At room temperature, 8-(3-(6-methanyl-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl)-8-azabicyclo[3.2.1] Octan-3-yl 2-hydroxy-2,2-bis(thiophen-2-yl) acetate (100mg, 0.176mmol) and ( R )-5-(2-amino-1-((third butyl) (Dimethylsilyl)oxy)ethyl)-8-hydroxyquinolin-2( 1H )-one (58.8mg, 0.193mmol) was dissolved in methanol (3mL), and ZnCl ₂ (71.8mg, 0.528 mmol) and stirred at 55°C for 1 hour. NaBH ₃ CN (22.2 mg, 0.352 mmol) was added, and stirring was continued for 2 hours at 55°C. Saturated NaHCO ₃ solution (20 mL) was added, extracted with CH ₂ Cl ₂ (5 mL x 3), and concentrated under reduced pressure to obtain 100 mg of the title compound as a pale yellow solid, with a yield of 64.1%.

LC-MS: m/z 887.29 [M+H] ⁺ .

Step 13: 8-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl) Amino) methyl)-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl)-8-azabicyclo[3.2.1]oct-3-yl 2-hydroxy-2 Preparation of ,2-bis(thiophen-2-yl)acetate ( 1 )

At room temperature, add 8-(3-(6-(((( R )-2-((tertiary butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo- 1,2-Dihydroquinolin-5-yl)ethyl)amino)methyl)-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl)-8-aza Bicyclo[3.2.1]oct-3-yl-2-hydroxy-2,2-bis(thiophen-2-yl))acetate (70.0mg, 0.0790mmol) was dissolved in THF (3mL) under nitrogen atmosphere , TEA.3HF (63.6mg, 0.395mmol) was added dropwise thereto. Stir overnight at room temperature. Concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um 100A, eluent: acetonitrile/water (1% ammonium acetate), gradient: 10%-40 %) in 30 minutes, 12 mg of the title compound was obtained as a white solid, with a yield of 19.7%.

LC-MS: m/z 773.21 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 13.31 (br, 1H), 10.32 (s, 1H), 8.26 (s, 1H), 8.11 (d, 1H), 7.56-7.48 (m, 3H), 7.42 (s, 2H), 7.09-6.98 (m, 5H), 6.93-6.91 (m, 1H), 6.44 (d, 1H), 5.11-4.91 (m, 2H), 3.80 (s, 2H), 2.98-2.96 (m, 2H), 2.75-2.65 (m, 1H), 2.28-2.21 (m, 3H), 2.05-1.89 (m, 2H), 1.59-1.45 (m, 6H), 1.39-1.22 (m, 4H) .

Example 2: ( R )-2-(3-(6-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[ d ]thiazole-3( 2H )-yl)propyl)-2-azaspiro[3.3]hepta-6-yl-2-hydroxy-2 Preparation of ,2-bis(thiophen-2-yl)acetate ( 2 )

The preparation method is the same as Example 1, except that 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Shanghai Haohong Biomedical Technology Co., Ltd.) is used instead of 3-hydroxy-8 -Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, and replacing the hydrochloric acid dioxane solution with formic acid in step 10, to obtain the title compound 2 .

LC-MS: m/z 759.19 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.02 (br, 1H), 8.22 (s, 1H), 8.13 (d, 1H), 7.58-7.42 (m, 3H), 7.13-7.01 (m, 5H) ,6.85-6.83(m,1H),6.44(d,1H),5.08-4.83(m,2H),2.97-2.63(m,4H),2.18-2.08(m,3H),2.05-1.89(m, 2H), 1.58-1.22 (m, 6H).

Example 3: ( R )-6-((3-(6-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl Yl)amino)methyl)-2-oxobenzo[ d ]thiazol-3( 2H )-yl)propyl)(methyl)amino)spiro[3.3]heptan-2-yl-2- Preparation of hydroxy-2,2-bis(thiophen-2-yl)acetate ( 3)

Step 1: Preparation of 6-(methylamino)spiro[3.3]heptan-2-ol ( 3a )

At room temperature, the tertiary butyl (6-hydroxyspiro[3.3]heptan-2-yl) carbamate (500mg, 2.20mmol) was dissolved in THF (10mL), and separated at 0°C under a nitrogen atmosphere. Lithium tetrahydroaluminum (416 mg, 11.0 mmol) was added in batches, and the reaction solution was heated to 50° C. and stirred for 4 hours. Methanol (10 mL) was added to the reaction solution to quench the reaction, filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 400 mg of the crude title compound as a yellow oil, which was directly used in the next reaction.

LC-MS: m/z 142.12 [M+H] ⁺ .

Step 2: Preparation of (6-hydroxyspiro[3.3]heptan-2-yl)(methyl)carbamic acid tert-butyl ester ( 3b )

At room temperature, 6-(methylamino)spiro[3.3]heptan-2-ol (400mg, 2.84mmol) and triethylamine (430mg, 4.26mmol) were dissolved in DCM (10mL) at 0°C, Add Boc ₂ O (742 mg, 3.40 mmol) in batches, and stir overnight at room temperature. The reaction solution was diluted with DCM (20mL), washed with saturated brine (2 x 20ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (extractant : DCM/MeOH=100:1-20:1), 400 mg of the title compound is obtained as a pale yellow oil, and the two-step yield: 75.3%.

LC-MS: m/z 242.17 [M+H] ⁺ .

The other steps are the same as the preparation method of Example 1, except that tertiary butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)carbamate ( 3b ) is used instead of 3-hydroxy-8-aza Bicyclo[3.2.1]octane-8-tert-butyl carboxylate, the title compound 3 was prepared .

LC-MS: m/z 787.22 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.35 (br, 1H), 8.18 (s, 1H), 8.10 (d, 1H), 7.58 (s, 1H), 7.48 (t, 2H), 7.20-7.18 (m,2H),7.08-7.06(m,3H),7.00-6.90(m,3H),6.47(d,1H),5.12-4.78(m,2H),3.93-3.82(m,4H),2.72 -2.62 (m, 2H), 2.55-2.40 (m, 3H), 2.45-2.20 (m, 3H), 2.13-1.72 (m, 8H), 1.74 (t, 4H).

Example 4: (1-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Yl)amino)methyl)-2-oxobenzo[ d ]thiazol-3( 2H )-yl)propyl)piperidin-3-yl)methyl-2-hydroxy-2,2-di (Thien-2-yl) acetate ( 4 ) preparation

4

The preparation method is the same as in Example 1, except that 3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (Shanghai Bide) is used instead of 3-hydroxy-8-azabicyclo[3.2.1]octane Tertiary butyl alkane-8-carboxylate to obtain the title compound 4 .

LC-MS: m/z 761.21 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.35 (br, 1H), 8.17 (s, 1H), 8.13 (d, 1H), 7.65 (s, 1H), 7.44 (t, 2H), 7.39-7.37 (m, 2H), 7.08-7.04 (m, 3H), 6.96-6.91 (m, 3H), 6.50 (d, 1H), 5.11-5.08 (m, 1H), 4.11-4.00 (m, 2H), 3.93 -3.90 (m, 4H), 2.78-2.76 (m, 2H), 2.54-2.51 (m, 5H), 2.27-2.20 (m, 2H), 1.78-1.50 (m, 8H), 1.48-0.95 (m, 2H).

Example 5: ( R )-6-(3-(6-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl)-6-azaspiro[3.4]oct-2-yl-2-hydroxy-2 Preparation of ,2-bis(thiophen-2-yl)acetate ( 5 )

The preparation method is the same as in Example 1, except that 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo[3.2 .1] Tert-butyl octane-8-carboxylate to obtain the title compound 5 .

LC-MS: m/z 773.21 [M+H] ⁺ .

¹ H NMR(300MHZ,DMSO- d ₆ ) δ 10.34(br,1H), 8.21(s,1H), 8.12(d,1H), 7.59(s,1H), 7.46(t,2H), 7.38(s , 2H), 7.08-7.05 (m, 3H), 6.99-6.92 (m, 3H), 6.47 (d, 1H), 5.20-4.80 (m, 2H), 3.90-3.80 (m, 4H), 2.72-2.60 (m, 2H), 2.52-2.40 (m, 10H), 2.12-1.90 (m, 2H), 1.81-1.72 (m, 5H).

Example 6: 2-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[ d ]thiazole-3( 2H )-yl)propyl)-2-azabicyclo[2.2.1]hept-5-yl-2-hydroxyl Preparation of -2,2-bis(thiophen-2-yl)acetate ( 6)

The preparation method is the same as in Example 1, except that 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo [3.2.1] Tertiary butyl octane-8-carboxylate to obtain the title compound 6 .

LC-MS: m/z 759.19 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.40 (br, 1H), 8.25 (s, 1H), 8.14 (d, 1H), 7.55 (s, 1H), 7.47 (s, 2H), 7.30 (t ,2H),7.09-7.04(m,3H),6.99-6.89(m,3H),6.46(d,1H),5.15-5.12(m,1H),4.72-4.69(m,1H),3.97-3.80 (m,4H),3.17(s,1H),2.72-2.70(m,3H),2.52-2.30(m,6H),2.25-1.98(m,2H),1.71-1.68(m,2H),1.25 -1.22(m,3H).

Example 7: 8-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[ d ]thiazole-3-(2 H )-yl)propyl)-1-oxa-8-azaspiro[4.5]dec-3-yl Preparation of -2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 7)

The preparation method is the same as in Example 1, except that 3-hydroxy-1-oxa-8-azaspiro[4,5]decane-8-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy- 8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, to obtain the title compound 7 .

LC-MS: m/z 803.22 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.34 (br, 1H), 8.20 (s, 1H), 8.12 (d, 1H), 7.60 (s, 1H), 7.49-7.46 (m, 2H), 7.35 (s, 2H), 7.09-7.03 (m, 3H), 6.99-6.95 (m, 2H), 6.92 (d, 1H), 6.47 (d, 1H), 5.30 (s, 1H), 5.13 (s, 1H) ), 3.95-3.88 (m, 5H), 3.73 (d, 1H), 2.74 (s, 2H), 2.32-2.18 (m, 7H), 1.99-1.89 (m, 1H), 1.76-1.71 (m, 3H) ), 1.45-1.38 (m, 5H).

Example 8: 7-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[ d ]thiazole-3(2 H )-yl)propyl)-7-azaspiro[3.5]non-1-yl-2-hydroxy-2 Preparation of ,2-bis(thiophen-2-yl)acetate ( 8 )

The preparation method is the same as in Example 1, except that 1-hydroxy-7-azaspiro[1-3]nonane-7-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo [3.2.1] Tertiary butyl octane-8-carboxylate to obtain the title compound 8 .

LC-MS: m/z 787.22 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.34 (br, 1H), 8.19 (s, 1H), 8.12 (d, 1H), 7.55 (s, 1H), 7.46 (t, 2H), 7.30 (s) , 2H), 7.10-7.04 (m, 3H), 7.00-6.89 (m, 3H), 6.47 (d, 1H), 5.10 (s, 2H), 4.71 (s, 1H), 3.92 (s, 2H), 3.84 (s, 2H), 2.71 (s, 2H), 2.27-2.18 (m, 5H), 1.95-1.89 (m, 3H), 1.73-1.59 (m, 4H), 1.40-1.31 (m, 4H).

Example 9: ( R )-6-(3-(5-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-6-azaspiro[3.4]oct-2-yl-2- Preparation of hydroxy-2,2-bis(thiophen-2-yl)acetate ( 9)

Step 1: Preparation of 4-((3-hydroxypropyl)amino)-3-nitrobenzonitrile ( 9a)

At room temperature, 4-fluoro-3-nitrobenzonitrile (1.00g, 6.02mmol) was dissolved in THF (5mL), and 3-aminopropan-1-ol (525mg, 7.04 mmol) and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added to the reaction, extracted with EA (2 x 20 mL), the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 1.20 g of the title compound was obtained as a yellow solid with a yield of 90.2%.

LC-MS: m/z 222.08 [M+H] ⁺ .

Step 2: Preparation of 3-amino-4-((3-hydroxypropyl)amino)benzonitrile ( 9b)

At room temperature, 4-((3-hydroxypropyl)amino)-3-nitrobenzonitrile (2.00g, 9.05mmol) was dissolved in ethanol (30mL), and Pd/C (10% wt, 300 mg), stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 1.5 g of the title compound as a brown solid with a yield of 86.7%.

LC-MS: m/z 192.11 [M+H] ⁺ .

Step 3: Preparation of 1-(3-hydroxypropyl)-1 H -benzo[d][1,2,3]triazole-5-carbonitrile ( 9c )

At room temperature, 3-amino-4-((3-hydroxypropyl)amino)benzonitrile (1.5g, 7.85mmol) was suspended in 5N HCl (16mL) and added to the above reaction solution at 0°C _{An aqueous solution (6 mL) of NaNO 2} (813 mg, 11.8 mmol) was added in portions, and stirring was continued for 4 hours. Water (30 mL) was added to the reaction solution, extracted with EA (3 x 30 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.20 g of the title compound as a brown solid , The yield is 75.7%.

LC-MS: m/z 203.09 [M+H] ⁺ .

Step 4: Preparation of 1-(3-hydroxypropyl)-1 H -benzo[ d ][1,2,3]triazole-5-carbaldehyde ( 9d )

Dissolve 1-(3-hydroxypropyl)-1 H -benzo[ d ][1,2,3]triazole-5-carbonitrile (900mg, 4.46mmol) in toluene (20mL) at room temperature At 0°C, 1 mol/L of diisobutylaluminum hydride in toluene solution (6.70 mL, 6.70 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was quenched by adding 1N HCl (10 mL), extracted with DCM (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase DCM/MeOH=50:1-10:1) to obtain 300 mg of the title compound as a brown-yellow solid, with a yield of 32.9%.

LC-MS: m/z 206.09 [M+H] ⁺ .

Step 5: Preparation of 3-(5-methanyl-1 H -benzo[ d ][1,2,3]triazol-1-yl)propyl methanesulfonate ( 9e )

At room temperature, combine 1-(3-hydroxypropyl)-1 H -benzo[ d ][1,2,3]triazole-5-carbaldehyde (100mg, 0.488mmol) and TEA (0.135mL, 0.976mmol) ) Was dissolved in DCM (5 mL), and methylsulfonyl chloride (0.0401 mL, 0.537 mmol) was added dropwise to the reaction solution at 0°C, and stirring was continued for 2 h. The reaction solution was diluted with DCM (10mL), washed with saturated sodium bicarbonate solution (10mL), washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 120mg of the title compound as a yellow solid. The yield was 86.9%.

Step 6: 2-(2-Hydroxy-2,2-bis(thiophen-2-yl)acetoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester ( 9f ) Preparation

At room temperature, the methyl 2-hydroxy-2,2-bis(thiophen-2-yl)acetate (1.02g, 4.00mmol) and 2-hydroxy-6-azaspiro[3.4]octane-6-carboxy Tertiary butyl ester (Nanjing Medicine Stone) (1.00 g, 4.41 mmol) was dissolved in 20 mL of toluene, sodium methoxide (86.5 mg, 1.61 mmol) was added to the reaction solution, and the reaction solution was heated to 90° C. and stirred overnight. 50 mL of water was added to the reaction solution, extracted with EA (2 x 20 mL), the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=10:1-5:1) to obtain 700 mg of the title compound as a yellow oil, with a yield of 38.9%.

LC-MS: m/z 450.13 [M+H] ⁺ .

Step 7: Preparation of 6-azaspiro[3.4]oct-2-yl-2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 9g )

Add 2-(2-hydroxy-2,2-bis(thiophen-2-yl)acetoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (650mg, 1.45mmol ) Was dissolved in DCM (10 mL), 6 mL of 4M hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 3 h. Add 10 mL of saturated sodium bicarbonate solution, extract with DCM (10 mL x 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 500 mg of the title compound as a blue-black oil with a yield of 99.0%.

LC-MS: m/z 350.08 [M+H] ⁺ .

Step 8: 6-(3-(5-Methanoyl-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-6-azaspiro[3.4]octane Preparation of -2-yl-2-hydroxy-2,2-bis(thiophen-2-yl)ethyl acetate ( 9h)

At room temperature, 6-azaspiro[3.4]oct-2-yl-2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 9g ) (300mg, 0.860mmol), 3- (5-methanyl-1H-benzo[d][1,2,3]triazol-1-yl)propyl methanesulfonate ( 9e ) (268mg, 0.946mmol), DIEA (166mg, 1.29mmol) ) And KI (357 mg, 2.15 mmol) were dissolved in DMF (10 mL), and the reaction solution was heated to 65° C. and stirred for 3 hours. The reaction solution was diluted by adding 100 mL EA, washed with saturated NaCl solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 183 mg of the title compound as a brown-yellow solid, with a yield of 39.7%.

LC-MS: m/z 537.16 [M+H] ⁺ .

Step 9: ( R )-6-(3-(5-(((2-((tertiary butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1, 2-Dihydroquinolin-5-yl)ethyl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-6-nitrogen Preparation of heterospiro[3.4]octane-2-yl-2-hydroxy-2,2-bis(thiophen-2)-yl)ethyl acetate ( 9i )

At room temperature, 6-(3-(5-methanyl-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-6-azaspiro[3.4 ] Oct-2-yl-2-hydroxy-2,2-bis(thiophen-2-yl) ethyl acetate (183mg, 0.341mmol) and R -5-(2-amino-1-((third butyl (Dimethylsilyl)oxy)ethyl)-8-hydroxyquinolin-2( 1H )-one( 1h )(114mg, 0.341mmol), ZnCl(139mg, 1.02mmol) dissolved in MeOH (10mL) The reaction solution was heated to 55° C. and stirred for 1 hour, NaBH ₃ CN (43.0 mg, 0.682 mmol) was added to the reaction solution, and stirring was continued for 1 hour. The reaction solution was quenched with water, diluted with DCM (50mL), washed with saturated sodium bicarbonate solution (50mL), washed with saturated brine (50mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid 350mg (crude product), directly used in the next reaction.

LC-MS: m/z 855.33 [M+H] ⁺ .

Step 10: ( R )-6-(3-(5-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl) (Amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-6-azaspiro[3.4]oct-2-yl-2-hydroxyl Preparation of -2,2-bis(thiophen-2-yl)acetate ( 9).

At room temperature, add ( R )-6-(3-(5-(((2-((tertiary butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo- 1,2-Dihydroquinolin-5-yl)ethyl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-6 -Azaspiro[3.4]octane-2-yl-2-hydroxy-2,2-bis(thiophen-2)-yl)ethyl acetate (300mg, 0.351mmol) was dissolved in THF (10mL) and added to the reaction solution ET ₃ N.3HF (283 mg, 1.76 mmol) was added to it. Stir overnight at room temperature. Pour off the supernatant, add 10 mL of acetonitrile, stir for 1 hour, filter, collect the filter cake, and prepare liquid phase separation by high pressure (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, Gradient: 10%-40%), 30 min, 23 mg of the title compound was obtained as an off-white solid, the yield was 8.83%.

LC-MS: m/z 741.25 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO- d ₆ ) δ 10.30(br,1H), 8.22(s,1H), 8.10(d, J =9.9Hz,1H), 7.94(s,1H), 7.77(d, J =8.5Hz,1H),7.53-7.43(m,3H),7.08-6.88(m,6H),6.42(d, J =9.9Hz,1H),5.10-4.94(m,2H),4.70-4.69( m, 2H), 3.95 (s, 2H), 2.78-2.72 (m, 2H), 2.54 (m, 1H), 2.49-2.26 (m, 7H), 2.01-1.99 (m, 4H), 1.80-1.75 ( m,2H).

Example 10: 2-(3-)5-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-2-azabicyclo[2.2.1]heptan-5-yl- Preparation of 2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 10 )

The preparation method is the same as in Example 9, except that 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 2-hydroxy-6-azaspiro And [3.4] octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 10 .

LC-MS: m/z 726.86 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO- d ₆ ) δ 8.22(s,2H), 8.14(d, J =9.9Hz,1H),7.99(s,1H),7.81(d, J =8.5Hz,1H), 7.57(dd, J =8.6,1.4Hz,1H),7.49(dd, J =5.0,1.3Hz,2H),7.10(td, J =4.6,2.2Hz,3H),7.01(ddd, J =4.9, 3.6, 1.2Hz, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.45 (d, J = 9.9 Hz, 1H), 5.15 (dd, J = 7.8, 4.6 Hz, 1H), 4.72 (d, J =6.2Hz,3H),4.01(s,2H),2.85-2.68(m,3H),2.46-2.35(m,2H),2.31(dt, J =11.8,7.0Hz,1H),2.17(dt , J =13.6,4.2Hz,1H),2.07-1.95(m,3H),1.52(d, J =9.8Hz,1H),1.44(d, J =9.7Hz,1H),1.30-1.22(m, 2H).

Example 11: ( R )-6-((3-(5-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Methyl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)(methyl)amino)spiro[3.3]heptan-2-yl Preparation of -2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 11)

The preparation method is the same as in Example 9, except that tertiary butyl (6-hydroxyspiro[3.3]hept-2-yl)(methyl)aminocarboxylate ( 3b ) is used instead of 2-hydroxy-6-azaspiro [3.4] Octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 11 .

LC-MS: m/z 755.26 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO- d ₆ ) δ 10.31(s,1H), 8.21(s,1H), 8.13(d, J =10.1Hz,1H), 7.97(s,1H), 7.81(d, J =8.6Hz,1H),7.59-7.46(m,3H),7.28(s,1H),7.12-7.06(m,3H),7.04-6.90(m,3H),6.44(d, J =9.7Hz, 1H), 5.12(s, 1H), 4.96-4.87(m, 1H), 4.70(t, J = 6.6Hz, 2H), 3.96(s, 2H), 2.74(dd, J =10.7, 6.1Hz, 2H ), 2.57(d, J =2.3Hz,2H),2.27(s,2H),2.11(s,2H),2.04(s,5H),1.97(s,5H),1.66(t, J =9.5Hz ,2H).

Example 12: 8-(3-(5-((((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Yl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-1-oxa-8-azaspiro[4.5]dec- Preparation of 3-yl-2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 12)

The preparation method is the same as in Example 9, except that 4-hydroxy-2-oxo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (Shanghai Bi De) is used instead of 2-hydroxy-6- Azaspiro[3.4]octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 12 .

LC-MS: m/z 771.26 [M+H] ⁺ .

¹ H NMR(300MHz,DMSO- d ₆ ) δ 10.20(br,1H), 8.22(s,1H), 8.10(d, J =9.9Hz,1H), 7.94(s,1H), 7.78(d, J =8.5Hz,1H),7.54-7.45(m,3H),7.08-6.88(m,6H),6.41(d, J =9.9Hz,1H),5.28-5.10(m,2H),4.70-4.68( m, 2H), 3.94-3.55 (m, 7H), 2.73-2.70 (m, 2H), 2.28-1.91 (m, 8H), 1.74-1.70 (m, 1H), 2.44-1.22 (m, 4H).

Example 13: 2-(3-(5-((((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Yl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-5-oxa-2-azaspiro[3.4]octyl Preparation of -7-yl-2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 13)

Step 1: Preparation of 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester ( 13a)

At room temperature, 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (1.00g, 4.41mmol) was dissolved in methanol (20mL), and At 0°C, sodium borohydride (502 mg, 13.2 mmol) was added in portions. Stir at 0°C for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, extracted with EA (30 mL x 3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oil 1.00g crude product of the title compound was used directly in the next reaction.

LC-MS: m/z 230.13 [M+H] ⁺ .

The other steps are the same as the preparation method of Example 9, except that 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (13a ) is used instead of 2-hydroxy-6 -Azaspiro[3.4]octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 13 .

LC-MS: m/z 775.19 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 10.28(br,1H), 8.18(s,1H), 8.11(d,1H), 7.96(s,1H), 7.79(d,1H), 7.54(d ,1H),7.48(t,2H),7.11-7.04(m,3H),7.02-6.96(m,2H),6.92(d,1H),6.44(d,1H),5.34(s,1H), 5.12(s,1H), 4.68(t,2H), 4.00-3.88(m,3H), 3.72(d,1H), 3.26(s,2H), 3.00(d,1H), 2.91(d,1H) , 2.89-2.66 (m, 3H), 2.37-2.12 (m, 4H), 2.01-1.81 (m, 3H).

Example 14: ( R )-2-(3-(5-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-1H-benzo[d][1,2,3]triazol-1-yl)propyl)-2-azaspiro[3.5]non-7-yl 2-hydroxy- Preparation of 2,2-bis(thiophen-2-yl)acetate ( 14)

The preparation method is the same as in Example 9, except that 7-hydroxy-2-azaspiro[3-4]nonane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 2-hydroxy-6-azaspiro And [3.4] octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 14 .

LC-MS: m/z 754.92 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO- d ₆ ) δ 10.28(br,1H), 8.19(s,1H), 8.11(d, J =10.0Hz,1H), 7.93(s,1H), 7.78(d, J =8.6Hz,1H),7.52(d, J =8.4Hz,1H),7.47(dd, J =5.1,1.3Hz,2H),7.08-7.04(m,3H),6.98(dd, J =5.1, 3.6Hz, 2H), 6.90 (d, J = 8.1 Hz, 1H), 6.42 (d, J = 9.9 Hz, 1H), 5.12-5.05 (m, 1H), 4.79 (s, 1H), 4.67 (t, J =6.9Hz, 2H), 3.94(s,2H), 2.84(d, J =3.1Hz,4H), 2.74-2.67(m,2H), 2.48-2.33(m,3H),2.02-1.85(m , 3H), 1.66-1.59 (m, 4H), 1.49-1.42 (m, 4H).

Example 15: 2-(3-(5-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-2-azaspiro[3.4]oct-6-yl-2- Preparation of hydroxy-2,2-bis(thiophen-2-yl)acetate ( 15)

The preparation method is the same as in Example 9, except that 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 2-hydroxy-6-azaspiro[ 3.4] Octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 15 .

LC-MS: m/z 741.25 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.23 (s, 2H), 7.92 (d, J = 9.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.39 (t, 2H), 7.28 (d,1H),7.18(s,1H),7.00-6.98(m,3H),6.57(d,1H),5.55-5.30(m,3H),4.70-4.68(m,2H),4.80(t , 2H), 4.56 (s, 1H), 4.24-4.05 (m, 3H), 3.68 (d, 2H), 3.27-3.25 (m, 3H), 2.28-1.80 (m, 7H).

Example 16: ( R )-2-(3-(5-((((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Yl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-2-azaspiro[3.3]hept-6-yl-2 -Hydroxy-2,2-bis(thiophen-2-yl)acetate ( 16 )

The preparation method is the same as in Example 9, except that 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (Shanghai Haohong Biomedical Technology Co., Ltd.) is used instead of 2-hydroxy-6 -Azaspiro[3.4]octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 16 .

LC-MS: m/z 727.23 [M+H] ⁺ .

¹ H NMR(300MHz,DMSO- d ₆ ) δ 10.31(br,1H), 8.26(s,1H), 8.15(d, J =9.9Hz,1H), 8.01(s,1H), 7.833(d, J =8.5Hz,1H),7.55(dd, J =8.6,1.4Hz,1H),7.44(dd, J =5.0,1.3Hz,2H),7.15-7.08(m,3H),6.96(ddd, J = 4.9, 3.6, 1.2 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.44 (d, J = 9.9 Hz, 1H), 5.10-4.73 (m, 2H), 3.96-3.83 (m, 2H) ), 2.86-2.66 (m, 2H), 2.60-2.43 (m, 3H), 2.42-2.28 (m, 3H), 2.10-1.80 (m, 6H), 1.77 (t, 4H).

Example 17: 2-(3-(5-((((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Yl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-2-azabicyclo[2.2.1]heptyl-6- Preparation of 2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 17)

The preparation method is the same as in Example 9, except that 6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 2-hydroxy-6-azaspiro [3.4] Octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 17 .

LC-MS: m/z 727.23 [M+H] ⁺ .

¹ H NMR(300MHz,DMSO- d ₆ ) δ 10.33(br,1H), 8.21(s,1H), 8.14(d,1H), 7.95(s,1H), 7.76(d,1H), 7.54(d ,1H),7.46(d,1H),7.33-7.16(m,1H),7.09-7.02(m,3H),6.96(dd,2H),6.88(d,1H),6.43(d,1H), 5.56-5.27(m,2H),5.12-4.62(m,4H),4.57-4.33(m,2H),4.22-3.14(m,3H),2.70-2.31(m,3H),2.28-2.19(m , 2H), 1.82-1.41 (m, 2H).

Example 18: (1-(3-(5-((((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) (Ethyl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propylpiperidin-3-yl)2-hydroxy-2,2-di (Thien-2-yl) acetate ( 18 ) preparation

The preparation method is the same as in Example 9, except that 3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (Shanghai Bide) is used instead of 2-hydroxy-6-azaspiro[3.4]octane 6 -Tert-butyl carboxylate (Nanjing Yaoshi), to obtain the title compound 18 .

LC-MS: m/z 729.25 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 10.30(br,1H), 8.18(s,1H), 8.13(d,1H), 7.95(s,1H), 7.76(d,1H), 7.54(d ,1H),7.46(dd, J =5.1,1.3Hz,1H),7.33-7.14(m, 1H),7.06-7.02(m,3H),6.96(dd, J =5.1,3.6Hz,2H), 6.92(d,1H),6.43(d,1H),5.13-5.09(m,1H),4.13-3.98(m,2H),3.92-3.86(m,4H),2.76-2.66(m,2H), 2.58-2.50 (m, 5H), 2.28-2.21 (m, 2H), 1.80-1.53 (m, 6H), 1.48-1.01 (m, 2H).

Example 19: ( R )-3-(3-(5-((((2-hydroxy-2-(8-hydroxy-2-carbonyl-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-3-azaspiro[5.5]undecane-9-yl- Preparation of 2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 19 )

The preparation method is the same as in Example 9, except that 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 2-hydroxy-6-azaspiro[ 3.4] Octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 19 .

LC-MS: m/z 783.29 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 10.29(br,1H), 8.16(s,1H), 8.10(d,1H), 7.95(s,1H), 7.77(d,1H), 7.51(d ,1H),7.43(dd, J =5.1,1.3Hz,1H),7.33-7.13(m,1H),7.06-7.02(m,3H),6.99(dd, J =5.1,3.6Hz,2H), 6.91(d, J =8.1Hz,1H),6.40(d, J =9.9Hz,1H),5.52-5.19(m,2H),4.73-4.32(m,3H),4.21-3.70(m,3H) ,3.65-3.21(m,4H),3.11-2.85(m,4H),2.66-2.10(m,6H),2.00-1.20(m,8H).

Example 20: 2-(3-(5-((((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Yl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-2-azabicyclo[2.2.2]octyl-5- Preparation of 2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 20)

The preparation method is the same as in Example 9, except that 5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 2-hydroxy-6-azaspiro [3.4] Octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 20 .

LC-MS: m/z 741.25 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO- d ₆ ) δ 10.26(br,1H), 8.18(s,1H), 8.13(d, J =10.0Hz,1H), 7.94(s,1H), 7.76(d, J =8.6Hz,1H),7.55(d, J =8.4Hz,1H),7.44(dd, J =5.1,1.3Hz,1H),7.33-7.16(m,1H),7.20-7.05(m,3H) ,6.99(dd, J =5.1,3.6Hz,2H),6.92(d, J =8.1Hz,1H),6.44(d, J =9.9Hz,1H),5.26-5.15(m,2H),4.72( d,3H),4.13(s,2H),2.95-2.66(m,3H),2.44-2.35(m,3H),2.17(t,1H),2.10-1.94(m,4H),1.68-1.19( m,6H).

Example 21: 3-(3-(5-((((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl (Yl)amino)methyl)-1 H -benzo[d][1,2,3]triazol-1-yl)propyl)-3-azabicyclo[3.1.1]heptyl-6- Preparation of 2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 21)

The preparation method is the same as in Example 9, except that 6-hydroxy-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (Jiangsu Aikang) is used instead of 2-hydroxy-6-aza Spiro[3.4]octane 6-carboxylic acid tert-butyl ester (Nanjing Yaoshi), to obtain the title compound 21 .

LC-MS: m/z 727.23 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 10.31(br,1H), 8.17(s,1H), 8.12(d,1H), 7.95(s,1H), 7.77(d,1H), 7.54(d ,1H),7.46(dd, J =5.1,1.3Hz,1H),7.31-7.15(m,1H),7.10-7.03(m,3H),6.97(dd, J =5.1,3.6Hz,2H), 6.89(d,1H),6.45(d,1H),5.73-5.26(m,4H),5.12-4.55(m,2H),4.74-4.35(m,3H),4.21-4.02(m,3H), 4.00-3.72 (m, 2H), 2.76-2.22 (m, 3H), 1.82-1.25 (m, 5H).

Example 22: 2-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[d]thiazol-3( 2H )-yl)propyl)-2-azaspiro[3.4]oct-6-yl-2-hydroxy-2 Preparation of ,2-bis(thiophen-2-yl)acetate ( 22 )

The preparation method is the same as in Example 1, except that 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo[3.2 .1] Tertiary butyl octane-8-carboxylate to obtain the title compound 22 .

LC-MS: m/z 773.21 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.43 (br, 1H), 8.31 (s, 1H), 8.16 (d, 1H), 7.54 (s, 1H), 7.46 (s, 2H), 7.31 (t ,2H),7.12-6.80(m,6H),6.42(d,1H),5.25-5.10(m,3H),4.75-4.60(m,3H),4.50-3.80(m,4H),3.56-3.28 (m, 2H), 2.72-2.50 (m, 4H), 2.25-1.98 (m, 3H), 1.98-1.22 (m, 6H).

Example 23: 2-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[d]thiazol-3( 2H )-yl)propyl)-2-azabicyclo[2.2.1]hepta-6-yl-2-hydroxyl Preparation of -2,2-bis(thiophen-2-yl)acetate ( 23)

The preparation method is the same as in Example 1, except that 6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo [3.2.1] Tertiary butyl octane-8-carboxylate to obtain the title compound 23 .

LC-MS: m/z 759.19 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.40 (br, 1H), 8.33 (s, 1H), 8.17 (d, 1H), 7.56 (s, 1H), 7.44 (s, 2H), 7.33 (t ,2H),7.22-6.69(m,6H),6.40(d,1H),5.55-5.23(m,2H),5.10-4.60(m,4H),4.55-4.32(m,2H),4.20-3.10 (m, 5H), 2.72-2.32 (m, 3H), 2.30-2.20 (m, 2H), 1.80-1.40 (m, 2H).

Example 24: 3-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[d]thiazol-3( 2H )-yl)propyl)-3-azabicyclo[3.1.1]hepta-6-yl-2-hydroxyl Preparation of -2,2-bis(thiophen-2-yl)acetate ( 24)

The preparation method is the same as in Example 1, except that 6-hydroxy-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (Jiangsu Aikang) is used instead of 3-hydroxy-8-aza Bicyclo[3.2.1]octane-8-tert-butyl carboxylate yielded the title compound 24 .

LC-MS: m/z 759.19 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.38 (br, 1H), 8.28 (s, 1H), 8.16 (d, 1H), 7.62 (s, 1H), 7.40 (s, 2H), 7.35 to 7.32 (m, 2H), 7.30-6.60 (m, 6H), 6.40 (d, 1H), 5.83-5.20 (m, 4H), 5.13-4.58 (m, 2H), 4.73-4.33 (m, 3H), 4.20 -4.06 (m, 3H), 4.00-3.70 (m, 2H), 2.78-2.20 (m, 3H), 1.80-1.40 (m, 3H).

Example 25: ( R )-3-(3-(6-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[d]thiazol-3( 2H )-yl)propyl)-3-azaspiro[5.5]undecane-9-yl-2-hydroxyl Preparation of -2,2-bis(thiophen-2-yl)acetate ( 25)

25

The preparation method is the same as in Example 1, except that 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo[ 3.2.1] Tert-butyl octane-8-carboxylate to obtain the title compound 25 .

LC-MS: m/z 815.25 [M+H] ⁺ .

¹ H NMR(300MHz, DMSO- d ₆ ) δ 10.42(br,1H), 8.30(s,1H), 8.15(d,1H), 7.53(s,1H), 7.49(s,2H), 7.33(t ,2H),7.22-6.93(m,6H),6.40(d,1H),5.52-5.20(m,2H),4.75-4.35(m,3H),4.20-3.73(m,3H),3.66-3.20 (m, 4H), 2.30-2.80 (m, 3H), 2.63-2.08 (m, 6H), 1.99-1.18 (m, 8H).

Example 26: 2-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[d]thiazol-3( 2H )-yl)propyl)-5-oxa-2-azaspiro[3.4]octane-7-yl Preparation of -2-hydroxy-2,2-bis(thiophen-2-yl)acetate ( 26)

The preparation method is the same as in Example 1, except that 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester ( 13a ) is used instead of 3-hydroxy-8-nitrogen Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, to obtain the title compound 26 .

LC-MS: m/z 775.19 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.43 (br, 1H), 8.32 (s, 1H), 8.15 (d, 1H), 7.58 (s, 1H), 7.42 (s, 2H), 7.30-7.26 (m, 2H), 7.24-6.60 (m, 6H), 6.37 (d, 1H), 5.35 (s, 1H), 5.10 (s, 1H), 4.60-6.55 (m, 2H), 4.10-3.80 (m ,3H),3.72-3.30(m,3H),3.05(d,1H),2.95(d,1H),2.90-2.50(m,3H),2.38-2.10(m,4H),1.92-1.60(m ,2H).

Example 27: ( R )-2-(3-(6-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[d]thiazol-3( 2H )-yl)propyl)-2-azaspiro[3.5]non-7-yl-2-hydroxy-2 Preparation of ,2-bis(thiophen-2-yl)acetate ( 27 )

The preparation method is the same as in Example 1, except that 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo[3.2 .1] tert-butyl octane-8-carboxylate to obtain the title compound 27 .

LC-MS: m/z 787.22 [M+H] ⁺ .

¹ H NMR(300MHz,DMSO- d ₆ ) δ 10.42(br,1H),8.35(s,1H),8.17(d,1H),7.55(s,1H),7.46(s,2H),7.33(t ,2H),7.20-6.60(m,6H),6.38(d,1H),5.22-5.15(m,1H),4.73(s,1H),4.70-4.60(m,2H),3.99(s,2H) ), 2.80-2.60 (m, 7H), 2.33-2.30 (m, 2H), 1.99-1.85 (m, 2H), 1.70-1.42 (m, 8H).

Example 28: 2-(3-(6-(((( R )-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl )Amino)methyl)-2-oxobenzo[d]thiazol-3( 2H )-yl)propyl)-2-azabicyclo[2.2.2]oct-5-yl-2-hydroxyl Preparation of -2,2-bis(thiophen-2-yl)acetate ( 28)

The preparation method is the same as in Example 1, except that 5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (Nanjing Yaoshi) is used instead of 3-hydroxy-8-azabicyclo [3.2.1] Tertiary butyl octane-8-carboxylate to obtain the title compound 28 .

LC-MS: m/z 773.21 [M+H] ⁺ .

¹ H NMR(300MHz,DMSO- d ₆ ) δ 10.47(br,1H),8.35(s,1H),8.15(d,1H),7.55(s,1H),7.38(s,2H),7.35(t ,2H),7.30-6.65(m,6H),6.37(d,1H),5.20-5.14(m,1H),4.70(d,3H),4.11(s,2H),2.93-2.68(m,3H) ), 2.45-2.35 (m, 3H), 2.18 (dt, 1H), 2.10-1.95 (m, 3H), 1.69-1.20 (m, 4H).

Biological test case

Test Example 1: Test of the binding activity of the compound of the present invention to human muscarinic M _{3 receptor}

The study on the binding activity of the compounds of the present invention to human muscarinic receptor 3 (hM _{3 ) was carried out using hM 3} membranes (PerkinElmer, RBHM3M400UA) prepared from CHO-K1 cells.

The total reaction system 500 μ L, containing 10mM HEPES (Sigma, H3375), reaction buffer, 1mM MgCl ₂ was added to 95 μ L 96 deep well plate (PerkinElmer, P-DW-11 -C). Subsequently compound 5 μ (containing 1% DMSO) is diluted after L added to the reaction system, the shock plate and mix 5 minutes. 0.25 μ L were added to each well of hM ₃ membrane (1U / μ L) and 300 μ L reaction buffer to a 96-well plate, the shock plate and mix 5 minutes. The reaction buffer and the final concentration of 02nM 3H- of scopolamine methyl chloride (PerkinElmer, NET636250UC) a mixture of 100 μ L was added to the reaction system, shock plate for 5 minutes and incubated at room temperature for 2 hours. (408727 Sigma,) 150 μ L process UNIFILTER-96 GF / C plates (PerkinElmer, 6005174), 4 ℃ incubated with 0.5% polyethyleneimine for 1 hour. Followed by 50 μ L wash with suction Universal Harvester (Perkin Elmer, UNIFILTER- 96) ( final concentration 500mMTris-base and the final concentration of 1.54M NaCl) wash UNIFILTER-96GF / C plate twice. The incubation buffer was transferred to a good response UNIFILTER-96GF / C plate, each well was added 900 μ L wash, rinsed four times with Universal Harvester, washed the UNIFILTER-96 GF / C plate 55 ℃ dried for 10 minutes. Then each well was added 40 μ L ULTIMA GOLD scintillation fluid (PerkinElmer, 77-16061), using Top Count (PerkinElmer, NTX) readings.

data analysis:

Use Xlfit 5.3.1 software to process the data, the X-axis is the compound concentration, and the Y-axis is the CPM value.

Press Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope)) formula to get IC ₅₀ value.

X: compound concentration; Y: inhibition rate; HillSlope: slope; Top: maximum inhibition rate; Bottom: minimum inhibition rate.

The binding activity of the compounds of the present invention to human muscarinic M ₃ receptors is shown in Table 1 below.

Table 1. The compound of the present invention has binding activity _{to human muscarinic M 3 receptor}

Further, Examples 15 to 17 and 20 to 28 in conjunction hM ₃ IC ₅₀ less than 10 nM, Examples 18 and 19 in conjunction hM ₃ IC ₅₀ less than 100nM.

Conclusion: The compound of the present invention has significant binding activity _{to human muscarinic M 3 receptor.}

Test Example 2: Test of the agonistic activity of the compound of the present invention on human adrenergic β _{2 receptor}

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

CHO cells (Pharmaron) (Flp-In-CHO-ADR β ₂ ) stably expressing human adrenergic β ₂ receptor (h β ₂ ) were cultured at 37°C and 5% CO ₂ containing Ham's F12K medium (Hyclone, SH30526.01) + 10% fetal calf serum (Gibco, 10999141) + 1 × penicillin-streptomycin (Gibco, 15140122) +800 μ g / mL hygromycin (Inviviogen, ant-hg-5 ) complete medium, After culturing to reach 90-100% confluence, digest with TrypLE (Gibco, 12604021), then resuspend the cells in complete medium and inoculate them in a 384-well cell culture plate (Perkin Elmer, 6007680) at a density of each well 8×103 cells, then incubate overnight. , 0.1% BSA (Perkin Elmer, CR84-100), 20mM diluted compound containing 1 × HBSS (Gibco, 14025092) HEPES (Gibco, 15630080) and 500 μ M IBMX (Sigma, I5879 ) of assay buffer gradient. After the cells were incubated overnight, medium was discarded and the culture plates, compound 15 μ L assay buffer and 5 μ l added to each well, incubated for 30 minutes 37 ℃. Using the LANCE UltraecAMP Kit (Perkin Elmer, TRF0263), add 10 μl Eu-cAMP tracer to each well, then add 10 μl Ulight-anti-cAMP, and centrifuge the reaction plate at 200g at room temperature for 30 seconds, 25°C after standing for 1 hour, using the Envision (Perkin Elmer, 2203-1060) collecting data, using GraphPad nonlinear fit formula compound EC _50.

According to Y=Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope)) formula to get the EC ₅₀ value.

X: compound concentration; Y: activation rate; HillSlope: slope; Top: maximum inhibition rate; Bottom: minimum inhibition rate.

The agonistic activity of the compound of the present invention on the human adrenergic receptor β ₂ receptor is shown in Table 2 below.

Table 2. The agonistic activity of the compounds of the present invention on human adrenergic receptor β _{2 receptors}

Further, Examples 15,16,22 and 26 h β agonist embodiment ₂ EC ₅₀ less than 10 nM; Example 1,4,8,17 ~ 21, 23 ~ 25, 27 and 28 excited h β ₂ EC ₅₀ less than 100nM.

Conclusion: The compound of the present invention has significant agonistic activity on human adrenergic receptor β _{2 receptor.}

Test Example 3: Dissociation time half-life test of the compound of the present invention on human muscarinic M _{3 receptor}

The study on the binding activity of the compounds of the present invention to human muscarinic receptor 3 (hM _{3 ) was carried out using hM 3} membranes (PerkinElmer, RBHM3M400UA) prepared from CHO-K1 cells.

The total reaction system 500 μ L, containing 10mM HEPES (Sigma, H3375), reaction buffer, 1mM MgCl ₂ was added to 195 μ L 96 deep well plate (PerkinElmer, P-DW-11 -C). The compound is then diluted with 5 μ L (containing 1% DMSO, at a concentration of 10 times the Ki values of test compounds) was added to the reaction system, 500rpm the shock plate and mix 5 minutes. Then each well is added 1 μ L membrane hM ₃ (1U / μ L) and 299 μ L reaction buffer to a 96 well plate, 500rpm the shock plate and mix 5 minutes. 5 μ L was then added to a final concentration of 10nM 3H- of scopolamine methyl chloride (PerkinElmer, NET636250UC) to the reaction system, shock plate 500 rpm for 5 minutes each at room temperature for 5 minutes, 30 minutes, 1 hour, 2 hours, 3 hours , 4 hours, 5 hours, 6 hours, 22 hours, 24 hours. (408727 Sigma,) 150 μ L process UNIFILTER-96 GF / C plates (PerkinElmer, 6005174), 4 ℃ incubated with 0.5% polyethyleneimine for 1 hour. Then use Universal Harvester (Perkin Elmer, UNIFILTER-96) to absorb 50 mL of washing solution (final concentration of 500mM Tris-base and final concentration of 1.54M NaCl) to wash UNIFILTER-96GF/C plate twice. The incubation buffer was transferred to a good response UNIFILTER-96GF / C plate, each well was added 900 μ L wash, rinsed four times with Universal Harvester, washed the UNIFILTER-96 GF / C plate 55 ℃ dried for 10 minutes. Then each well was added 40 μ L ULTIMA GOLD scintillation fluid (PerkinElmer, 77-16061), using Top Count (PerkinElmer, NTX) readings. The compound half-life (HalfLife, t _1/2 ) was calculated using the GraphPad nonlinear fitting formula.

The dissociation time half-life of the compound of the present invention on human muscarinic receptor 3 (hM ₃ ) is shown in Table 3 below.

Table 3. Dissociation time half-life of the compounds of the present invention on human muscarinic receptor 3 (hM ₃₎

Conclusion: The compound of the present invention has a longer dissociation time and half-life _{for human muscarinic receptor 3 (hM 3 ).}

Test Example 4: Inhibitory effect of the compound of the present invention on acetylcholine chloride-induced bronchoconstriction in guinea pigs

250-400g male guinea pigs were purchased from Beijing Fangyuanyuan, and the experiment was started after 2-3 days of adaptive feeding. / ML solution, diluted times over different doses of the test compound formulated as sterile water for injection with 100 μ g. The compound or solvent to be tested is placed in a nebulization cup and nebulized into an aerosol. The animal is placed in an nebulization exposure box, and the lung function is evaluated after 10 minutes and 45 minutes after nebulization administration.

25min before evaluating lung function, 2% sodium pentobarbital (Merck, P11011) 1.5mL/kg anesthesia. Separate the guinea pig jugular vein, and introduce a venous indwelling needle filled with saline into the vein for intravenous injection of acetylmethylcholine chloride (MCh) (Macklin, M838535); separate the trachea and intubate the trachea with a catheter. After completion, connect A small animal ventilator (Chengdu Taimeng Technology Co., Ltd., HX-100E) is used to ventilate animals with a tidal volume of 10 mL/kg body weight and a breathing rate of 60 breaths/min. The T-shaped connector is connected to the exhalation tube of the ventilator to detect the ventilation pressure (P), the converter is connected to the amplifier, and the computer is connected to collect pressure data (Lab Chart 8). The heating plate maintains the animal's body temperature at 37°C. Before data collection, intraperitoneal injection of sodium pentobarbital (25 mg/kg) was used to inhibit the spontaneous breathing of the animals and stabilize the respiratory baseline. The data collection interface records the changes of P. After collecting the baseline parameters for at least 5 minutes, the animals are injected intravenously with 15ug/kg of MCh. The inhibitory effect of the compound of the present invention on methacholine chloride-induced bronchoconstriction in guinea pigs is obtained by the dose-inhibition rate response curve of tracheal contraction.

The compound is administered by nebulized inhalation, and the dose is expressed as the concentration of the nebulized solution. Before intravenous injection of Mch, the baseline value of P _{base is} collected, and after intravenous injection, the maximum value of P _{peak is} collected.

The airway resistance calculation formula is:

R: resistance value at the collection point; Flow: respiratory flow; Weight: body weight; Tidal volume: tidal volume; Respiratory rate: respiratory frequency; AR: airway resistance value

The calculation formula of the inhibition rate is:

The dose-inhibition rate response curve of tracheal contraction was obtained by fitting the logistic four-parameter equation, and the compound IC ₅₀ value was calculated.

The inhibitory effect of the compound of the present invention on methacholine chloride-induced bronchoconstriction in guinea pigs is shown in Table 4 below.

Table 4. Inhibitory effects of the compounds of the present invention on acetylcholine chloride-induced bronchoconstriction in guinea pigs

Conclusion: The compound of the present invention has a significant inhibitory effect on acetylcholine chloride-induced bronchoconstriction in guinea pigs.

Claims (19)

A compound represented by general formula (I) or its mesosome, racemate, enantiomer, diastereomer, or a mixture thereof, or its prodrug, or its pharmaceutically acceptable salt,

among them, R ¹ is

； R ^1a and R ^1b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or (CH _{2) p} R ^a, the alkyl, alkenyl Group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group optionally further selected from halogen, amine group, nitro group, cyano group, pendant oxy group, hydroxyl group, mercapto group, carboxyl group, ester group, alkane group Group, haloalkyl, OR ^a , SR ^a , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, one of -OC(O)R ^b or -C(O)R ^b Or multiple groups are substituted, provided that R ^1a and R ^{1b are} not hydrogen at the same time; R ^{1c is} selected from hydrogen, hydroxyl, cyano, amino, alkyl, OR ^a , SR ^a or -C(O)NR ^b R ^c ; R ² and R ³ are each independently selected from hydrogen or alkyl; B is selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are further selected from halogen, hydroxy, amino, nitro, Cyano group, pendant oxy group, mercapto group, carboxyl group, ester group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, -(CH ₂ ) _p OR ^a , -C(O)OR ^a , -C(O )R ^b , -NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , -NR ^b S(O) ₂ NR ^b R ^c , -S(O) ₂ NR ^b R ^c ,- OC(O)R ^b or -NR ^b (CH ₂ ) _p R ^c is substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is further selected from halogen, Amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl One or more groups are substituted; A ¹ and A ² are each independently selected from an alkylene group, an alkenylene group or an alkynylene group; the alkylene group, an alkenylene group or an alkynylene group may be further selected from halogen, a hydroxyl group, an amino group, a carboxyl group, and a cyanide group as necessary One of group, nitro group, alkyl group, haloalkyl group, OR ^a , SR ^a , -OC(O)R ^b , -C(O)R ^b , cycloalkyl, heterocyclyl, aryl or heteroaryl Or multiple groups substituted; L ^{1 is} selected from a single bond, -NR ^b -or -O-; L ^{2 is} selected from single bond, -O-, -NR ^b -, -S(O) _m -, -NR ^b C(O)-, -C(O)NR ^b -, -NR ^b C(O)( CH ₂ ) _p O-, -O(CH ₂ ) _p C(O)NR ^b -, -NR ^b (CH ₂ ) _p O-, -O(CH ₂ ) _p NR ^b -, -NR ^b C(O )NR ^c -, -C(O)-, -C(O)O-, -OC(O)-, -S(O) _m NR ^b -, -NR ^b S(O) _m -, -NR ^b S(O) _m NR ^c -, -NR ^b S(O) _m (CH ₂ ) _p S-, -S(CH ₂ ) _p S(O) _m NR ^b -, -NR ^b (CH ₂ ) _p S -, -S(CH ₂ ) _p NR ^b -, -C(O)NR ^b S(O) _m -or -S(O) _m NR ^b C(O)-; Ring C is selected from cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is further selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, pendant oxy, alkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^a ,- C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O) ) (R ^b ) ₂ is substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are further selected from halogen, amine group, nitro group as required One or more of group, cyano group, pendant oxy group, hydroxyl group, mercapto group, carboxyl group, ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Group substitution requirement is,

Not for

,

,

,

Among them, ˙ represents the site connected to O; ^* represents the site connected to A ^1; G is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl may be further selected from hydrogen, halogen, amine, nitro, cyano if necessary Group, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O )R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ are substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group If necessary, the group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic group. One or more groups of aryl, aryl, and heteroaryl; The condition is that when G is a phenyl group, L ^{2 is} not directly connected to it with a -O-, -NHC(O)-, -C(O)NH- or -NHC(O)O- group; R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro , Cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl one or more groups Group replacement Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups; m is 0, 1 or 2; p is an integer from 0 to 6. The compound represented by the general formula (I) of claim 1 or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug, or Its medicinal salt, among them, Ring C is selected from cycloalkyl or heterocyclic group, preferably 5-12 membered spirocycloalkyl, 6-12 membered bridged cycloalkyl, 5-12 membered spiroheterocyclic group, 6-12 membered bridged heterocyclic group, Wherein the cycloalkyl or heterocyclic group is further selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclic group if necessary , Aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC One or more of (O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ Group substitution, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted with one or more selected from halogen, amine group, nitro group, cyano group, pendant oxy group , Hydroxy, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups; R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups; Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups; m is 0, 1, or 2. The compound represented by the general formula (I) of claim 1 or 2 or its mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or prodrug thereof , Or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II),

among them, Ring D is selected from heterocyclic group, preferably 5-12 membered spiro heterocyclic group and 6-12 membered bridged heterocyclic group, wherein the heterocyclic group is further selected from hydrogen, halogen, amine, nitro, cyano Group, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O )R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ are substituted by one or more groups, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group If necessary, the group is further selected from one or more halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl groups. , One or more groups of heterocyclic group, aryl group, heteroaryl group; R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups; Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups; m is 0, 1 or 2; A ¹ , A ² , R ¹ , R ² , R ³ , L ¹ , L ² , G, and B are as defined in claim 1. The compound represented by the general formula (I) in any one of claims 1 to 3 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, B is selected from

,

or

; Better

； among them: R ⁴ a each is independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, ^{alkoxy, -C (O) OR a,} -C (O) R b, - NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , -NR ^b S(O) ₂ NR ^b R ^c , -OC(O)R ^b , or -NR ^b (CH ₂ ) _p R ^c ; wherein the alkyl group and alkoxy group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group as necessary , Substituted by one or more groups of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R ⁵ is independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, alkyl, ^{alkoxy, -C (O) OR a,} -C (O) R b, - NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , NR ^b S(O) ₂ NR ^b R ^c , -OC(O)R ^b , or -NR ^b (CH ₂ ) _p R ^c ; Wherein the alkyl group and alkoxy group are optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, One or more group substitutions of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ^{6 is} selected from hydrogen, halogen, hydroxyl, amino, carboxy, cyano, nitro, alkyl, alkoxy, -C(O)OR ^a , -C(O)R ^b , -NR ^b C(O ) R ^c , -NR ^b S(O) ₂ R ^c , NR ^b S(O) ₂ NR ^b R ^c , -OC(O)R ^b , or -NR ^b (CH ₂ ) _p R ^c ; wherein the alkane The group and alkoxy group are optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkane Substitution of one or more groups of group, heterocyclic group, aryl group, heteroaryl group; M is selected from -C(R ^d )=C(R ^e ), -CR ^d R ^e CR ^d R ^e , -O-, -S-, -OCR ^d R ^e -, -CR ^d R ^e O-,- SCR ^d R ^e - and -CR ^d R ^e S-, wherein, R ^d and R ^e are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, oxo, mercapto, carboxyl, ester Group, alkyl, alkoxy, cycloalkyl, heterocyclyl, -(CH ₂ ) _p OR ^a , -C(O)OR ^a , -C(O)R ^b , -NR ^b C(O)R ^c , -NR ^b S(O) ₂ R ^c , -NR ^b S(O) ₂ NR ^b R ^c , -S(O) ₂ NR ^b R ^c , -OC(O)R ^b or -NR ^b (CH ₂ ) _p R ^c , wherein the alkyl group, alkoxy group, cycloalkyl group and heterocyclic group are optionally further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, pendant oxygen One or more group substitutions of group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups; Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups; n is an integer from 0 to 4; q is an integer from 0 to 4. The compound represented by the general formula (I) of claim 4 or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug, or Its medicinal salt, among them, M is selected from -C(R ^d )=C(R ^e ), -CR ^d R ^e CR ^d R ^e , -O-, -S-, -OCR ^d R ^e -, -CR ^d R ^e O-,- SCR ^d R ^e -and -CR ^d R ^e S-, wherein R ^d and R ^e are each independently selected from hydrogen or alkyl. The compound represented by the general formula (I) in any one of claims 1 to 5 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, B is selected from

,

,

,

,

,

,

,

,

,

with

, Better

with

, Better

. The compound represented by the general formula (I) in any one of claims 1 to 6 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, R ^1a and R ^1b are each independently selected from hydrogen, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3 to 8-membered heterocyclyl, C _5-10 aryl, 3 To 10-membered heteroaryl, C _3-10 cycloalkyl-C _1-6 alkylene or 3 to 10-membered heterocyclyl-C _1-6 alkylene, preferably C _3-7 cycloalkyl, 3 To 6-membered heterocyclyl, C _5-6 aryl and 5 to 6-membered heteroaryl, more preferably 5 to 6-membered heteroaryl, the alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic group , Aryl and heteroaryl are optionally further selected from halogen, hydroxyl, amino, carboxy, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, -OC(O)C _1-6 alkyl, -C(O)C _1-6 alkyl, or -C _3-6 cycloalkoxy One or more groups of is substituted; provided that R ^1a and R ^{1b are} not hydrogen at the same time; R ^{1c is} selected from hydrogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio or -C(O)NH ₂ , preferably hydroxyl. The compound represented by the general formula (I) of any one of claims 1 to 7, or the meso, racemate, enantiomer, diastereomer, or mixture form thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, R ^{1 is} selected from

,

,

,

,

with

, Better

with

, Better

. The compound represented by the general formula (I) of any one of claims 1 to 8 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, G is selected from C _5-10 aryl or 5-10 membered heteroaryl, preferably phenyl and 7-10 membered fused heteroaryl, more preferably phenyl and

, Where ˙ represents the site connected ^{to A 2 and *} represents the site connected to L ^2, Wherein the aryl or heteroaryl group is optionally further selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, Aryl, heteroaryl, -NR ^b R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^a , -C(O)NR ^b R ^c , -NHC( O) R ^b , -S(O) _m R ^b , -S(O) _m NR ^b R ^c , -NHS(O) _m R ^b and -P(O)(R ^b ) ₂ Group substitution, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, pendant oxy group, hydroxyl group, and mercapto group as required , Carboxyl group, ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; X, Y and Z are each independently selected from -N-, -C-, -S-, -O- or -C(O)-, wherein Z is preferably N, and X is preferably N, O, C or S , Y is preferably N, C or -C(O)-; R ^a is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein The alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group as necessary , Ester group, pendant oxy group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; R ^b and R ^c are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl , Heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amine, nitro, cyano , Hydroxy, mercapto, carboxy, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl group substituted by one or more groups; Or R ^b and R ^c together with the atoms to which they are connected form a heterocyclic group, and the heterocyclic group may be further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxy, and ester groups as needed. , Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substituted by one or more groups; m is 0, 1, or 2. The compound represented by the general formula (I) of any one of claims 1 to 9 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, G is selected from

with

； Among them, ˙ represents the site connected ^{to A 2 and *} represents the site connected to L ^2. The compound represented by the general formula (I) in any one of claims 1 to 10, or the meso, racemate, enantiomer, diastereomer, or mixture form thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, L ^{1 is} selected from single bond, -NR ^b -and -O-, preferably single bond and -NR ^b -; R ^{b is} selected from hydrogen, halogen, and alkyl, where the alkyl group is further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxy, ester, pendant oxy, alkyl, and alkoxy if necessary. One or more of the group is substituted by the group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. The compound represented by the general formula (I) in any one of claims 1 to 11 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, among them, L ^{2 is} selected from single bond, -NR ^b -, -S-, -SO ₂ -, -C(O)-, -C(O)O-, -S(O) ₂ NR ^b -, -NR ^b S (O) ₂ -, -NR ^b C(O)(CH ₂ )O-, -O(CH ₂ )C(O)NR ^b -, -NR ^b C(O)NR ^c -and -C(O) NR ^b S(O) ₂ -; preferably single bond, -NH-, -S-, -SO ₂ -, -C(O)-, -NR ^b C(O)NR ^c -and -O(CH ₂ )(CO)NR ^b , preferably a single bond and -O(CH ₂ )(CO)NR ^b ; Wherein, R ^b and R ^c are each independently selected from hydrogen, halogen, and alkyl group, wherein the alkyl group is further selected from halogen, amine group, nitro group, cyano group, hydroxyl group, sulfhydryl group, carboxyl group, ester group, side One or more groups of oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted. The compound represented by the general formula (I) of any one of claims 1 to 12 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, Wherein, A ¹ and A ² are each independently selected from C _1-10 alkylene, preferably C _1-6 alkylene; if necessary, the alkylene is further selected from halogen, hydroxyl, amino, carboxy, cyano Group, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, -OC(O) C _1-6 alkyl, -C(O)C _1-6 alkyl, C _3-6 cycloalkoxy, C _5-6 aryl and C _3-7 cycloalkyl substituted by one or more groups . The compound represented by the general formula (I) of any one of claims 1 to 13 or its meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its prodrug, or its pharmaceutically acceptable salt, wherein the compound is selected from:

A preparation of the compound represented by the general formula (I) in any one of claims 1 to 14 or its meso, racemate, enantiomer, diastereomer, or mixture thereof Form, or its prodrug, or its pharmaceutically acceptable salt method, which comprises the following steps: When -L ¹ -A ¹ -is -CH ₂ -CH ₂ -CH ₂ -and A ² is -CH ₂ -,

1) In the presence of a catalyst and a reducing agent, the compound Ie is reacted with the compound If to obtain the compound Ig, the catalyst is preferably anhydrous zinc chloride, and the reducing agent is preferably sodium cyanoborohydride; 2) In the presence of a catalyst, the compound Ig undergoes deprotection reaction to obtain the compound of general formula (I), the protecting group is preferably TBS, and the catalyst is preferably triethylamine hydrofluoride; Among them, R ¹ , R ² , R ³ , B, G, L ² , and C are as defined in claim 1. A pharmaceutical composition containing the compound represented by the general formula (I) of any one of claims 1 to 14 or its meso, racemate, enantiomer, or diastereomer Body, or the form of a mixture, or a prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A compound represented by the general formula (I) of any one of claims 1 to 14 or its meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its prodrug, or its pharmaceutically acceptable salt or the use of the pharmaceutical composition according to claim 16, which is used in the preparation of muscarinic receptor antagonists and β -adrenergic receptor agonists. A compound represented by the general formula (I) of any one of claims 1 to 14 or its meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its prodrug, or its pharmaceutically acceptable salt or the use of the pharmaceutical composition as claimed in claim 16, which is used in the preparation of prevention and/or treatment of muscarinic receptor and β -adrenergic receptor activity related Drugs for diseases; the diseases are preferably respiratory diseases, such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema. A compound represented by the general formula (I) of any one of claims 1 to 14 or its meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its prodrug, or its pharmaceutically acceptable salt, or the use of the pharmaceutical composition of claim 16 in combination with another or more therapeutic agents, which is used in the preparation of prevention and/or treatment of respiratory diseases such as asthma and chronic obstructive Drugs for lung disease, bronchitis, and emphysema, wherein the other one or more therapeutic agents are preferably selected from PDE4 inhibitors, muscarinic receptor antagonists, corticosteroids and β -adrenergic receptor agonists.