WO2019205983A1

WO2019205983A1 - Oxa-spiro compound and preparation method therefor and uses thereof

Info

Publication number: WO2019205983A1
Application number: PCT/CN2019/082841
Authority: WO
Inventors: 田强; 张毅涛; 宋智泉; 宋立强; 蔡家强; 王利春; 王晶翼
Original assignee: 四川科伦博泰生物医药股份有限公司
Priority date: 2018-04-28
Filing date: 2019-04-16
Publication date: 2019-10-31
Also published as: CN111836807A

Abstract

Disclosed are an oxa-spiro compound and a preparation method therefor and uses thereof. In particular, provided are a compound shown in formula (I), a solvate, a stereisomer, a crystal form, and a pharmaceutically acceptable salt or ester thereof, or any combination of the above, and a preparation method therefor and uses thereof in activating the activity of an opioid receptor and preparing analgesic drugs.

Description

Oxyspirocyclic compound, preparation method and use thereof

This application is based on the CN application number 201810402312.3, the application date is April 28, 2018, and the CN application number is 201811358917.3, and the application date is November 15, 2018, and the priority is claimed. The disclosure is hereby incorporated by reference in its entirety.

Technical field

The present application relates to the field of medicine, and in particular to an oxaspirocyclic compound, a process for its preparation and its use in activating opioid receptor activity.

Background technique

Opioid receptors are an important class of G protein coupled receptors (GPCRs), widely distributed in the central and peripheral nervous systems, mainly in three subtypes of μ, δ and κ, and are opioids. And the target of analgesic effects of endogenous opioid peptides. Traditional opioid receptor agonists, such as morphine and its derivatives, are primarily active against the mu receptor and are most effective in the treatment of chronic arthritis, inflammatory neuralgia, postoperative pain, and moderate to severe pain caused by various cancers. Drug. These traditional drugs have side effects such as respiratory depression, gastrointestinal side effects, drug addiction, confusion, and tolerance problems, which are closely related to the function of β-arrestin.

Studies have found that opioid receptors mediate and regulate physiological functions mainly through the G protein pathway and the β-arrestin pathway. Excited μ receptors, in addition to analgesic effects, there will be significant respiratory depression and gastrointestinal adverse reactions such as constipation and nausea. Animal models of gene knockout confirmed that side effects such as analgesic effects and respiratory depression were achieved through two distinct signaling pathways. Among them, the analgesic effect is achieved by activating the downstream signaling pathway of G protein, and the recruitment of β-arrestin promotes the activation of its downstream signaling pathway to produce side effects such as respiratory depression and constipation. When the morphine was injected into the β-arrestin2 knockout mice, the analgesic effect was stronger and the maintenance time was longer. This result fully demonstrates the efficacy and safety of the G protein pathway (Bohn et al, Science, 1999).

Therefore, there is still a need to develop novel opioid receptor agonists that selectively act on the G protein pathway and have fewer side effects in the field of analgesic research.

Summary of the invention

The present inventors have discovered a class of oxaspirocyclic compounds which selectively act on the G protein pathway to activate opioid receptors, and the present application is based on the above findings.

Accordingly, in one aspect, the present application provides a compound of formula (I), a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof,

Wherein R ^{1 is} selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , CO ₂ R ^a and -C(O)NR ^b R ^c ; alternatively, R ¹ forms a ring with ring A;

R ^{2 is} selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , -CO ₂ R ^a and -C(O)NR ^b R ^c ;

R ³ is selected from hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or, R ² and R ³ to form a ring;

R ^{a is} selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected Substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;

R ^b and R ^{c are} independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkane The aryl group, the aryl group, the heteroaryl group, the acyl group, the sulfonyl group are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;

W and U are independently selected from -(CR ^d R ^e ) _m1 -, -(CR ^d R ^e ) _m1 -O-, -(CR ^d R ^e ) _m1 -NR ^f -, -(CR ^d R ^e ) _m1 -C(=O)-, -(CR ^d R ^e ) _m1 -S(O) _q -, -C(=O)-NR ^f - and -C(=O)-;

V is selected from C and N;

R ^d , R ^e and R ^{f are} independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl and heterocycloalkyl; or R ^d and R ^e are bonded to a carbon atom to which they are attached;

m _{1 is} selected from 1, 2, 3 and 4;

Ring A is selected from the group consisting of an aromatic ring, a heteroaryl ring, an aliphatic carbocyclic ring, and an aliphatic heterocyclic ring;

m and n are independently selected from 0, 1, 2, 3, 4 and 5;

x and y are independently selected from 1, 2, 3 and 4;

q is selected from 0, 1, and 2.

In certain embodiments, R ¹ is selected from hydroxy, cyano, halo, alkyl, haloalkyl, cycloalkyl, aryl, ^{^{^{heteroaryl, -OR a, -NR b R c}}} , -SR a, - CO ₂ R ^a and -C(O)NR ^b R ^c ; alternatively, R ¹ forms a ring with ring A.

In other embodiments, R ¹ is heterocycloalkyl.

In certain embodiments, R ² is selected from hydroxy, cyano, halo, alkyl, haloalkyl, cycloalkyl, aryl, ^{^{^{heteroaryl, -OR a, -NR b R c}}} , -SR a, - CO ₂ R ^a and -C(O)NR ^b R ^c .

In other embodiments, R ^{2 is} selected from the group consisting of hydrogen and alkenyl.

In certain preferred embodiments, the compound has the structure shown in formula (II),

W and U are independently selected from -(CR ^d R ^e ) _m1 -, -(CR ^d R ^e ) _m1 -O-, -(CR ^d R ^e ) _m1 -S(O) _q -, -(CR ^d R ^e ) _m1 -NR ^f - and -C(=O)-;

R ^d , R ^e and R ^{f are} independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl and alkoxy; or R ^d and R ^e are bonded to a carbon atom to which they are attached;

m _{1 is} selected from 1, 2, 3 and 4;

m and n are independently selected from 0, 1, 2, 3, 4 and 5;

x and y are independently selected from 1, 2, 3 and 4;

q is selected from 0, 1, and 2.

In certain embodiments, in formula (II),

R ^{1 is} selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , -CO ₂ R ^a and -C (O)NR ^b R ^c ; alternatively, R ¹ forms a ring with ring A;

R ^{2 is} selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , -CO ₂ R ^a and -C (O)NR ^b R ^c ;

W and U are independently selected from -(CR ^d R ^e ) _m1 -, -(CR ^d R ^e ) _m1 -O- and -(CR ^d R ^e ) _m1 -NR ^f -;

m _{1 is} selected from 1, 2, 3 and 4;

m and n are independently selected from 0, 1, 2, 3, 4 and 5;

x and y are independently selected from 1, 2, 3 and 4.

In certain preferred embodiments, the compound has the structure shown in formula (III),

Wherein each group and substituent are as defined above.

In certain preferred embodiments, the compound has the structure of formula (III-1) or formula (III-2),

Wherein each group and substituent are as defined above.

In certain embodiments, W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -, -(CR ^d R ^e ) _m1 -O-, -(CR ^d R ^e ) _m1 -S(O) _q - and -C(=O)-; R ^d and R ^e are each independently selected from hydrogen, hydroxy, halogen, C _1-6 alkyl , C _1-6 alkoxy, C _3-8 cycloalkyl, and 4-8 membered heterocycloalkyl; or, R ^d and R ^e are attached to the carbon atoms 3-7 membered aliphatic heterocyclic; m ₁ is selected from From 1 and 2; q is selected from 0, 1 and 2; x is selected from 1, 2 and 3.

In certain embodiments, W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -, -(CR ^d R ^e ) _m1 -O-, -(CR ^d R ^e ) _m1 -SO ₂ - and -C(=O)-; R ^d and R ^{e are} independently selected from hydrogen, hydroxy, halogen, C _1-4 alkyl, C _{1- 4} alkoxy, C _3-6 cycloalkyl, and 3-6 membered heterocycloalkyl; m ₁ is 1 or 2; x is selected from 1, 2 and 3.

In certain embodiments, W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -, -(CR ^d R ^e ) _m1 -O-, -(CR ^d R ^e ) _m1 -SO ₂ - and -C(=O)-; R ^d and R ^{e are} independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-4 alkyl and C _{1- 4} alkoxy; m ₁ is 1 or 2; x is 1 or 2.

In certain embodiments, various types I, Formula II, Formula III, Formula III-1 and III-2 in the formula W is independently selected from _{_{-CH 2 -, - CH 2 CH}} 2 -, - CH 2 -O- , -CH ₂ -SO ₂ - and -C(=O)-; x is 1.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -O-; R ^d and R ^{e are} independently Is selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl and 4-8 membered heterocycloalkyl; or R ^d and R ^e are linked to The carbon atom forms a 3-7 membered alicyclic ring; m ₁ is 1 or 2; and x is 1, 2 or 3.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -O-; R ^d and R ^{e are} independently Is selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl and C _1-6 alkoxy; or R ^d and R ^e form a 3-7 membered heterocyclic ring with the attached carbon atom; m ₁ is 1 or 2; x is 1, 2 or 3.

In certain embodiments, W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R ^d and R ^{e are} independently selected from the group consisting of hydrogen, hydroxyl, halogen, C _1-6 alkyl and C _{1 -6} alkoxy; m ₁ is 1 or 2; x is 1, 2 or 3.

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is attached to the 4-position in the formula; R ^d and R ^{e are} independently selected from the group consisting of hydrogen, hydroxyl, halogen, C _1-4 alkyl and C _{1 -4} alkoxy; m ₁ is 1 or 2; x is 1 or 2.

Wherein, the 1 position is connected to the 3 position in the formula, and the 2 position is connected to the 4 position in the formula; x is 1 or 2.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -NR ^f -, -(CR ^d R ^e ) _m1 -C(=O)-, -(CR ^d R ^e ) _m1 -S(O) _q -, -C(=O)- and -C(=O)-NR ^f -; R ^d , R ^e and R ^{f are} independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl and 4-8 membered heterocycloalkyl; or, R ^d And R ^e form a 3-7 membered heterocyclic ring with the attached carbon atom; m ₁ is 1 or 2; q is 0, 1 or 2; and x is 1, 2 or 3.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -NR ^f -, -(CR ^d R ^e ) _m1 -C(=O)-, -(CR ^d R ^e ) _m1 -S(O) _q -, -C(=O)- and -C(=O)-NR ^f -; R ^d , R ^e and R ^{f are} independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl, and C _1-6 alkoxy; or, R ^d and R ^e form a 3-7 membered heterocyclic ring with the attached carbon atom; m ₁ is 1 or 2; q is 0, 1 or 2; x is 1, 2 or 3.

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R ^d , R ^e and R ^{f are} independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl And C _1-6 alkoxy; m ₁ is 1 or 2; q is 0, 1 or 2; x is 1, 2 or 3.

Wherein, the 1-position is bonded to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R ^d , R ^e and R ^{f are} independently selected from hydrogen, hydroxy, halogen, C _1-4 alkyl And C _1-4 alkoxy; m ₁ is 1 or 2; q is 0, 1 or 2; x is 1 or 2.

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R ^d , R ^e and R ^{f are} independently selected from the group consisting of hydrogen, hydroxyl, fluorine, chlorine, methyl and B. Base; m ₁ is 1 or 2; q is 0, 1 or 2; x is 1 or 2.

Wherein the 1 position is connected to the 3 position in the formula, and the 2 position is connected to the 4 position in the formula; x is 1 or 2.

And -C(=O)-, wherein the 1 position is linked to the 3 position in the formula, and the 2 position is linked to the 4 position in the formula; x is 1.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 - and -(CR ^d R ^e ) _m1 -O-; R ^d and R ^e are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl and 4-8 membered heterocycloalkane Or; R ^d and R ^e are a 3-7 membered heterocyclic ring with a carbon atom to be bonded; m _{1 is} selected from 1, 2, 3 and 4; q is selected from 0, 1 and 2; y is selected from 1, 2 And 3.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 - and -(CR ^d R ^e ) _m1 -O-; R ^d and R ^e are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl and 3-6 membered heterocycloalkane Or; R ^d and R ^e are a 3-6 membered alicyclic ring with a carbon atom to be bonded; m _{1 is} selected from 1 and 2; y is selected from 1, 2 and 3.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e ) _m1 -; R ^d and R ^{e are} independently selected From hydrogen, hydroxy, halogen, C _1-4 alkyl and C _1-4 alkoxy; m ₁ is 1 or 2; y is selected from 1 or 2.

In certain embodiments, various types I, Formula II, Formula III, Formula III-1 and III-2 in the formula U is independently selected from -CH ₂ - and -CH _₂ CH ₂ -; y is 1.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e )m ₁ -O-; R ^d and R ^e Independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl and 4-8 membered heterocycloalkyl; m ₁ is 1, 2 or 3 ;y is 1, 2 or 3.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR ^d R ^e )m ₁ -O-; R ^d and R ^e Independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl and C _1-6 alkoxy; m ₁ is 1, 2 or 3; y is 1, 2 or 3.

In certain embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is attached to the 5-position in the formula; R ^d and R ^{e are} independently selected from the group consisting of hydrogen, hydroxyl, halogen, C _1-6 alkyl and C _{1 -6} alkoxy; m ₁ is 1 or 2; y is 1, 2 or 3.

In certain preferred embodiments, each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is attached to the 5-position in the formula; R ^d and R ^{e are} independently selected from the group consisting of hydrogen, hydroxyl, halogen, C _1-4 alkyl and C _{1 -4} alkoxy; m ₁ is 1 or 2; y is 1 or 2.

Wherein, the 1 position is connected to the 3 position in the formula, and the 2 position is connected to the 5 position in the formula; y is 1 or 2.

In certain preferred embodiments, W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -(CR ^d R ^e ) _m1 -; R ^d and R ^{e is} independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl and 4-8 membered heterocycloalkyl; m ₁ is 1 or 2 ;x and y are independently selected from 1, 2 and 3.

In certain preferred embodiments, W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -(CR ^d R ^e ) _m1 -; wherein, R ^d and R ^{e are} independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-6 alkyl and C _1-6 alkoxy; m ₁ is 1 or 2; and x and y are independently selected from 1, 2 and 3.

In certain preferred embodiments, W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -(CR ^d R ^e ) _m1 -; R ^d and R ^{e is} independently selected from the group consisting of hydrogen, hydroxy, halogen, C _1-4 alkyl and C _1-4 alkoxy; m ₁ is 1 or 2; and x and y are independently 1 or 2.

In certain preferred embodiments, W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -CH ₂ - and -CH ₂ CH ₂ -; x And y are independently 1 or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C _1-6 alkyl, halo. C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , -CO ₂ R ^a and -C(O)NR ^b R ^c ; or R ¹ forms a ring with ring A, said ring is ring A and a 5-6 membered heterocyclic ring or ring A 5-6 yuan heteroaryl ring;

R ^{a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl; C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C _1-6 alkyl and halo C _1-6 alkyl;

R ^b and R ^{c are} independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, a C _1-6 alkanoyl group and a C _1-6 alkylsulfonyl group; wherein the C _1-6 alkyl group, the C _3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, and the C _6-10 aryl group; The base, 5-10 membered heteroaryl, C _1-6 alkanoyl and C _1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C _1-6 alkyl group and a halogenated C _1-6 alkyl group;

m is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C _1-6 alkyl, halo. C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , -CO ₂ R ^a And -C(O)NR ^b R ^c ; or R ¹ forms a ring with ring A, said cyclo ring is ring A and 5-6 membered alicyclic ring or ring A and 5-6 membered heteroaryl ring;

m is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C _1-6 alkyl, and Or ^a ; or, R ¹ forms a ring with ring A, and the ring is ring A and a 5-6 membered heterocyclic ring;

m is selected from 0, 1, 2, 3 and 4.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxy, cyano, halogen, C _1-4 alkyl, and Or ^a ; or, R ¹ forms a ring with ring A, and the ring is ring A and a 5-6 membered heterocyclic ring;

R ^{a is} selected from the group consisting of hydrogen, C _1-4 alkyl and 5-6 membered heterocycloalkyl; wherein said C _1-4 alkyl group and 5-6 membered heterocycloalkyl group are optionally one or more Substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, C _1-4 alkyl and halo C _1-4 alkyl;

m is 1 or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, bromo, iodo, methyl , ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , tert-butoxy, isobutoxy and tetrahydrofuranyloxy; or, R ¹ forms a ring with ring A, and the ring is ring A and 1,4-dioxane;

m is 1 or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, methyl, ethyl, a methoxy group, an ethoxy group, a n-propoxy group, and a tetrahydrofuranyloxy group; or, R ¹ forms a ring with a ring A, and the ring is a ring A and a 1,4-dioxane ring;

m is 1 or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, fluoro, methoxy, and tetrahydrofuranyloxy; , R ¹ forms a ring with ring A, and the ring is ring A and 1,4-dioxane;

m is 1 or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from cyano, halo, and —OR ^a ; or, R ¹ and A forms a cis ring, and the cyclized ring is a ring A and a 5-6 membered heterocyclic ring;

m is selected from 0, 1, 2, 3 and 4;

m is 1 or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, fluoro, chloro, bromo, iodo, methoxy, Ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy and tetrahydrofuranyloxy; or, R ¹ forms a ring with ring A, and the ring is Ring A and 1,4-dioxane;

m is 1 or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from cyano, halo, and 3-6 membered heterocycloalkyl;

m is 0, 1, or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, halo, and 5-6 membered heterocycloalkyl;

m is 0, 1, or 2.

In certain preferred embodiments, R ^{1 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, fluoro, and morpholinyl;

m is 0 or 1.

In certain preferred embodiments, R ^{2 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C _1-6 alkyl, halo. C _1-6 alkyl, C _1-6 hydroxyalkyl, -C _1-4 alkyl-OC _1-4 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C _{2 -6} alkenyl, halo C _2-6 alkenyl, C _2-6 alkynyl, halo C _2-6 alkynyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ^a , NR ^b R ^c , -SR ^a , -CO ₂ R ^a and -C(O)NR ^b R ^c ;

R ^b and R ^{c are} independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, a C _1-6 alkanoyl group, a C _1-6 alkylsulfonyl group; wherein the C _1-6 alkyl group, the C _3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, the C _6-10 aryl group; The base, 5-10 membered heteroaryl, C _1-6 alkanoyl and C _1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C _1-6 alkyl group and a halogenated C _1-6 alkyl group;

n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

In certain preferred embodiments, R ^{2 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C _1-6 alkyl, halo. C _1-6 alkyl, C _1-6 hydroxyalkyl, -C _1-4 alkyl-OC _1-4 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C _{6 -10} aryl, 5-10 membered heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , -CO ₂ R ^a and -C(O)NR ^b R ^c ;

n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

In certain preferred embodiments, R ^{2 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxy, cyano, halogen, C _1-4 alkyl, halo. C _1-4 alkyl, C _1-4 hydroxyalkyl, C _3-6 cycloalkyl, -C _1-4 alkyl-OC _1-4 alkyl, -OR ^a and -CO ₂ R ^a ;

n is selected from 0, 1, 2, 3 and 4.

In certain preferred embodiments, R ^{2 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxy, cyano, halogen, C _1-4 alkyl, halo. C _1-4 alkyl, C _1-4 hydroxyalkyl, C _3-6 cycloalkyl, -C _1-3 alkyl-OC _1-3 alkyl, -OR ^a and -CO ₂ R ^a ;

n is 1 or 2.

In certain preferred embodiments, R ^{2 of} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, bromo, iodo, methyl ,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxymethyl , 1-hydroxyethyl, 2-hydroxyethyl, -CH ₂ OCH ₃ , cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy , isobutoxy, tetrahydrofuranyloxy and -C(O)OCH ₃ ;

n is 1 or 2.

In certain preferred embodiments, R ^{2 of} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, methyl, ethyl, N-propyl, isopropyl, fluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, -CH ₂ OCH ₃ , cyclopropyl, methoxy, ethoxy, tetrahydrofuranyloxy and C(O)OCH ₃ ;

n is 1 or 2.

In certain preferred embodiments, R ^{2 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C _1-6 alkyl, halo. C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ^a , -NR ^b R ^c , -SR ^a , -CO ₂ R ^a And -C(O)NR ^b R ^c ;

n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

In certain preferred embodiments, various types I, Formula II, Formula III, Formula III-1 and III-2 in the formula R ² is independently selected from hydroxy, cyano, halo and -OR ^a;

n is selected from 0, 1, 2, 3 and 4.

n is 1 or 2.

In certain preferred embodiments, R ^{2 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, bromo, iodo, methoxy Base, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy and tetrahydrofuranyloxy;

n is 1 or 2.

In certain preferred embodiments, R ^{2 of each of} Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is selected from the group consisting of hydroxyl, methoxy, and tetrahydrofuranyloxy;

n is 1 or 2.

In certain preferred embodiments, Formula I and / or Formula II and / or III and / or Formula III-1 and and / or the formula ^III-2 R 2 is independently selected from C _2-6 alkenyl, Halogenated C _2-6 alkenyl, C _2-6 alkynyl or halo C _2-6 alkynyl.

In certain preferred embodiments, Formula I and / or Formula II and / or III and / or Formula III-1 and / or Formula III-2 in R ² is independently selected from C _2-4 alkenyl group, Halogenated C _2-4 alkenyl, C _2-4 alkynyl or halo C _2-4 alkynyl.

In certain preferred embodiments, Formula I and / or Formula II and / or III and / or Formula III-1 and / or Formula III-2 in R ² is independently selected from vinyl, propenyl, fluoro Vinyl, 1,1-difluorovinyl, 2-methylpropenyl, ethynyl, propynyl, fluoroethynyl. In certain preferred embodiments, R ^{2 of} Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, C _1-6 alkyl, C _1-6 hydroxyalkane And C _2-6 alkenyl;

n is 0, 1, or 2.

In certain preferred embodiments, R ^{2 of} Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are independently selected from the group consisting of hydroxyl, C _1-4 alkyl, C _1-4 hydroxyalkyl And C _2-4 alkenyl;

n is 0, 1, or 2.

In certain preferred embodiments, R ^{2 of} Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, methyl, hydroxymethyl, and vinyl;

n is 0 or 1.

In certain preferred embodiments, Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of C _6-10 aromatic rings, 5-10 membered heteroaryl rings, C _3-8 aliphatic carbocyclic ring and 3-8 membered aliphatic heterocyclic ring.

In certain preferred embodiments, Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a C _6-10 aromatic ring and a 5-10 membered heteroaryl ring.

In certain preferred embodiments, Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring and a 5-6 membered heteroaryl ring.

In certain preferred embodiments, Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, Imidazole ring, thiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,2,4-1H-triazole ring and pyrazole ring.

In certain preferred embodiments, Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, Imidazole ring, thiazole ring, pyridine ring, pyrimidine ring, pyrazine ring and pyridazine ring.

In certain preferred embodiments, Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring and a thiophene ring.

In certain embodiments, Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently a phenyl ring.

In certain preferred embodiments, R ^{3 of} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, hydroxy, C _1-6 alkyl, halo C _{1 -6} alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl.

In certain preferred embodiments, R ^{3 of} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, hydroxy, C _1-6 alkyl, and halo C _{1 -6} alkyl.

In certain preferred embodiments, R ^{3 of} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen and C _1-4 alkyl.

In certain preferred embodiments, R ^{3 in} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl. , n-butyl, isobutyl and tert-butyl.

In certain preferred embodiments, R ^{3 of} each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, and isopropyl. .

In certain preferred embodiments, R ^{3 in each} of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is hydrogen.

In certain preferred embodiments, the compound is selected from the group consisting of

In certain embodiments, the pharmaceutically acceptable salt of the compound is a trifluoroacetate, formate.

In another aspect, the application provides a pharmaceutical composition comprising a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, as hereinbefore described; It also contains one or more pharmaceutical excipients.

In an embodiment of the present application, the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, and muscular. Internal, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or input, or by means of an explant reservoir. Among them, oral administration, intraperitoneal or intravenous administration is preferred.

When administered orally, the compounds of the present application can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsule formulation generally comprises lactose and dried cornstarch. Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some sweeteners, fragrances or colorants may also be added to the above oral formulations.

In the case of topical administration, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present application may be formulated into different topical preparations according to different affected faces or organs. The form is as follows:

When applied topically to the eye, the compound of the present application can be formulated into a micronized suspension or solution in a form of isotonic, sterile saline at a pH which may or may not be added with a preservative such as benzyl chloride. Alkoxide. For ophthalmic use, the compound can also be formulated in the form of a cream such as a Vaseline cream.

When applied topically to the skin, the compounds of the present invention can be formulated into a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the present application can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

In another aspect, the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition as hereinbefore described, for use in the preparation of an activated opioid Use in drugs that are active for substance receptors (eg, mu-opioid receptors).

In another aspect, the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition thereof, as described above, for use in activating opioids Sample receptor (eg, μ-opioid receptor) activity.

In another aspect, the application provides a method of activating an opioid receptor (eg, mu-opioid receptor) activity in a subject, comprising administering to the subject an effective amount of a compound as hereinbefore described, A solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination of the foregoing, or a pharmaceutical composition.

In another aspect, the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition as hereinbefore described in the preparation of an analgesic drug the use of.

In another aspect, the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition thereof, as described above, for analgesia .

In another aspect, the application provides a method of analgesia comprising administering to a subject in need thereof an effective amount of a compound, solvate, stereoisomer, crystalline form thereof, pharmaceutically acceptable, as hereinbefore described a salt or ester, or any combination of the above, or a step of a pharmaceutical composition.

In another aspect, the application provides a method of preparing a compound as hereinbefore described, comprising the steps of:

Wherein R ¹ , R ² , R ³ , W, U, V, A, m, n, x, y are as described above;

The compound of formula I is obtained by reductive amination of a compound of formula I-A and a compound of formula I-B. The reductive amination reaction can be carried out with reference to experimental conditions generally employed in the art. In certain preferred embodiments, an acid and/or a reducing agent is added to the reductive amination reaction. In certain preferred embodiments, the acid is selected from the group consisting of AcOH and TFA.

In certain preferred embodiments, the reducing agent is selected from the group consisting of NaBH ₄ , NaCNBH _{3 ,} and NaBH(OAc) ₃ .

In certain preferred embodiments, the method of preparing the compound comprises the steps of:

Wherein R ¹ , R ² , R ³ , W, U, A, m, n, x, y are as described above;

The compound of formula II is obtained by reductive amination of a compound of formula IA and a compound of formula II-B. The reductive amination reaction can be carried out with reference to experimental conditions generally employed in the art. In certain preferred embodiments, an acid and/or a reducing agent is added to the reductive amination reaction. In certain preferred embodiments, the acid is selected from the group consisting of AcOH and TFA. In certain preferred embodiments, the reducing agent is selected from the group consisting of NaBH ₄ , NaCNBH _{3 ,} and NaBH(OAc) ₃ .

As used herein, the term "solvate" means a substance formed by combining a compound of the present application with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, acetic acid, and the like. Solvates include stoichiometric amounts of solvates and non-stoichiometric amounts of solvates, preferably hydrates.

As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein the configurational isomers primarily include cis and trans isomers and optical isomers. The compounds described herein may exist in stereoisomeric forms and thus encompass all possible stereoisomeric forms, as well as any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above. When the compounds described herein contain an olefinic double bond, it includes the cis isomer and the trans isomer, as well as any combination thereof, unless otherwise specified.

In addition, the molecules, atoms or ions of some natural or artificial compounds can be repeatedly arranged in a regular cycle in space, and the arrangement has a periodicity of three-dimensional space, which is repeated at a certain distance. At this time, the compound may exist in two or more crystalline states, and the molecules having the same structure are crystallized into different solid forms, which are called polymorphs or polymorphs. When referring to a particular crystalline form, it is often referred to as "crystal form", the term "crystalline form" as used in this application.

The term "pharmaceutically acceptable salt," as used herein, refers to a salt of a compound of the present application that is pharmaceutically acceptable and has pharmacological activity of the parent compound. Such salts include: acid addition salts with inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids such as acetic acid, propionic acid, Caproic acid, cyclopentanoic acid, glycolic acid, pyruvic acid, trifluoroacetic acid, formic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid , mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, sticky a salt formed by substitution of an acidic proton present on a parent compound with a metal ion such as an alkali metal ion or an alkaline earth metal ion; or a complex compound formed with an organic base such as ethanolamine, Ethanolamine, triethanolamine, N-methylglucamine, and the like.

As used herein, the term "pharmaceutically acceptable ester" refers to an ester which is formed by esterification of an alcohol when a compound of the present application is present; when the compound of the present application has a hydroxyl group, it is organic An ester formed by an esterification reaction of an acid, an inorganic acid, an organic acid salt or the like. The ester can be hydrolyzed to form the corresponding acid or alcohol in the presence of an acid or a base.

As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group which may be a monocyclic or polycyclic fused system and which may be fused to an aromatic ring. For example, C _3-8 cycloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkyl, C _5-6 cycloalkyl, and the like. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term "heterocycloalkyl" refers to a monocyclic or bicyclic saturated or partially saturated ring, optionally substituted with at least one and up to four heteroatoms independently selected from N, O or S. A group such as a 3-8 membered heterocycloalkyl group, a 3-6 membered heterocycloalkyl group, a 4-6 membered heterocycloalkyl group or a 5-6 membered heterocycloalkyl group. Examples of such groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl or piperazinyl, and the like.

As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic group containing at least one aromatic ring, preferably a _C6-10 aryl group, ie 6, 7, 8, 9 or 10 carbon atoms. Aryl. Examples of the aromatic group in the present application include a phenyl group, a naphthyl group, a 1,2,3,4-tetrahydronaphthyl group, an anthracenyl group and the like.

As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring group, optionally substituted with at least one heteroatom independently selected from N, O or S, preferably 5-10 members. Aryl group, 5-6 membered heteroaryl group, and the like. Examples of such groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, Isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, triazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, fluorenyl, iso Mercapto, pyridazinyl, pyrazinyl, quinolyl and the like.

As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. The term " _C1-6 alkyl" means a straight or branched alkyl group having from 1 to 6, ie 1, 2, 3, 4, 5 or 6 carbon atoms, typically methyl, ethyl, positive Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, pentyl and hexyl. Similarly, the term "C _1-4 alkyl" means a straight or branched alkyl group having 1, 2, 3 or 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, and Butyl, isobutyl, sec-butyl and tert-butyl groups.

As used herein, the term "halogen" refers to fluoro, chloro, bromo and iodo.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as previously described. For example, a halogenated C _1-6 alkyl group, a halogenated C _1-4 alkyl group or the like. Specific examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, chloroethyl, and the like.

As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, as described above. For example, C1-6 hydroxyalkyl, C1-4 hydroxyalkyl. Specific examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.

As used herein, the term "alkoxy" refers to a group having an alkyl-O- structure, wherein the alkyl group is as previously described. For example, C _1-6 alkoxy group, C _1-4 alkoxy group, and the like. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

As used herein, the term "acyl" refers to a group having an alkyl-C(O)- structure, wherein the alkyl group is as previously described. For example, a C _1-6 alkanoyl group, a C _1-4 alkanoyl group, and the like. Specific examples include, but are not limited to, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butanoyl, and the like.

As used herein, the term "sulfonyl" refers to a group having the structure of an alkyl-S(O) _2- structure, wherein the alkyl group is as previously described. For example, a C _1-6 alkylsulfonyl group, a C _1-4 alkylsulfonyl group or the like. Specific examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butyl Sulfonyl and the like.

As used herein, the term "aromatic ring" refers to a monocyclic or polycyclic ring system comprising at least one aromatic ring. For example, a C _6-10 aromatic ring, that is, an aromatic ring of 6, 7, 8, 9 or 10 carbon atoms. Examples of the aromatic ring in the present application include a benzene ring, a naphthalene ring, a 1,2,3,4-tetrahydronaphthalene ring, an anthracene ring, and the like.

As used herein, the term "heteroaromatic ring" refers to an aromatic monocyclic or polycyclic ring system containing from 5 to 14 ring atoms, wherein one to four ring atoms are independently O, N or S, and the remaining rings The atom is a carbon atom. For example, a 5-10 member heteroaromatic ring, a 5-6 membered heteroaryl ring, and the like. Specific examples include, but are not limited to, pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, triazole ring, tetrazole ring, oxazole ring, isoxazole ring, oxadiazole ring, thiazole ring, isothiazole Ring, thiadiazole ring, pyridine ring, pyrimidine ring, triazine ring, benzimidazole ring, benzoxazole ring, benzothiazole ring, benzofuran ring, benzothiophene ring, anthracene ring, isoindole Ring, pyridazine ring, pyrazine ring, quinoline ring, and the like.

As used herein, the term "aliphatic carbocycle" refers to a saturated or partially saturated non-aromatic hydrocarbon ring which may be a monocyclic or polycyclic fused system. For example, a C _3-8 aliphatic carbocyclic ring, a C _3-6 aliphatic carbocyclic ring, a C _3-5 aliphatic carbocyclic ring or the like. Specific examples include, but are not limited to, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.

As used herein, the term "aliphatic heterocycle" refers to a saturated or partially saturated non-aromatic monocyclic ring, optionally substituted with at least one and up to four heteroatoms independently selected from N, O or S. Multi-ring. For example, a 3-8-membered aliphatic heterocyclic ring, a 3-6-membered aliphatic heterocyclic ring, and a 3-5-membered aliphatic heterocyclic ring. Specific examples include, but are not limited to, a pyrrolidine ring, a tetrahydrofuran ring, a dihydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a morpholine ring or a piperazine ring, and the like.

When a group is described as "optionally substituted with one or more substituents selected from the group consisting of", the group may be unsubstituted or (2) substituted. If a carbon on a group is described as being optionally substituted with one or more substituents selected from the group consisting of one or more hydrogens on the carbon (to the extent of any hydrogen present), alone and / Alternatively, they may be replaced by an optional substituent that is independently selected. If a nitrogen on a group is described as being optionally substituted with one or more of the following substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Optional substituent substitution.

The invention also includes pharmaceutically acceptable isotopic compounds of the compounds which are structurally identical to the compounds of the invention, except that one or more atoms are of the same atomic number but differ in atomic mass or mass number from atoms which are dominant in nature. Atomic substitution of mass or mass number. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., ² H, ³ H); isotopes of carbon (e.g., ¹¹ C, ¹³ C, and ¹⁴ C); isotopes of chlorine (e.g. ³⁶ Cl); isotope of fluorine (eg ¹⁸ F); isotopes of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O, ¹⁷ O and ¹⁸ O) ); an isotope of phosphorus (eg, ³² P); and an isotope of sulfur (eg, ³⁵ S).

As used herein, the term "pharmaceutical excipient" refers to the excipients and additives used in the manufacture of pharmaceuticals and formulation formulations, which means that in addition to the active ingredients, a reasonable assessment has been made in terms of safety. And a substance contained in a pharmaceutical preparation. In addition to prototyping, acting as a carrier and improving stability, pharmaceutical excipients also have important functions such as solubilization, solubilization, and controlled release, which are important components that may affect the quality, safety and effectiveness of drugs. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials. According to its action and use, it can be divided into: solvent, propellant, solubilizer, cosolvent, emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, Glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.; For oral, injection, mucosal, transdermal or topical administration, nasal or oral inhalation and ocular administration. The same pharmaceutical excipient can be used for pharmaceutical preparations of different administration routes, and has different effects and uses.

As used herein, the term "subject" refers to an animal, particularly a mammal, preferably a human.

As used herein, the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect. For example, a prophylactically effective amount refers to an amount sufficient to prevent, arrest, or delay the onset of a disease; a therapeutically effective amount refers to an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determination of such an effective amount is well within the capabilities of those skilled in the art. For example, the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously. and many more.

detailed description

The embodiments of the present invention will be described in detail below with reference to the accompanying drawings, however, the following examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Those who do not specify the specific conditions in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.

The structure of the compound described in the following examples was determined by nuclear magnetic resonance ( ¹ H NMR) or mass spectrometry (MS).

The nuclear magnetic resonance ( ¹ H NMR) measuring instrument used a Bruker 400 MHz nuclear magnetic resonance apparatus; the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), and hexa- dimethyl sulfoxide (DMSO-d _6). ); the internal standard substance is tetramethylsilane (TMS). All δ values are expressed in ppm.

The abbreviations in the nuclear magnetic resonance (NMR) spectra used in the examples are shown below:

s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quadruple Quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet , br: broad peak, J: coupling constant, Hz: Hertz, DMSO-d ₆ : deuterated dimethyl sulfoxide.

The mass spectrometer (MS) assay instrument used an Agilent (ESI) mass spectrometer, model Agilent 6120B.

The compounds in the examples were purified using preparative liquid phase (Prep-HPLC), and the methods for preparing liquid phase purification included methods A, B and C.

Method A for Preparing Liquid Phase Purification:

Liquid chromatography instrument model: Agilent 1260;

Column: Waters SunFire Prep C18 OBD (19 mm × 150 mm × 5.0 μm);

Column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm, 254 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

Method B for preparing liquid phase purification:

Liquid chromatography instrument model: Agilent 1260;

Column: Waters SunFire Prep C18 OBD (19 mm × 150 mm × 5.0 μm);

Column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm, 254 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous trifluoroacetic acid solution.

Method for preparing liquid phase purification C:

Liquid chromatography instrument model: Agilent 1260;

Column: Waters XBridge Prep C18 OBD (19 mm × 150 mm × 5.0 μm);

Column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm, 254 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium hydrogencarbonate solution.

Example 1: N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro-1H-indole- Preparation of 2-amine

Step 1: Synthesis of 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde

Add 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetonitrile (1.55 g, 6.05 mmol) to dry toluene (35 mL) Cool to -78 °C. Diisobutylaluminum hydride (1.28 g, 9.07 mmol) was added dropwise. After completion of the dropwise addition, the mixture was stirred at -78 ° C for 2 hours. After the reaction was completed by LCMS, a saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was stirred at room temperature for 1 hour. 6N hydrochloric acid was added to the reaction liquid, and the mixture was heated to 85 ° C and stirred for 6 hours. The reaction solution was cooled to room temperature, sodium hydrogencarbonate was added, the pH was adjusted to 8, and the liquid phase was separated, and the aqueous phase was concentrated to dryness. The mixture was stirred for 30 minutes with DCM and anhydrous sodium sulfate, filtered and concentrated to give 2-(9-(pyridine- 2-L)-6-oxaspiro[4.5]decane-9-yl) crude acetaldehyde 1.2 g. ESI-MS (m/z): 260.16 [M+H] ⁺ .

Step 2: N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro-1H-indole-2 -Amine synthesis

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (80 mg, 0.308 mmol) and 2-aminoindole hydrochloride (under a nitrogen atmosphere) 49.3 mg, 0.291 mmol) was added to dichloromethane (15 mL), and anhydrous magnesium sulfate (222.78 mg, 1. Sodium cyanoborohydride (23.26 mg, 0.37 mmol) and methanol (5 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. After purification by preparative liquid phase (preparation of liquid phase was purified by Method A), 9.5 g of the title compound was obtained.

ESI-MS (m/z): 377.2 [M+H] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.50 (m, 1H), 8.29 (s, 1H), 7.67 (m, 1H), 7.33 (m, 1H), 7.20-7.09 (m, 5H), 3.84- 3.60 (m, 3H), 3.13 (m, 2H), 3.00 (m, 2H), 2.82 (m, 1H), 2.52 - 2.41 (m, 1H), 2.40 - 2.26 (m, 2H), 2.18 (m, 1H), 2.03–1.88 (m, 2H), 1.84–1.57 (m, 3H), 1.56–1.30 (m, 4H), 1.15–1.01 (m, 1H), 0.65 m, 1H).

Example 2: N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalene Synthesis of 2-amine

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (75 mg, 0.289 mmol) and 1,2,3,4- under N2 Tetrahydronaphthalen-2-amine (75.55 mg, 0.289 mmol) was added to dichloromethane (15 mL). Sodium cyanoborohydride (90.87 mg, 1.45 mmol) and methanol (3 mL) were added and the mixture was stirred at room temperature overnight. The raw material was not completely reacted by LC-MS, and a product was formed. Directly post-treatment, adding diatomaceous earth, filtering, and concentrating the filtrate under reduced pressure, adding 100 mL of water, extracting with ethyl acetate (30 mL×3), concentrating the organic phase, drying over anhydrous sodium sulfate, concentrating, and then purifying by preparative liquid phase (Preparation of the liquid phase was carried out by Method B), and lyophilized to give 22.9 mg of the title compound.

ESI-MS (m/z): 391.56 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 66.3 Hz, 2H), 8.66 (t, J = 6.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.63 (d) , J = 8.0 Hz, 1H), 7.52 (t, J = 6.2 Hz, 1H), 7.18 - 6.94 (m, 4H), 4.68 (s, 5H), 3.87 - 3.66 (m, 2H), 3.29 (s, 1H), 3.05 (d, J = 15.9 Hz, 2H), 2.87 (s, 3H), 2.73 - 2.52 (m, 1H), 2.20 (d, J = 14.8 Hz, 2H), 2.02 (d, J = 13.8) Hz, 1H), 1.93–1.74 (m, 3H), 0.81–0.65 (m, 1H).

Example 3: 2-((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amine)-2,3-dihydro-1H Synthesis of 茚-1-ol

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (75 mg, 0.289 mmol) and 2-amino-2,3- under N2 Dihydro-1H-indol-1-ol (51.77 mg, 0.347 mmol) was added to dichloromethane (15 mL). Sodium cyanoborohydride (21.81 mg, 0.347 mmol) and methanol (3 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. After purification by preparative liquid phase (preparative liquid phase purification using Method B) lyophilized to give the title compound as trifluoroacetic acid salt.

ESI-MS (m/z): 393.53 [M+H] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.68 (m, 1H), 8.11 (m, 1H), 7.60 (m, 2H), 7.37 (d, J = 7.2Hz, 1H), 7.27 (m, 2H) , 7.16 (m, 1H), 5.16 (m, 1H), 4.18 (m, 1H), 3.88 - 3.54 (m, 3H), 3.09 (m, 3H), 2.67 (m, 1H), 2.47 - 2.15 (m , 4H), 2.02 (d, J = 13.9 Hz, 1H), 1.85 (d, J = 11.4 Hz, 2H), 1.67 (m, 1H), 1.62-1.36 (m, 4H), 1.15 (s, 3H) .

Example 4: 5-Fluoro-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro- Synthesis of 1H-indole-2-amine

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (75 mg, 0.289 mmol) and 5-fluoro-2,3- under N2 Dihydro-1H-indol-2-amine (52.46 mg, 0.347 mmol) was added to dichloromethane (15 mL). Sodium cyanoborohydride (21.81 mg, 0.347 mmol) and methanol (3 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. After purification by preparative liquid phase (preparative liquid phase purification using Method B) lyophilized to give the title compound as trifluoroacetic acid salt.

ESI-MS (m/z): 395.52 [M+H] ⁺ ;

_{1H NMR (400MHz, CDCl 3)} δ8.56 (d, J = 5.2Hz, 1H), 8.08 (m, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.52 (m, 1H), 7.02 ( m,1H), 6.88–6.69 (m, 2H), 3.87–3.71 (m, 2H), 3.64 (m, 1H), 3.06 (m, 5H), 2.51 (m, 1H), 2.28 (m, 4H) , 1.97 (d, J = 14.0 Hz, 1H), 1.89 - 1.69 (m, 2H), 1.70 - 1.54 (m, 1H), 1.56 - 1.31 (m, 4H), 1.18 (m, 1H), 1.09 (m) , 1H), 0.85–0.58 (m, 1H).

Example 5: 2-((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amine)-2,3-dihydro-1H -茚-5- nitrile

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (75 mg, 0.289 mmol) and 2-amino-2,3- under N2 Dihydro-1H-indole-5-carbonitrile (54.9 mg, 0.347 mmol) was added to dichloromethane (15 ml). Sodium cyanoborohydride (21.81 mg, 0.347 mmol) and methanol (3 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. After purification by preparative liquid phase (preparative liquid phase purification using Method B) lyophilized to give the title compound as trifluoroacetic acid salt.

ESI-MS (m/z): 402.54 [M+H] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.69 (s, 1H), 8.27-8.07 (m, 1H), 7.76-7.57 (m, 2H), 7.47 (m, 1H), 7.41 (d, J = 3.9 Hz, 1H), 7.27 (m, 1H), 6.55 (s, 1H), 3.95 - 3.77 (m, 2H), 3.71 (m, 1H), 3.21 (m, 4H), 3.01 (m, 1H), 2.55 (d, J = 12.0 Hz, 1H), 2.37 (m, 3H), 2.20 (m, 1H), 2.02 (d, J = 13.5 Hz, 1H), 1.95 - 1.75 (m, 2H), 1.76 - 1.60 ( m, 1H), 1.60–1.36 (m, 4H), 1.36–1.05 (m, 1H), 0.73 (m, 1H).

Example 6: (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro- Synthesis of 1H-indole-2-amine

Step 1: Synthesis of (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde

Add (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetonitrile (1.00 g, 3.90 mmol) to dry toluene (35 mL) It was cooled to -78 ° C under a nitrogen atmosphere, and diisobutylaluminum hydride (0.83 g, 5.85 mmol) was added dropwise. After completion of the dropwise addition, the mixture was stirred at -78 ° C for 2 hours. After the reaction was completed by LCMS, a saturated aqueous solution of ammonium chloride was added and the mixture was stirred at room temperature for 1 hour. 6N hydrochloric acid was added to the reaction liquid, and the mixture was heated to 85 ° C and stirred for 6 hours. The reaction solution was cooled to room temperature, sodium hydrogencarbonate was added, the mixture was adjusted to pH=8, and the mixture was separated, and the aqueous phase was concentrated to dryness. The mixture was stirred for 30 minutes with dichloromethane and anhydrous sodium sulfate. Pre-HPLC purification gave (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde 0.30 g.

Step 2: (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro-1H -茚-2-Amine synthesis

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (88.0 mg, 0.34 mmol) and 2-amino The hydrazine hydrochloride (69.1 mg, 0.41 mmol) was added to dichloromethane (15 mL). Sodium cyanoborohydride (25.59 mg, 0.41 mmol) and methanol (5 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. Purification by preparative liquid phase (preparation of liquid phase using Method B) followed by lyophilization afforded 12.6 mg of the title compound.

ESI-MS (m/z): 377.2 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d6) δ8.62-8.58 (m, 1H), 8.55 (s, 2H), 7.84-7.80 (m, 1H), 7.52 (d, J = 8.1Hz, 1H), 7.34 -7.26(m,1H), 7.26-7.14(m,4H),3.94-3.87(m,1H),3.72-3.54(m,2H), 3.20-3.14(m,2H),2.94-2.82(m, 3H), 2.51-2.37 (m, 3H), 2.35-2.23 (m, 2H), 2.06-1.98 (m, 1H), 1.89-1.77 (m, 2H), 1.73-1.57 (m, 2H), 1.56- 1.42 (m, 2H), 1.37-1.35 (m, 2H), 1.04-0.95 (m, 1H), 0.68-0.60 (m, 1H).

Example 7: N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl)-5-morpholine-2,3 -Synthesis of dihydro-1H-indol-2-amine

Step 1: N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl)-5-morpholine-2,3- Synthesis of dihydro-1H-indol-2-amine

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (88.0 mg, 0.34 mmol) and 5-? To a solution of methylene chloride (15 mL), EtOAc (EtOAc, m. Sodium cyanoborohydride (107 mg, 1.70 mmol) and methanol (3 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. Purification by preparative liquid phase (preparative liquid phase purification using Method C), lyophilized to give the title compound 3.7 mg.

ESI-MS (m/z): 462.2 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (dd, J = 4.9, 1.7 Hz, 1H), 7.99-7.94 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.47 - 7.39 (m,1H), 7.20 (dd, J=8.3, 2.1 Hz, 1H), 7.06–6.97 (m, 2H), 3.91–3.84 (m, 4H), 3.77 (dd, J=7.7, 2.8 Hz, 2H) ), 3.25–3.19 (m, 4H), 3.07–2.81 (m, 4H), 2.57–2.38 (m, 3H), 2.19-2.10 (m, 1H), 2.04–1.85 (m, 3H), 1.82–1.69 (m, 2H), 1.67–1.37 (m, 6H), 1.35-1.25 (m, 2H), 1.7-1.05 (m, 1H).

Example 8: (S)-N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl-1,2,3 Synthesis of 4-tetrahydronaphthalen-2-amine

Step 1: (S)-N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl-1,2,3, Synthesis of 4-tetrahydronaphthalen-2-amine

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (80.0 mg, 0.31 mmol) and (S) under N2 -1,2,3,4-tetrahydronaphthalen-2-amine (90.8 mg, 0.62 mmol) was added to dichloromethane (15 mL). Sodium cyanoborohydride (97.0 mg, 1.54 mmol) and methanol (3 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. After purification by preparative liquid phase (preparation of liquid phase by preparative method C), the title compound is obtained by lyophilization, and the mixture is dissolved in acetonitrile, and then added to 1 mol/L of dilute hydrochloric acid for 30 minutes, and lyophilized to obtain the title compound hydrochloride 29.6 mg. .

ESI-MS (m/z): 391.2 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 - 8.59 (m, 1H), 7.94-7.90 (m, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.40-7.37 (m, 1H) ), 7.18–7.03 (m, 4H), 3.61 (t, J = 11.6 Hz, 2H), 3.32-3.28 (m, 1H), 3.04-2.91 (m, 2H), 2.87–2.61 (m, 3H), 2.48–2.18 (m, 4H), 2.07-2.03 (m, 2H), 1.95–1.80 (m, 2H), 1.75–1.41 (m, 6H), 1.40-1.30 (m, 2H), 1.03-0.95 (m) , 1H), 0.68-0.60 (m, 1H).

Example 9: (R)-N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl)benzodihydropyrrolidine Synthesis of m--3-amine

Step 1: (R)-N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl)chromanol) Synthesis of 3-amine

(R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (60.0 mg, 0.23 mmol) and (R) under N2 -Chlorohydropyran-3-amine (43.0 mg, 0.23 mmol) was added to dichloromethane (15 mL). Sodium cyanoborohydride (93.1 mg, 1.16 mmol) and methanol (3 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. Purification by preparative liquid phase (preparation of liquid phase by preparative method C), lyophilized to give the title compound, which was dissolved in acetonitrile, and then added to 1 mol/L of diluted hydrochloric acid for 30 minutes, and then lyophilized to give 13.5 mg of the title compound.

ESI-MS (m/z): 393.2 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ8.63 (d, J = 5.0Hz, 1H), 7.96 (s, 1H), 7.62 (d, J = 8.2Hz, 1H), 7.42 (s, 1H) , 7.16–7.06 (m, 2H), 6.92–6.89 (m, 1H), 6.81 (d, J = 7.8 Hz, 1H), 4.22–4.15 (m, 2H), 3.58 (t, J = 11.1 Hz, 4H) ), 3.17–3.04 (m, 1H), 2.94–2.78 (m, 2H), 2.44 (d, J = 13.9 Hz, 3H), 2.16–2.06 (m, 1H), 1.97 (t, J = 11.1 Hz, 1H), 1.86 (d, J = 13.7 Hz, 1H), 1.76 - 1.60 (m, 2H), 1.57 - 1.31 (m, 5H), 1.04 - 0.92 (m, 1H), 0.73 - 0.64 (m, 1H) .

Example 10: (S)-N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl)benzodihydropyrrolidine Synthesis of m--3-amine

Step 1: (S)-N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl)chromanol) Synthesis of 3-amine

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (60.1 mg, 0.23 mmol) and (S) under N2 -Chlorohydropyran-3-amine (43.0 mg, 0.23 mmol) was added to dichloromethane (15 mL). Sodium cyanoborohydride (93.2 mg, 1.16 mmol) and methanol (3 mL) were added. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (5 mL), filtered and evaporated. Purification by preparative liquid phase (preparation of liquid phase by preparative method C), lyophilized to give the title compound, which was dissolved in acetonitrile, and then added to 1 mol/L of diluted hydrochloric acid for 30 minutes, and then lyophilized to obtain 23.4 mg of the title compound.

ESI-MS (m/z): 393.2 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ8.63 (d, J = 5.0Hz, 1H), 7.96 (s, 1H), 7.62 (d, J = 8.2Hz, 1H), 7.42 (s, 1H) , 7.16–7.06 (m, 2H), 6.92–6.89 (m, 1H), 6.81 (d, J = 7.8 Hz, 1H), 4.22–4.15 (m, 2H), 3.58 (t, J = 11.1 Hz, 4H) ), 3.17–3.04 (m, 1H), 2.94–2.78 (m, 2H), 2.44 (d, J=13.9 Hz, 3H), 2.16–2.06 (m, 1H), 1.97 (t, J=11.1 Hz, 1H), 1.86 (d, J = 13.7 Hz, 1H), 1.76 - 1.60 (m, 2H), 1.57 - 1.31 (m, 5H), 1.04 - 0.92 (m, 1H), 0.73 - 0.64 (m, 1H) .

Example 11: (R)-(2-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2,3 Synthesis of dihydro-1H-indol-2-yl)methanol

Step 1: Synthesis of (2-amino-2,3-dihydro-1H-indol-2-yl)methanol

2-Amino-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester hydrochloride (50.3 mg, 0.21 mmol) was dissolved in THF (35 mL), and then LiAlH ₄ (24.5 mg, 0.64 mmol) ), react at 25 ° C for 2 hours. After the reaction was completed by LCMS, water and 15% NaOH solution were added to the reaction mixture to quench the reaction, then dried over anhydrous sodium sulfate, filtered and concentrated to give (2-amino-2,3-dihydro-1H-indole-2 -Base) 30.5 mg of crude methanol.

ESI-MS (m/z): 164.22 [M+H] ⁺ .

Step 2: (R)-(2-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2,3-di Synthesis of hydrogen-1H-indol-2-yl)methanol

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (50.2 mg, 0.19 mmol) and (2-amino-2, 3-Dihydro-1H-indol-2-yl)methanol (39.7 mg, 0.19 mmol) was added to MeOH (5 mL). Sodium cyanoborohydride (123.6 mg, 1.93 mmol) was added and the reaction was continued at room temperature for 4 hours. By LC-MS detection, the raw materials disappeared and the target product was produced. Filtration, the filtrate was concentrated to remove a portion of the solvent, and the residue was purified by preparative liquid.

^{_{1 H NMR (400MHz, CD 3}} OD) δ8.48 (d, J = 4.0Hz, 1H), 7.73 (t, J = 8.0Hz, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.21 ( Dd, J = 7.2, 5.2 Hz, 1H), 7.11 - 6.99 (m, 4H), 3.78 - 3.66 (m, 2H), 3.38 (d, J = 11.2 Hz, 1H), 3.34 (d, J = 11.2 Hz) , 1H), 2.80 (dd, J = 16.4, 10.8 Hz, 2H), 2.68 (dd, J = 16.0, 14.4 Hz, 2H), 2.49 - 2.32 (m, 3H), 1.98 - 1.84 (m, 3H), 1.77–1.58 (m, 4H), 1.57–1.36 (m, 4H), 1.14–1.03 (m, 1H), 0.70 (dt, J=13.6, 8.8 Hz, 1H).

Example 12: (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-6,7,8, Synthesis of 9-tetrahydro-5H-benzo[7]cyclopentene-7-amine

Step 1: (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-6,7,8,9- Synthesis of tetrahydro-5H-benzo[7]cyclopentene-7-amine

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (44.5 mg, 0.17 mmol) and 6,7,8,9 under N2 Tetrahydro-5H-benzo[7]cyclopentene-7-amine (35.2 mg, 0.17 mmol) was added to MeOH (5 mL). Sodium cyanoborohydride (39.5 mg, 1.72 mmol) was added and the reaction was continued at room temperature for 4 hours. By LC-MS detection, the raw materials disappeared and the target product was produced. Filtration, the filtrate was concentrated to remove a portion of the solvent, and the residue was purified by preparative liquid phase.

ESI-MS (m/z): 405.3 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ 8.62 - 8.53 (m, 1H), 7.81 (td, J = 8.0, 2.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.28 (ddd , J=7.6, 4.8, 0.8 Hz, 1H), 7.13–6.99 (m, 4H), 3.85–3.72 (m, 2H), 2.77–2.66 (m, 4H), 2.65–2.51 (m, 3H), 2.46 (dd, J=14.0, 2.0 Hz, 1H), 2.12–1.88 (m, 5H), 1.78–1.62 (m, 4H), 1.61–1.39 (m, 4H), 1.19–0.99 (m, 3H), 0.75 (dt, J = 13.6, 9.2 Hz, 1H).

Example 13: (R)-2-Methyl-nitro-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2 Synthesis of 3-dihydro-1H-indol-2-amine

Step 1: (R)-2-Methyl-nitro-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3 -Synthesis of dihydro-1H-indol-2-amine

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (60.2 mg, 0.23 mmol) and 2-methyl-2 under N2. 3-Dihydro-1H-indol-2-amine (43.8 mg, 1.23 mmol) was added to MeOH (5 mL). Sodium cyanoborohydride (148.4 mg, 2.31 mmol) was added and the reaction was continued at room temperature for 4 hours. By LC-MS detection, the raw materials disappeared and the target product was produced. Filtration, the filtrate was concentrated to remove a portion of the solvent, and the residue was purified by preparative liquid phase.

ESI-MS (m/z): 391.3 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 - 8.47 (m, 1H), 7.75 (td, J = 8.0, 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.23 (ddd , J=7.6, 4.8, 0.8 Hz, 1H), 7.10–7.03 (m, 4H), 3.79–3.68 (m, 2H), 2.79 (dd, J=15.6, 6.4 Hz, 2H), 2.67 (dd, J =15.6, 11.6 Hz, 2H), 2.52–2.38 (m, 3H), 1.99–1.86 (m, 3H), 1.77–1.61 (m, 4H), 1.57–1.40 (m, 4H), 1.13–1.08 (m) , 1H), 1.08 (s, 3H), 0.72 (dt, J = 13.6, 8.8 Hz, 1H).

Example 14: 3-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)thiochroman 1 Synthesis of 1-dioxide

2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (30.0 mg, 0.12 mmol) and 3-aminothiochroman under nitrogen atmosphere 1,1-dioxide (22.8 mg, 0.12 mmol) was added to MeOH (5 mL). Sodium cyanoborohydride (74.2 mg, 1.16 mmol) was added and the reaction was continued at room temperature for 4 hours. By LC-MS detection, the raw materials disappeared and the target product was produced. Filtration, the filtrate was concentrated to remove a portion of the solvent, and the residue was purified by preparative liquid phase (preparation of the liquid phase using the procedure C) to afford 8.4 mg of the title compound.

ESI-MS (m/z): 441.2 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (d, J = 4.4 Hz, 1H), 7.84 - 7.71 (m, 2H), 7.58 - 7.48 (m, 2H), 7.45 (t, J = 7.6 Hz) , 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.28 - 7.21 (m, 1H), 3.83 - 3.69 (m, 2H), 3.48 (t, J = 13.6 Hz, 1H), 3.40 - 3.31 ( m,1H), 3.19–3.04 (m, 2H), 2.75 (ddd, J=16.4, 10.8, 5.2 Hz, 1H), 2.66–2.50 (m, 2H), 2.43 (d, J = 13.2 Hz, 1H) , 2.19–2.08 (m, 1H), 2.04–1.97 (m, 1H), 1.91 (d, J = 13.3 Hz, 1H), 1.78–1.67 (m, 3H), 1.66–1.35 (m, 5H), 1.15 –1.01 (m, 1H), 0.78–0.65 (m, 1H).

Example 15: (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-vinyl-2 Synthesis of 3-dihydro-1H-indol-2-amine

Step 1: Synthesis of 2-aminoindan-2-carboxylic acid hydrochloride

Add 4M hydrochloric acid dioxane solution (10 mL) to N-tert-butoxycarbonyl-2-aminoindan-2-carboxylic acid (1.13 g, 4.07 mmol), react at room temperature for 2 hours, and observe the reaction after LC-MS. The title compound was obtained as a white solid (yield: 0.85 g).

Step 2: Synthesis of 2-amino-2,3-dihydro-1H-indole-2-methanol

2-Aminoindan-2-carboxylic acid hydrochloride (0.85 g, 3.98 mmol) was dissolved in THF (50 mL). EtOAc (EtOAc) The reaction was carried out for 3 hours at room temperature. After the reaction was completed by LC-MS, the mixture was washed with water (0.4 mL), 15% NaOH aqueous solution (0.4 mL), water (1.2 ml), and the mixture was stirred for 30 min. The filtrate was concentrated and purified with EtOAcjjjjjjjjjj

Step 3: Synthesis of tert-butyl-N-(2(hydroxymethyl)indol-2-yl)carbamate

2-Amino-2,3-dihydro-1H-indole-2-methanol (0.15 g, 0.92 mmol) was dissolved in DCM (10 mL), and triethylamine (1.38 mmol, 0.19 mL) Butyl ester (1.01 mmol, 0.23 mL) was reacted at 25 ° C for 2 hours.

The reaction was quenched by EtOAc (EtOAc)EtOAc.

Step 4: Synthesis of tert-butyl-N-(2-formylhydrazin-2-yl)carbamate

The oxalyl chloride (0.15 g, 1.18 mmol) was dissolved in DCM (5 mL), EtOAc (EtOAc) (EtOAc) After reacting for 1 hour, a solution of t-butyl-N-(2(hydroxymethyl)indol-2-yl)carbamate (0.21 g, 0.79 mmol) in DCM (5 mL) After an hour, triethylamine (0.32 g, 3.14 mmol) was added and the mixture was allowed to react to room temperature for 2 hours. The reaction was monitored by TLC to the end point. The title compound was obtained as a colorless oily liquid (yield: 136 mg).

Step 5: Synthesis of tert-butyl N-(2-vinylindol-2-yl)carbamate

Methyltriphenylphosphonium iodide (556 mg, 1.38 mmol) was dissolved in THF (10 mL), the solution was dark yellow, and n-BuLi (2.5 M n-hexane solution) (1.38 mmol, 0.55 mL) was added under ice bath. After reacting at this temperature for 30 minutes, the solution turned pale yellow, and tert-butyl-N-(2-formylhydrazin-2-yl)carbamate (45 mg, 0.17 mmol) in THF (5 mL) Solution. The reaction was slowly raised to room temperature for 2 hours. The reaction was detected by LC-MS to the end point. After the mixture was diluted with water (20 mL), EtOAc (EtOAc m.

Step 6: Synthesis of 2-vinylindole-2-amine hydrochloride

To a solution of tert-butyl N-(2-vinylindol-2-yl)carbamate (30 mg, 0.12 mmol) was added hydrochloric acid (4M dioxane, 12.0 mmol, 3 mL). The reaction was monitored by LC-MS to the end point. Concentration gave the title compound as a pale yellow solid.

Step 7: (R)-N-(2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-vinyl-2,3 -Synthesis of dihydro-1H-indol-2-amine

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (32 mg, 0.12 mmol) and 2-ethyl The indole-2-amine hydrochloride (22 mg, 0.11 mmol) was dissolved in MeOH (5 mL), EtOAc (EtOAc) EtOAc (EtOAc) ), continue to react for 18 hours. The reaction was quenched to the end by LC-MS, filtered, concentrated, and purified by preparative liquid chromatography (preparation of liquid crystals of procedure C).

ESI-MS (m/z): 403.2 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ 8.55 - 8.46 (m, 1H), 7.75 (td, J = 7.6, 2.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.27-7. (m,1H), 7.13–7.01 (m, 4H), 5.72 (dd, J=17.2, 10.8 Hz, 1H), 4.94–4.91 (m, 2H), 3.80–3.66 (m, 2H), 3.00–2.74 (m, 4H), 2.51–2.31 (m, 3H), 2.01–1.83 (m, 3H), 1.76–1.37 (m, 8H), 1.13–1.04 (m, 1H), 0.76–0.63 (m, 1H) .

Example 16: 5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-4H-cyclo Synthesis of Pentane[b]thiophene-6(5H)-one

Step 1: Synthesis of (E)-5-(indenyl)-4H-cyclopenta[b]thiophene-6(5H)-one

4H-Cyclopenta[b]thiophene-6(5H)-one (0.60 g, 4.34 mmol) was added to methanol (7.5 mL), and the mixture was warmed to 40 ° C and stirred. n-Butyl nitrite (0.90 g, 8.68 mmol) was added dropwise to the reaction system, and after completion of dropwise addition, concentrated hydrochloric acid (1 mL) was added dropwise. After further stirring at 40 ° C for 1.5 hours, LC-MS showed that 50% of the raw materials were still not converted, cooled to room temperature, concentrated and purified, prepared (liquid phase purification was carried out by Method C) and lyophilized to obtain (E)-5-( Indenyl)-4H-cyclopenta[b]thiophene-6(5H)-one 0.38 g.

Step 2: Synthesis of 5-amino-4H-cyclopenta[b]thiophene-6(5H)-one

(E)-5-(indolyl)-4H-cyclopenta[b]thiophene-6(5H)-one (70 mg, 0.42 mmol) was added to methanol (25 mL) and HCl (0.5 mL). After palladium on carbon (8.8 mg, 0.07 mmol), the mixture was stirred three times with hydrogen overnight. LC-MS showed that the starting material was completely reacted, and concentrated by filtration to give 65 mg of 5-amino-4H-cyclopentane[B]thiophene-6(5H)-one hydrochloride. The crude product was used directly in the next step.

Step 3: 5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-4H-cyclopentane And [b] Synthesis of thiophene-6(5H)-one

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (82.0 mg, 0.32 mmol) and 5-amino -4H-cyclopenta[b]thiophene-6(5H)-one hydrochloride (60.1 mg, 0.32 mmol) was added to dichloromethane (25 mL). And sodium cyanoborohydride (23.9 mg, 0.38 mmol). After stirring for 18 hours, the reaction was observed by LC-MS. The product was formed, the starting material was not completely converted, the diatomaceous earth was filtered, the methanol was rinsed, the residue was dried under reduced pressure, and the preparation and purification (preparation of liquid phase was carried out by method C) was freeze-dried to obtain 5- ((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-4H-cyclopenta[b]thiophene -6 (5H)-ketone 3.8 mg.

ESI-MS (m/z): 397.54 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 - 8.50 (m, 1H), 8.15 - 8.13 (m, 1H), 7.79 - 7.74 (m, 1H), 7.52 - 7.49 (m, 1H), 7.25 - 7.22 (m, 1H), 7.10 (d, J = 4.8 Hz, 1H), 3.79 - 3.71 (m, 2H), 3.26 - 3.18 (m, 1H), 2.72 - 2.47 (m, 3H), 2.43 - 2.39 ( m,1H), 2.21–1.95 (m, 2H), 1.92 (d, J = 13.8 Hz, 1H), 1.80–1.36 (m, 10H), 0.76–0.67 (m, 1H).

Example 17: N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-5,6-dihydro Synthesis of -4H-cyclopenta[b]thiophene-5-amine

Step 1: Synthesis of tert-butyl (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)carbamate

Di-tert-butyl dicarbonate (50 mg, 0.23 mmol) and (E)-5-(indolyl)-4H-cyclopenta[B]thiophene-6(5H)-one (38.3 mg, 0.23 mmol) were added. After adding palladium carbon (27.8 mg, 0.23 mmol) to methanol (6 mL), the mixture was stirred three times with hydrogen overnight. LC-MS showed the starting material was taken up, directly filtered, and concentrated to give <RTI ID=0.0>> The crude product was used directly in the next step.

Step 2: Synthesis of tert-butyl (6-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)carbamate

Sodium borohydride (19.4 mg, 0.52 mmol) was added to tetrahydrofuran (15 mL) and then tert-butyl (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5- The carbamate (65.2 mg, 0.26 mmol) in methanol (5 mL) was added dropwise to the mixture and the mixture was stirred overnight. LC-MS showed that the starting material was completely reacted, and the reaction mixture was concentrated to dryness. Water and DCM were separated and the aqueous phase was extracted twice with DCM. The organic phase was combined and concentrated to give tert-butyl (6-hydroxy-5,6- Dihydro-4H-cyclopenta[B]thiophen-5-yl)carbamate 35.5 mg.

Step 3: Synthesis of 5,6-dihydro-4H-cyclopenta[b]thiophen-5-amine

tert-Butyl (6-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)carbamate (35.1 mg, 0.14 mmol) was dissolved in dichloromethane (17 mL) Further, trifluoroacetic acid (1.7 mL, 0.14 mmol) and Et ₃ SiH (1.7 mL, 0.14 mmol) were added, and the mixture was reacted at 0 ° C for 0.5 hour. LC-MS showed the reaction was completed and directly concentrated to give 3,6-dihydro-4H-cyclopentane[b]thiophen-5-amine 30.5 mg. The crude product was used directly in the next step.

Step 4: N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-5,6-dihydro-4H -Synthesis of cyclopenta[b]thiophene-5-amine

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (74.5 mg, 0.29 mmol) and 5,6 under N2 -Dihydro-4H-cyclopenta[b]thiophene-5-amine (40.2 mg, 0.29 mmol) was added to dichloromethane (5 mL), anhydrous magnesium sulfate (207.5 mg, 1. Sodium borohydride (21.7 mg, 0.34 mmol). After stirring for 18h, the reaction was observed by LC-MS. The product was formed, the raw material was not completely converted, the diatomaceous earth was filtered, the methanol was rinsed, the residue was dried under reduced pressure, and the preparation and purification (preparation of liquid phase was carried out by method C) was freeze-dried to obtain N-( 2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-5,6-dihydro-4H-cyclopentane[ b] thiophene-5-amine 4.8 mg.

ESI-MS (m/z): 383.2 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 - 7.53 (m, 1H), 7.80 - 7.76 (m, 1H), 7.53 - 7.51 (m, 1H), 7.26 - 7.23 (m, 1H), 7.18 - (7, m) ), 2.46–2.34 (m, 2H), 2.08–1.95 (m, 2H), 1.91 (d, J=13.7 Hz, 1H), 1.79–1.36 (m, 9H), 1.14–1.05 (m, 1H), 0.76–0.68 (dt, J=13.6, 8.8 Hz, 1H).

Example 18: (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro Synthesis of -1H-indol-2-amine

Step 1: (R)-N-(2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro-1H -non-2-amine (hydrochloride)

(R)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (235.0 mg, 0.91 mmol) and 2-amino The hydrazine hydrochloride (153.7 mg, 0.91 mmol) was added to dichloromethane (50 mL). Sodium cyanoborohydride (68.3 mg, 1.09 mmol) and methanol (10 mL) were added and the mixture was stirred at room temperature overnight. By LC-MS detection, the raw materials disappeared and the target product was produced. The reaction was quenched by the addition of methanol (15 mL), filtered and evaporated. After preparative liquid phase purification (preparative liquid phase purification using Method C), lyophilization gave 107 mg of the free compound. This compound was added to 35 mL of dilute hydrochloric acid (1N), and stirred for 30 min.

ESI-MS (m/z): 377.2 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d6) δ9.35 (s, 1H), 9.22 (s, 1H), 8.78-8.58 (m, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 7.59 (s, 1H), 7.29–7.11 (m, 4H), 3.90–3.83 (m, 1H), 3.73–3.68 (m, 1H), 3.63–3.51 (m, 1H), 3.18–3.12 (m, 2H) , 3.06–2.99 (m, 2H), 2.85–2.83 (m, 1H), 2.54–2.44 (m, 2H), 2.35–2.31 (m, 1H), 2.25–2.12 (m, 1H), 2.06–2.02 ( m,1H), 1.93 (d, J = 13.8 Hz, 1H), 1.76 - 1.69 (m, 2H), 1.63 - 1.30 (m, 5H), 1.04 - 1.00 (m, 1H), 0.73 - 0.66 (m, 1H).

Biological evaluation

Experimental example 1

1.1 Purpose of the test

The purpose of this assay was to test the agonistic effects of compounds on the μ opioid receptor (μOR) G protein signaling pathway.

1.2 Test principle

Activation of the μ protein G signal pathway regulates intracellular cAMP levels, and changes in intracellular cAMP levels by homogeneous time-resolved fluorescence (HTRF) reflect the agonistic activity of the compound. The maximal effect E _max (100% of the maximum effect of 1 μM full agonist DAMGO (H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH)) based on the compound causing changes in cAMP levels and half of the maximum effect The compound concentration EC _{50 was used to} evaluate the in vitro activity of the compounds.

1.3 Test methods

1.3.1 Test materials and instruments

1.3.2 Test procedure

Serial dilutions of the test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to the experimental plate (Corning-3824) using an Echo machine, transferring 30 nL per well, and transferring 30 nL positive control DAMGO (HPE) and negative. Control DMSO (ZPE) to the corresponding wells. Then, 5 μL of stimulation buffer (STB) and 5 μL of hMOR/CHO cell suspension (10000 cells/well) were sequentially added to each well of the experimental plate, and the final concentrations of the compounds of IBMX and NKH477 in the 10 μL system were 100 μM and 1.5 μM, respectively. The plate was incubated for 40 min in a 37 ° C incubator. The cAMP levels were then tested according to the cAMP Dynamic 2 kit instructions.

1.4 test results

The levels of the agonistic μOR G protein signaling pathway of the tested compounds were determined by the above assay, and the measured EC ₅₀ and E _max results are shown in Table 1 (100% with a maximum effect of 1 μM full agonist DAMGO).

Table 1. Test compound Inflammatory μOR G protein signaling pathways influence the level of cAMP EC ₅₀ and E _max

实施例Example	EC ₅₀(nM) EC ₅₀ (nM)	E _max(％) E _max (%)
实施例一Embodiment 1	1.01.0	83.483.4
实施例二Embodiment 2	7.27.2	68.368.3
实施例三Embodiment 3	12.412.4	63.563.5
实施例四Embodiment 4	13.713.7	67.167.1
实施例六Embodiment 6	0.10.1	61.761.7
实施例七Example 7	97.297.2	100.9100.9
实施例八Example eight	9.39.3	71.371.3
实施例九Example nine	8.58.5	81.181.1
实施例十Example ten	17.617.6	74.974.9

实施例十一Embodiment 11	57.557.5	79.479.4
实施例十二Example twelve	15.315.3	73.673.6
实施例十三Example thirteen	21.421.4	63.463.4
实施例十五Example fifteen	22.522.5	100.8100.8
实施例十六Example sixteen	23.023.0	70.370.3
实施例十七Example seventeen	1.01.0	65.865.8
实施例十八Example 18	1.31.3	63.963.9

Conclusion: The compounds of this application have strong agonistic activity on the μ opioid receptor (μOR) G protein signaling pathway.

Experimental example 2

2.1 Purpose of the test

The purpose of this assay was to test the activity of the μ opioid receptor (μOR) to recruit β inhibitory protein 2 after activation by the compounds of the present application.

2.2 Test principle

The mu opioid receptor (μOR) was detected by enzyme fragment complementation (EFC) to recruit β inhibitory protein 2 after activation by the compound. The agonist binds to the μ opioid receptor (μOR) overexpressing the β-gal fragment and recruits the β-inhibitor-coupled β-gal complementary fragment to form a fully catalytically active enzyme, which catalyzes the substrate to produce chemiluminescence. . The maximum effect Emax (maximum effect of 1 μM full agonist DAMGO is 100%) based on the level of β-arrestin 2 recruitment by the compound.

2.3 Test methods

2.3.1 Test materials and instruments

2.3.2 Test procedure

Serial dilutions of the test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to a test plate (PerkinElmer) using an Echo machine, transferring 60 nL per well while transferring 60 nL positive control DAMGO (HPE) and negative control DMSO ( ZPE) to the corresponding hole. Then, 20 μL of U2OS/OPRM1 cell suspension (7500 cells/well) was added to each well of the assay plate, centrifuged at 300 rpm for 30 s, and incubated at room temperature for 2 hours. Then, 6 μL of PathHunter detection reagent was added to each well of the assay plate according to the PathHunter test kit instructions, and allowed to stand on Envision after standing at room temperature for 60 minutes.

2.4 test results

The level of recruitment of β-inhibitor 2 after activation of μOR by the test compound was determined by the above test, and the measured E _max results are shown in Table 2 (100% of the maximum effect of 1 μM full agonist DAMGO).

Table 2. Test compound activated μOR recruitment β 2 inhibitory protein level E _max.

实施例Example	E _max(％) E _max (%)
实施例一Embodiment 1	<3<3
实施例二Embodiment 2	<3<3
实施例六Embodiment 6	<3<3
实施例八Example eight	<3<3
实施例十Example ten	<3<3
实施例十五Example fifteen	<3<3
实施例十六Example sixteen	N/AN/A
实施例十七Example seventeen	N/AN/A
实施例十八Example 18	<3<3

Note: “N/A” means no agonistic activity.

Conclusion: The level of recruitment of β-inhibitor 2 after the activation of the μ opioid receptor (μOR) by the compounds of the present application is weak.

Effect of Experimental Example 3 on Respiratory System in Unconscious C57 Mice

3.1 Experimental purpose

In this experiment, the compound of Example 18 was administered by single injection of awake unbound C57 mice to evaluate its effect on the respiratory system of awake unbound C57 mice.

3.2 Experimental methods

A total of 4 groups were given in this experiment, respectively, PBS (vehicle control group), 1.2 mg/kg of Example 18, 2.4 mg/kg of Example 18 and 10 mg/kg of morphine hydrochloride injection, each group. Six animals, half male and half female. Respiratory system parameters (respiratory frequency, RR; tidal volume, TV; minute ventilation, MV) were recorded and analyzed using a whole body plethysmography system before administration, at 0.25, 0.75, 2, and 4 hours after administration.

3.3 Experimental results

The results of respiratory index test showed that there was no abnormality at each time point after administration of the vehicle control group compared with before administration. Under the conditions of this experiment, the doses of single subcutaneous injection were 1.2 mg/kg and 2.4 mg/kg. Example 18 has no inhibitory effect on the respiratory system of awake unbound C57 mice.

In summary, the compounds of the present application selectively agonize the μ opioid receptor (μOR) G protein signaling pathway.

While the embodiments of the present invention have been described in detail, various modifications and alterations of the details of the embodiments of the present invention can be made by those skilled in the art. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

a compound represented by the formula (I), a solvate thereof, a stereoisomer, a crystal form, a pharmaceutically acceptable salt or ester, or any combination thereof,

Wherein R 1 is selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , CO 2 R a and -C(O)NR b R c ; alternatively, R 1 forms a ring with ring A;

R 2 is selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ;

R 3 is selected from hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or, R 2 and R 3 to form a ring;

R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected Substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;

R b and R c are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkane The aryl group, the aryl group, the heteroaryl group, the acyl group, the sulfonyl group are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;

W and U are independently selected from -(CR d R e ) m1 -, -(CR d R e ) m1 -O-, -(CR d R e ) m1 -NR f -, -(CR d R e ) m1 -C(=O)-, -(CR d R e ) m1 -S(O) q -, -C(=O)-NR f - and -C(=O)-;

V is selected from C and N;

R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl and heterocycloalkyl; or R d and R e are bonded to a carbon atom to which they are attached;

m 1 is selected from 1, 2, 3 and 4;

Ring A is selected from the group consisting of an aromatic ring, a heteroaryl ring, an aliphatic carbocyclic ring, and an aliphatic heterocyclic ring;

m and n are independently selected from 0, 1, 2, 3, 4 and 5;

x and y are independently selected from 1, 2, 3 and 4;

q is selected from 0, 1, and 2.
A compound according to claim 1, a solvate, a stereoisomer, a crystal form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, which has a structure represented by the formula (II).

Wherein R 1 is selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , CO 2 R a and -C(O)NR b R c ; alternatively, R 1 forms a ring with ring A;

R 2 is selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ;

R 3 is selected from hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or, R 2 and R 3 to form a ring;

R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected Substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;

R b and R c are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkane The aryl group, the aryl group, the heteroaryl group, the acyl group, the sulfonyl group are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;

W and U are independently selected from -(CR d R e ) m1 -, -(CR d R e ) m1 -O-, -(CR d R e ) m1 -NR f -;

R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl and alkoxy; or R d and R e are bonded to a carbon atom to which they are attached;

m 1 is selected from 1, 2, 3 and 4;

Ring A is selected from the group consisting of an aromatic ring, a heteroaryl ring, an aliphatic carbocyclic ring, and an aliphatic heterocyclic ring;

m and n are independently selected from 0, 1, 2, 3, 4 and 5;

x and y are independently selected from 1, 2, 3 and 4.
The compound according to claim 1 or 2, a solvate, a stereoisomer, a crystal form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, which has a structure represented by the formula (III).

Wherein each group and substituent are as defined in claim 1 or 2.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 3, which has the formula (III-1) or formula ( III-2) the structure shown,

Wherein each group and substituent are as defined in claim 1 or 2.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 4, wherein

W is selected from -(CR d R e ) m1 -; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl And a 4-8 membered heterocycloalkyl; m 1 is 1 or 2; x is selected from 1, 2 and 3;

Preferably, W is selected from -(CR d R e ) m1 -; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy; m 1 is 1 Or 2; x is selected from 1, 2 and 3;

Preferably, W is selected from -(CR d R e ) m1 -; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-4 alkyl and C 1-4 alkoxy; m 1 is 1 Or 2; x is 1 or 2;

Preferably, W is selected from the group consisting of -CH 2 - and -CH 2 CH 2 -; x is 1 or 2.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 4.

Wherein W is selected from -(CR d R e ) m1 -O-; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 -cycloalkyl and 4-8 membered heterocycloalkyl; or, R d and R e form a 3-7 membered heterocyclic ring with the attached carbon atom; m 1 is 1 or 2; x is 1, 2 or 3;

Preferably, W is selected from -(CR d R e ) m1 -O-; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy; or R d and R e form a 3-7 membered heterocyclic ring with a carbon atom to be bonded; m 1 is 1 or 2; x is 1, 2 or 3;

Preferably, W is selected from
Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d and R e are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1-6 alkyl and C 1 -6 alkoxy; m 1 is 1 or 2; x is 1, 2 or 3;

Preferably, W is selected from
Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is attached to the 4-position in the formula; R d and R e are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1-4 alkyl and C 1 -4 alkoxy; m 1 is 1 or 2; x is 1 or 2;

Preferably, W is selected from
Wherein, the 1 position is connected to the 3 position in the formula, and the 2 position is connected to the 4 position in the formula; x is 1 or 2.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 4.

Wherein W is selected from -(CR d R e ) m1 -NR f -, -(CR d R e ) m1 -C(=O)-, -(CR d R e ) m1 -S(O) q -, -C(=O)- and -C(=O)-NR f -; R d , R e and R f are independently selected from hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy a C 3-8 cycloalkyl group and a 4-8 membered heterocycloalkyl group; or, R d and R e form a 3-7 membered heterocyclic ring with the attached carbon atom; m 1 is 1 or 2; q is 0. , 1 or 2; x is 1, 2 or 3;

Preferably, W is selected from -(CR d R e ) m1 -NR f -, -(CR d R e ) m1 -C(=O)-, -(CR d R e ) m1 -S(O) q - , -C(=O)- and -C(=O)-NR f -; R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkane Or an oxygen group; or, R d and R e form a 3-7 membered heterocyclic ring with a carbon atom to be bonded; m 1 is 1 or 2; q is 0, 1 or 2; x is 1, 2 or 3;

Preferably, W is selected from

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl And C 1-6 alkoxy; m 1 is 1 or 2; q is 0, 1 or 2; x is 1, 2 or 3;

Preferably, W is selected from

Wherein, the 1-position is bonded to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d , R e and R f are independently selected from hydrogen, hydroxy, halogen, C 1-4 alkyl And C 1-4 alkoxy; m 1 is 1 or 2; q is 0, 1 or 2; x is 1 or 2;

Preferably, W is selected from

Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxyl, fluorine, chlorine, methyl and B. Base; m 1 is 1 or 2; q is 0, 1 or 2; x is 1 or 2;

Connect at position; x is 1 or 2;

Preferably, W is selected from
And -C(=O)-, wherein the 1 position is linked to the 3 position in the formula, and the 2 position is linked to the 4 position in the formula; x is 1.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 4.

Wherein W is selected from -(CR d R e ) m1 -, -(CR d R e ) m1 -O-, -(CR d R e ) m1 -S(O) q - and -C(=O)- ; R d and R e are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 4-8 membered heterocycloalkyl; , R d and R e are a 3-7 membered heterocyclic ring with a carbon atom to be bonded; m 1 is selected from 1 and 2; q is selected from 0, 1 and 2; and x is selected from 1, 2 and 3;

Preferably, W is selected from the group consisting of -(CR d R e ) m1 -, -(CR d R e ) m1 -O-, -(CR d R e ) m1 -SO 2 - and -C(=O)-; d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl; m 1 is 1 Or 2; x is selected from 1, 2 and 3;

Preferably, W is selected from the group consisting of -(CR d R e ) m1 -, -(CR d R e ) m1 -O-, -(CR d R e ) m1 -SO 2 - and -C(=O)-; d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-4 alkyl and C 1-4 alkoxy; m 1 is 1 or 2; x is 1 or 2;

Preferably, W is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 -O-, -CH 2 -SO 2 -, and -C(=O)-; x is 1.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1-8.

Wherein U is selected from -(CR d R e ) m1 -; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 ring An alkyl group and a 4-8 membered heterocycloalkyl group; m 1 is 1 or 2; y is selected from 1, 2 and 3;

Preferably, U is selected from -(CR d R e ) m1 -; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy; m 1 is 1 Or 2; y is selected from 1, 2 and 3;

Preferably, U is selected from -(CR d R e ) m1 -; R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-4 alkyl and C 1-4 alkoxy; m 1 is 1 Or 2; y is 1 or 2;

Preferably, U is selected from -CH 2 - and -CH 2 CH 2 -; y is 1 or 2.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1-9.

Wherein R 1 is selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ; or R 1 forms a ring with ring A The parallel ring is a ring A and a 5-6 membered heterocyclic ring or a ring A and a 5-6 membered heteroaryl ring;

R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;

R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group and a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, and the C 6-10 aryl group; The base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;

m is selected from 0, 1, 2, 3, 4 and 5;

Preferably, R 1 is selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered hetero An aryl group, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ; or R 1 forms a ring with ring A, said ring is a ring A and 5-6 membered aliphatic heterocyclic ring or ring A and 5-6 membered heteroaryl ring;

R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;

R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group and a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, and the C 6-10 aryl group; The base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;

m is selected from 0, 1, 2, 3, 4 and 5;

Preferably, R 1 is selected from the group consisting of cyano, halogen and 3-6 membered heterocycloalkyl;

m is 0, 1 or 2;

Preferably, R 1 is selected from the group consisting of cyano, halogen and 5-6 membered heterocycloalkyl;

m is 0, 1 or 2;

Preferably, R 1 is selected from the group consisting of cyano, fluoro and morpholinyl;

m is 0 or 1.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 10.

Wherein R 2 is selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl, -C 1-4 alkyl-OC 1-4 alkane , C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl , C 6-10 aryl, 5-10 membered heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ;

R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;

R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group, a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, the C 6-10 aryl group; The base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;

n is selected from 0, 1, 2, 3, 4 and 5;

Preferably, R 2 is selected from the group consisting of a hydroxyl group, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, and a C 2-6 alkenyl group;

n is 0, 1 or 2;

Preferably, R 2 is selected from the group consisting of a hydroxyl group, a C 1-4 alkyl group, a C 1-4 hydroxyalkyl group, and a C 2-4 alkenyl group;

n is 0, 1 or 2;

Preferably, R 2 is selected from the group consisting of hydroxyl, methyl, hydroxymethyl and vinyl;

n is 0 or 1.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1-11.

Wherein ring A is selected from the group consisting of a C 6-10 aromatic ring, a 5-10 membered heteroaryl ring, a C 3-8 aliphatic carbocyclic ring, and a 3-8 membered aliphatic heterocyclic ring;

Preferably, ring A is selected from the group consisting of a C 6-10 aromatic ring and a 5-10 membered heteroaryl ring;

Preferably, ring A is selected from the group consisting of a benzene ring and a 5-6 membered heteroaryl ring;

Preferably, Ring A is selected from the group consisting of a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, an imidazole ring, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, 1, 2, 4-1H. a triazole ring and a pyrazole ring;

Preferably, Ring A is selected from the group consisting of a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, an imidazole ring, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring.
A compound according to any one of claims 1 to 12, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof,

Wherein R 3 is selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, and 5-10 yuan heteroaryl;

Preferably, R 3 is selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl and halo C 1-6 alkyl;

Preferably, R 3 is selected from the group consisting of hydrogen and C 1-4 alkyl;

Preferably, R 3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl;

Preferably, R 3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and isopropyl;

Preferably, R 3 is hydrogen.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 13, wherein the compound is selected from the group consisting of:

Preferably, the compound is selected from the group consisting of

Preferably, the compound is selected from the group consisting of
A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof; optionally further comprising One or more pharmaceutical excipients.
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15 for use in the preparation of an active opium Use in drugs for the activity of a sample receptor (e.g., mu-opioid receptor).
A compound, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15 for the preparation of an analgesic drug Use in.
A compound according to any one of claims 1 to 14, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition according to claim 15 for use in activating Opioid receptor (eg, μ-opioid receptor) activity.
A compound according to any one of claims 1 to 14, a solvate, a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition according to claim 15 for use in the town pain.
A method of activating an opioid receptor (e.g., mu-opioid receptor) activity in a subject, comprising administering to the subject an effective amount of a compound of any of claims 1-14, a solvate thereof , a stereoisomer, a crystalline form, a pharmaceutically acceptable salt or ester, or any combination of the foregoing, or a step of the pharmaceutical composition of claim 15.
An analgesic method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 14, a solvate, a stereoisomer, a crystalline form thereof, a pharmaceutically acceptable salt or The step of the ester, or any combination of the above, or the pharmaceutical composition of claim 15.
A method of preparing a compound according to claim 1 or 2, comprising the steps of:

Wherein R 1 , R 2 , R 3 , W, U, V, A, m, n, x, y are as described in claim 1;

The compound of formula I is obtained by reductive amination of a compound of formula I-A and a compound of formula I-B;

Preferably,

Wherein R 1 , R 2 , R 3 , W, U, A, m, n, x, y are as described in claim 2;

A compound of formula II is obtained by reductive amination of a compound of formula I-A and a compound of formula II-B;

Preferably, the reductive amination reaction is carried out by adding an acid and/or a reducing agent; preferably, the acid is selected from the group consisting of AcOH and TFA; preferably, the reducing agent is selected from the group consisting of NaBH 4 , NaCNBH 3 and NaBH(OAc) 3 .