CN111836807A

CN111836807A - Oxaspiro compounds, preparation method and application thereof

Info

Publication number: CN111836807A
Application number: CN201980016139.6A
Authority: CN
Inventors: 田强; 张毅涛; 宋智泉; 宋立强; 蔡家强; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2018-04-28
Filing date: 2019-04-16
Publication date: 2020-10-27
Also published as: WO2019205983A1

Abstract

An oxaspiro compound and a preparation method and application thereof, in particular to a compound shown in a formula (I), a solvate, a stereoisomer, a crystal form, a pharmaceutically acceptable salt or ester thereof, or any combination of the compounds, the preparation method thereof and the application thereof in activating opioid receptor activity and preparing analgesic drugs,

Description

Oxaspiro compounds, preparation method and application thereof

the present application is based on and claims priority from applications having CN application No. 201810402312.3, application date 2018, 28/4, and CN application No. 201811358917.3, application date 2018, 11/15, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

The application relates to the field of medicine, in particular to an oxaspiro compound, a preparation method thereof and application thereof in activating opioid receptor activity.

Background

Opioid receptors are important G Protein Coupled Receptors (GPCRs) which are widely distributed in central and peripheral nervous systems, mainly comprise three subtypes of mu, kappa and kappa, and are targets of analgesic effects of opioid drugs and endogenous opioid peptides. Conventional opioid agonists, such as morphine and its derivatives, which act primarily on the mu receptor activation, are the most effective drugs for the treatment of chronic arthritis, inflammatory neuralgia, postoperative pain, and moderate to severe pain caused by various cancers. These traditional drugs can cause side effects such as respiratory depression, gastrointestinal adverse reactions, drug addiction, confusion and tolerance problems, etc., which are closely related to the function of beta-arrestin (beta-arrestin).

Studies have found that opioid receptors mediate and regulate physiological functions primarily through the G protein pathway and the β -arrestin pathway. The stimulation of the mu receptor can not only produce the analgesic effect, but also have obvious respiratory depression and gastrointestinal adverse reactions such as constipation, nausea and the like. Animal models of gene knockout demonstrate: side effects such as analgesia and respiratory depression are achieved through two different signal pathways. Among them, the analgesic action is achieved by activating the downstream signal pathway of G protein, and promotion of recruitment of β -arrestin (β -arrestin) leads to activation of the downstream signal pathway thereof to produce side effects such as respiratory depression and constipation. After morphine is injected into a beta-arrestin 2 gene knockout mouse, the analgesic effect is stronger and the maintenance time is longer. This result is a good indication of the effectiveness and safety of the G protein pathway (Bohn et al, Science, 1999).

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

Disclosure of Invention

The present inventors have discovered a class of oxaspiro compounds that selectively act on the G protein pathway to activate opioid receptors, and have made this application based on these 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 of the foregoing,

wherein R is¹Selected from hydroxy, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or, R¹Form a ring with ring A;

R²selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

R³Selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or, R³And R²Connecting to form a ring;

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

R^band R^cIndependently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, sulfonyl is optionally substituted with 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)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-NR^f-、-(CR^dR^e)_m1-C(＝O)-、-(CR^dR^e)_m1-S(O)_q-、-C(＝O)-NR^f-and-C (═ O) -;

v is selected from C and N;

R^d、R^eand R^fIndependently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; or, R^dAnd R^eForm a ring with the attached carbon atom;

m₁selected from 1,2,3 and 4;

ring a is selected from the group consisting of aromatic, heteroaromatic, aliphatic carbocycle, and lipoheterocycle;

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, R¹Selected from hydroxy, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or, R¹Form a loop with ring a.

In other embodiments, R¹Is a heterocycloalkyl group.

In certain embodiments, R²Selected from hydroxy, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c。

In other embodiments, R²Selected from hydrogen and alkenyl.

In certain preferred embodiments, the compounds have the structure of formula (II),

w and U are independently selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-S(O)_q-、-(CR^dR^e)_m1-NR^f-and-C (═ O) -;

R^d、R^eand R^fIndependently selected from hydrogen, hydroxy, halogen, alkyl and alkoxy; or, R^dAnd R^eIs connected withThe carbon atom of (a) forms a ring;

m₁selected 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 said formula (II),

R¹selected from hydroxy, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or, R¹Form a ring with ring A;

R²selected from hydroxy, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

w and U are independently selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-and- (CR)^dR^e)_m1-NR^f-；

R^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, alkyl and alkoxy; or, R^dAnd R^eForm a ring with the attached carbon atom;

m₁selected 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 compounds have the structure of formula (III),

wherein the groups and substituents are as defined above.

In certain preferred embodiments, the compounds have a structure represented by formula (III-1) or formula (III-2),

wherein the groups and substituents are as defined above.

In certain embodiments, W in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-S(O)_q-and-C (═ O) -; r^dAnd R^eEach independently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; or, R^dAnd R^eTo the carbon atom to which they are attached3-7 membered lipoheterocyclic; m is₁Selected 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-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-SO₂-and-C (═ O) -; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl and 3-6 membered heterocycloalkyl; m is₁Is 1 or 2; x is selected from 1,2 and 3.

In certain embodiments, W in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-SO₂-and-C (═ O) -; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; x is 1 or 2.

In certain embodiments, W in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from-CH₂-、-CH₂CH₂-、-CH₂-O-、-CH₂-SO₂-and-C (═ O) -; x is 1.

In certain embodiments, W in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-O-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; x is 1,2 or 3.

In certain embodiments, W in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-O-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; x is 1,2 or 3.

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

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1 or 2; x is 1,2 or 3.

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; x is 1 or 2.

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

In certain embodiments, W in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-NR^f-、-(CR^dR^e)_m1-C(＝O)-、-(CR^dR^e)_m1-S(O)_q-, -C (═ O) -, and-C (═ O) -NR^f-；R^d、R^eAnd R^fIndependently selectFrom hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1,2 or 3.

In certain embodiments, W in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-NR^f-、-(CR^dR^e)_m1-C(＝O)-、-(CR^dR^e)_m1-S(O)_q-, -C (═ O) -, and-C (═ O) -NR^f-；R^d、 R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1,2 or 3.

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1,2 or 3.

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1 or 2.

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, fluoro, chloro, methyl and ethyl; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1 or 2.

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

and-C (═ O) -, where the 1 position is attached to the 3 position in the formula and the 2 position is attached to the 4 position in the formula; x is 1.

In certain embodiments, U in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-and- (CR)^dR^e)_m1-O-；R^dAnd R^eEach independently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; or, R^dAnd R^eTo the carbon atom to which it is attached to form a 3-7 membered heterocyclic ring; m is₁Selected 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, U in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-and- (CR)^dR^e)_m1-O-；R^dAnd R^eEach independently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl and 3-6 membered heterocycloalkyl; or, R^dAnd R^eTo the carbon atom to which it is attached to form a 3-6 membered heterocyclic ring; m is₁Selected from 1 and 2; y is selected from 1,2 and 3.

In certain embodiments, U in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; y is selected from 1 or 2.

In certain embodiments, U in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from-CH₂-and-CH₂CH₂-; y is 1.

In certain embodiments, U in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)m₁-O-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; m is₁Is 1,2 or 3; y is 1,2 or 3.

In certain embodiments, U in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from- (CR)^dR^e)m₁-O-；R^dAnd R^eIs independently selected fromHydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1,2 or 3; y is 1,2 or 3.

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

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 5 in the general formula; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1 or 2; y is 1,2 or 3.

In certain preferred embodiments, U in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 5 in the general formula; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; y is 1 or 2.

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

In certain preferred embodiments, W and U in each of formula I, formula II, formula III-1, and formula III-2 are each independently selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; m is₁Is 1 or 2; x and y are independently selected from1.2 and 3.

In certain preferred embodiments, W and U in each of formula I, formula II, formula III-1, and formula III-2 are each independently selected from- (CR)^dR^e)_m1-; wherein R is^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 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-1, and formula III-2 are each independently selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; x and y are independently 1 or 2.

In certain preferred embodiments, W and U in each of formula I, formula II, formula III-1, and formula III-2 are each independently selected from-CH₂-and-CH₂CH₂-; x and y are independently 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or R¹Form a fused ring with ring a, said fused ring being a ring a and 5-6 membered lipoheterocyclic ring or a ring a and 5-6 membered heteroaromatic ring;

R^aselected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

R^band R^cIndependently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6An alkylsulfonyl group; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6Alkylsulfonyl is optionally substituted with one or more substituents selected from: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

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

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl, 5-10 membered heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or R¹Form a fused ring with ring a, said fused ring being a ring a and 5-6 membered lipoheterocyclic ring or a ring a and 5-6 membered heteroaromatic ring;

R^band R^cIndependently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6An alkylsulfonyl group; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-to 10-membered heteroaryl,C_1-6Alkanoyl and C_1-6Alkylsulfonyl is optionally substituted with one or more substituents selected from: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

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

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from hydroxy, cyano, halogen, C_1-6Alkyl and-OR^a(ii) a Or, R¹Form a fused ring with ring A, said fused ring is ring A and 5-6 membered lipoheterocycle;

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

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from hydroxy, cyano, halogen, C_1-4Alkyl and-OR^a(ii) a Or, R¹Form a fused ring with ring A, said fused ring is ring A and 5-6 membered lipoheterocycle;

R^aselected from hydrogen, C_1-4Alkyl and 5-6 membered heterocycloalkyl; wherein, said C_1-4Alkyl and 5-6 membered heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, C_1-4Alkyl and halo C_1-4An alkyl group;

m is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from hydroxy, cyano, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butylSec-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy and tetrahydrofuryloxy; or, R¹Form a fused ring with ring A, wherein the fused ring is ring A and 1, 4-dioxane;

m is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from hydroxy, cyano, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, n-propoxy and tetrahydrofuryloxy; or, R¹Form a fused ring with ring A, wherein the fused ring is ring A and 1, 4-dioxane;

m is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from cyano, fluoro, methoxy and tetrahydrofuryloxy; or, R¹Form a fused ring with ring A, wherein the fused ring is ring A and 1, 4-dioxane;

m is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from cyano, halogen and-OR^a(ii) a Or, R¹Form a fused ring with ring A, said fused ring is ring A and 5-6 membered lipoheterocycle;

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

in certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from cyano, halogen and-OR^a(ii) a Or, R¹Form a loop with the ring A, saidAnd the ring is ring A and 5-6 membered lipoheterocycle;

m is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from cyano, fluoro, chloro, bromo, iodo, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, and tetrahydrofuranyloxy; or, R¹Form a fused ring with ring A, wherein the fused ring is ring A and 1, 4-dioxane;

m is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from cyano, halogen and 3-6 membered heterocycloalkyl;

m is 0, 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from cyano, halogen and 5-6 membered heterocycloalkyl;

m is 0, 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2¹Independently selected from cyano, fluoro and morpholinyl;

m is 0 or 1.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl, -C_1-4alkyl-O-C_1-4Alkyl radical, C_3-8Cycloalkyl, 4-8 membered heterocycloalkyl, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_6-10Aryl, 5-to 10-membered heteroarylRadical, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

R^band R^cIndependently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl radical, C_1-6An alkylsulfonyl group; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6Alkylsulfonyl is optionally substituted with one or more substituents selected from: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

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

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl, -C_1-4alkyl-O-C_1-4Alkyl radical, C_3-8Cycloalkyl, 4-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

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

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Hydroxyalkyl radical, C_3-6Cycloalkyl, -C_1-4alkyl-O-C_1-4Alkyl, -OR^aand-CO₂R^a；

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

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Hydroxyalkyl radical, C_3-6Cycloalkyl, -C_1-3alkyl-O-C_1-3Alkyl, -OR^aand-CO₂R^a；

n is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, 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, -CH₂OCH₃Cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, tetrahydrofuryloxy and-C (O) OCH₃；

n is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, -CH₂OCH₃Cyclopropyl, methoxy, ethoxy, tetrahydrofuryloxy and-C (O) OCH₃；

n is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl, 5-10 membered heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

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

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, halogen and-OR^a；

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

n is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Independently selected from hydroxy, cyano, fluoro, chloro, bromo, iodo, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, and tetrahydrofuryloxy;

n is 1 or 2.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2²Selected from the group consisting of hydroxy, methoxy and tetrahydrofuryloxy;

n is 1 or 2.

In certain preferred embodiments, R in formula I and/or formula II and/or formula III-1 and/or formula III-2²Independently selected from C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl or halo C_2-6Alkynyl.

In certain preferred embodiments, R in formula I and/or formula II and/or formula III-1 and/or formula III-2²Independently selected from C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl or halo C_2-4Alkynyl.

In certain preferred embodiments, R in formula I and/or formula II and/or formula III-1 and/or formula III-2²Independently selected from ethenyl, propenyl, fluoroethenyl, 1-difluoroethenyl, 2-methylpropenyl, ethynyl, propynyl, fluoroethynyl. In certain preferred embodiments, R in formula I, formula II, formula III-1, and formula III-2²Independently selected from hydroxy, C_1-6Alkyl radical, C_1-6Hydroxyalkyl and C_2-6An alkenyl group;

n is 0, 1 or 2.

In certain preferred embodiments, R in formula I, formula II, formula III-1, and formula III-2²Independently selected from hydroxy, C_1-4Alkyl radical, C_1-4Hydroxyalkyl and C_2-4An alkenyl group;

n is 0, 1 or 2.

In certain preferred embodiments, R in formula I, formula II, formula III-1, and formula III-2²Independently selected from the group consisting of hydroxy, methyl, hydroxymethyl, and vinyl;

n is 0 or 1.

In certain preferred embodiments, the ring A in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from C_6-10Aromatic ring, 5-10 membered heteroaromatic ring, C_3-8Aliphatic carbocycles and 3-8 membered aliphatic heterocycles.

In certain preferred embodiments, the ring A in each of formula I, formula II, formula III-1, and formula III-2 is independently selected from C_6-10Aromatic rings and 5-10 membered heteroaromatic rings.

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

In certain preferred embodiments, ring a in each of formulas I, II, III-1, and 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, an imidazole ring, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a 1,2, 4-1H-triazole ring, and a pyrazole ring.

In certain preferred embodiments, ring a in each of formula I, formula II, 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, an imidazole ring, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring.

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

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

In certain preferred implementationsIn the scheme, R in each formula I, formula II, formula III-1 and formula III-2³Independently selected from hydrogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2³Independently selected from hydrogen, hydroxy, C_1-6Alkyl and halo C_1-6An alkyl group.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2³Independently selected from hydrogen and C_1-4An alkyl group.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2³Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2³Independently selected from hydrogen, methyl, ethyl, n-propyl and isopropyl.

In certain preferred embodiments, R in each of formulas I, II, III-1, and III-2³Is hydrogen.

In certain preferred embodiments, the compound is selected from:

in certain preferred embodiments, the compound is selected from:

in certain preferred embodiments, the compound is selected from:

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

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

In embodiments of the present application, the pharmaceutical composition may be administered in any of the following ways: oral, aerosol inhalation, rectal, nasal, buccal, topical, parenteral, e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or via an external reservoir. Among them, oral, intraperitoneal or intravenous administration is preferable.

When administered orally, the compounds of the present application may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may be added to the above oral dosage forms.

When the compound is used for local administration, particularly for treating affected surfaces or organs which are easy to reach by local external application, such as eyes, skin or lower intestinal tract neurogenic diseases, the compound can be prepared into different local administration preparation forms according to different affected surfaces or organs, and the specific description is as follows:

when administered topically to the eye, the compounds of the present application may be formulated as a micronized suspension or solution in sterile saline at a pH that is isotonic, with or without the addition of preservatives such as benzylalkenoxides. For ophthalmic use, the compounds may also be formulated in the form of ointments such as vaseline.

When applied topically to the skin, the compounds of the present application can be formulated in a suitable ointment, lotion, or cream formulation, in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the present application may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or solutions. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.

In another aspect, the present application provides the use of a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition thereof, as described hereinbefore, for the manufacture of a medicament for activating the activity of an opioid receptor (e.g., a μ -opioid receptor).

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

In another aspect, the present application provides a method of activating opioid receptor (e.g., μ -opioid receptor) activity in a subject, comprising the step of administering to the subject an effective amount of a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition as described above.

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

In another aspect, the present application provides a compound, solvate, stereoisomer, crystal form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition as described hereinbefore for use in analgesia.

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

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

wherein R is¹、R²、R³W, U, V, A, m, n, x, y are as previously described;

the compound of formula I is prepared by carrying out reductive amination reaction on the compound of formula I-A and the compound of formula I-B. The reductive amination reaction can be carried out with reference to experimental conditions commonly 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 AcOH and TFA.

In certain preferred embodiments, the reducing agent is selected from NaBH₄、NaCNBH₃And NaBH (OAc)₃。

In certain preferred embodiments, the compounds are prepared by a process comprising the steps of:

wherein R is¹、R²、R³W, U, A, m, n, x, y are as described above;

the compound of formula II is prepared by the reductive amination reaction of the compound of formula I-A and the compound of formula II-B. The reductive amination reaction can be carried out with reference to experimental conditions commonly 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 AcOH and TFA. In certain preferred embodiments, the reducing agent is selected from NaBH₄、NaCNBH₃And 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 and non-stoichiometric amounts of solvates, preferably hydrates.

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

In addition, molecules, atoms or ions of partial natural or artificial compounds can be arranged in a certain regular periodic repetition mode in space, the arrangement has periodicity of three-dimensional space, and the molecules, atoms or ions can repeatedly appear at a certain distance. In this case, the compounds may exist in two or more crystalline states, molecules of the same structure, crystallized in different solid forms, called polymorphs or polymorphs (polymorphs). When referring to a particular crystalline form, it is often referred to as "crystal form", that is the term "crystalline form" as used in this application.

As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is pharmaceutically acceptable and that has the pharmacological activity of the parent compound. Such salts include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids; such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic 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, muconic acid, and the like; or salts formed when an acidic proton present on the parent compound is replaced by a metal ion, e.g., an alkali metal ion or an alkaline earth metal ion; or a complex compound with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like.

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

As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group which may be a monocyclic or polycyclic fused system, andand may be fused to an aromatic ring. E.g. C_3-8Cycloalkyl radical, C_3-6Cycloalkyl radical, C_4-6Cycloalkyl radical, C_5-6Cycloalkyl groups, 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 cyclic group, such as 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl, optionally substituted with at least one and up to four heteroatoms independently selected from N, O or S. Examples of such groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, or the like.

As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic group comprising at least one aromatic ring, preferably C_6-10Aryl, i.e. aryl of 6,7,8,9 or 10 carbon atoms. Examples of the aromatic group in the present application include phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indenyl and the like.

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

As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. The term "C_1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6, i.e. 1,2,3,4, 5 or 6 carbon atoms, typically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, pentyl, hexyl and the like. Similarly, the term "C_1-4Alkyl "means a straight or branched chain alkyl group having 1,2,3 or 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

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 halo C_1-6Alkyl, halo C_1-4Alkyl groups, and 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 hydroxyl groups, wherein the alkyl group is as described previously. For example, C1-6 hydroxyalkyl, C1-4 hydroxyalkyl. Specific examples include, but are not limited to, hydroxymethyl, 1-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 the structure alkyl-O-, wherein the alkyl is as described previously. E.g. C_1-6Alkoxy radical, C_1-4Alkoxy, and the like. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like.

As used herein, the term "acyl" refers to a group having the structure alkyl-c (o) -wherein the alkyl is as described previously. E.g. C_1-6Alkanoyl radical, C_1-4Alkanoyl groups, and the like. Specific examples include, but are not limited to, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl, and the like.

As used herein, the term "sulfonyl" refers to a compound having an alkyl-S (O)₂-a group of structure (la) wherein the alkyl group is as described hereinbefore. E.g. C_1-6Alkylsulfonyl radical, C_1-4Alkylsulfonyl and the like. Specific examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, and the like.

As used herein, the term "aromatic ring" refers to a monocyclic or polycyclic ring system comprising at least one aromatic ring. E.g. C_6-10Aromatic rings, i.e. aromatic rings 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 indene ring and the like.

As used herein, the term "heteroaromatic ring" refers to an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms are independently O, N or S, and the remaining ring atoms are carbon atoms. Such as 5-10 membered heteroaromatic rings, 5-6 membered heteroaromatic rings, and the like. Specific examples include, but are not limited to, a pyrrole ring, a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiazole ring, an isothiazole ring, a thiadiazole ring, a pyridine ring, a pyrimidine ring, a triazine ring, a benzimidazole ring, a benzoxazole ring, a benzothiazole ring, a benzofuran ring, a benzothiophene ring, an indole ring, an isoindole ring, a pyridazine ring, a pyrazine ring, a 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. E.g. C_3-8Aliphatic carbocyclic ring, C_3-6Aliphatic carbocyclic ring, C_3-5Aliphatic carbocycles, and the like. Specific examples include, but are not limited to, cyclopropane rings, cyclobutane rings, cyclopentane rings, and cyclohexane rings.

As used herein, the term "aliphatic heterocycle" refers to a saturated or partially saturated, non-aromatic, monocyclic or polycyclic ring optionally substituted with at least one and up to four heteroatoms independently selected from N, O or S. For example, 3-to 8-membered aliphatic heterocyclic ring, 3-to 6-membered aliphatic heterocyclic ring, 3-to 5-membered aliphatic heterocyclic ring, etc. Specific examples include, but are not limited to, pyrrolidine ring, tetrahydrofuran ring, dihydrofuran ring, tetrahydrothiophene ring, piperidine ring, morpholine ring, piperazine ring, or 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 (1) unsubstituted or (2) substituted. If a carbon on a group is described as optionally substituted with one or more substituents selected from the group consisting of those described below, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If a nitrogen on a group is described as being optionally substituted with one or more of the following substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.

The invention also includes pharmaceutically acceptable isotopic compounds of the compounds which are identical in structure to the compounds of the invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. hydrogen)²H、³H) (ii) a Isotopes of carbon (e.g. of¹¹C、¹³C and¹⁴C) (ii) a Isotopes of chlorine (e.g. of chlorine)³⁶Cl); isotopes of fluorine (e.g. of fluorine)¹⁸F) (ii) a Isotopes of iodine (e.g. of iodine)¹²³I and¹²⁵I) (ii) a Isotopes of nitrogen (e.g. of¹³N and¹⁵n); isotopes of oxygen (e.g. of¹⁵O、¹⁷O and¹⁸o); isotopes of phosphorus (e.g. of phosphorus)³²P); and isotopes of sulfur (e.g. of³⁵S)。

As used herein, the term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and refers to substances which have been reasonably evaluated in terms of safety and which are included in pharmaceutical formulations, in addition to active ingredients. The pharmaceutic adjuvant has important functions of solubilization, dissolution assistance, sustained and controlled release and the like besides excipient, carrier and stability improvement, and is an important component which may influence the quality, safety and effectiveness of the medicine. They can be classified into natural, semi-synthetic and total synthetic ones according to their origin. According to their action and use, they can be divided into: solvents, propellants, solubilizers, solubilizing agents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, permeation promoters, pH regulators, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, and the like; according to the administration route, the medicine can be divided into oral administration, injection, mucous membrane, percutaneous or local administration, nasal or oral inhalation administration, ocular administration and the like. The same pharmaceutic adjuvant can be used for pharmaceutic preparations of different administration routes and has different functions and purposes.

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 obtain, or at least partially obtain, a desired effect. For example, a prophylactically effective amount is an amount sufficient to prevent, or delay the onset of disease; a therapeutically effective amount is an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. It is well within the ability of those skilled in the art to determine such effective amounts. For example, an amount effective for therapeutic use will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient, e.g., age, weight and sex, the mode of administration of the drug, and other treatments administered concurrently, and the like.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

The structures of the compounds described in the following examples were determined by nuclear magnetic resonance (¹H NMR) or Mass Spectrometry (MS).

Nuclear magnetic resonance (¹H NMR) was performed using a Bruker 400MHz nuclear magnetic resonance apparatus; the solvent was determined to be deuterated methanol (CD)₃OD), deuterated chloroform (CDCl)₃) Hexadeuterio dimethyl sulfoxide (DMSO-d)₆) (ii) a The internal standard substance is Tetramethylsilane (TMS). All values are expressed in ppm.

Abbreviations in Nuclear Magnetic Resonance (NMR) spectra used in the examples are shown below:

s: unimodal (singlet), d: doublet (doublt), t: triplet (triplet), q: quartet (quartz), dd: doublet (doubledoubledoublet), qd: quartet doubtet, ddd: double doublet (double doublet), ddt: double double triplet (double double triple), dddd: double double doublet (double double doublet), m: multiplet (multiplex), br: broad (broad), J: coupling constant, Hz: hertz, DMSO-d₆: deuterated dimethyl sulfoxide.

Mass Spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

The compounds of the examples were purified using preparative liquid phase (Prep-HPLC) methods including methods A, B and C.

Method a for preparing liquid phase purification:

liquid chromatography instrument model: agilent 1260;

a chromatographic column: waters SunAire Prep C18 OBD (19 mm. times.150 mm. times.5.0 μm);

temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214nm and 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 preparation of liquid phase purification:

liquid chromatography instrument model: agilent 1260;

temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214nm and 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.

Method C for preparation of liquid phase purification:

liquid chromatography instrument model: agilent 1260;

a chromatographic column: waters Xbridge Prep C18 OBD (19 mm. times.150 mm. times.5.0 μm);

temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214nm and 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 bicarbonate solution.

The first embodiment is as follows: preparation of N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-indene-2-amine

The method comprises the following steps: synthesis of 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde

Reacting 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl) acetonitrile (1.55g,6.05mmol) was added to dry toluene (35mL) and cooled to-78 ℃ under nitrogen. Diisobutylaluminum hydride (1.28g,9.07mmol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at-78 ℃ for 2 hours, and after completion of the reaction was monitored by LCMS, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 1 hour. 6N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 6 hours while the temperature was raised to 85 ℃. Cooling the reaction solution to room temperature, adding sodium bicarbonate, adjusting pH to 8, separating, concentrating the aqueous phase to dryness, adding DCM and anhydrous sodium sulfate, stirring for 30 minutes, filtering, and concentrating to obtain 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl) acetaldehyde crude 1.2 g. ESI-MS (M/z) 260.16[ M + H]⁺。

Step two: synthesis of N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-indene-2-amine

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (80mg,0.308mmol) and 2-aminoindene hydrochloride (49.3mg,0.291mmol) were added to dichloromethane (15mL) under nitrogen, anhydrous magnesium sulfate (222.78mg,1.85mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (23.26mg,0.37mmol) and methanol (5mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. The reaction was quenched by addition of methanol (15mL), filtered, and the solvent was evaporated under reduced pressure to give 150mg of crude product. After purification from the preparative liquid phase (preparative liquid phase purification using method A) lyophilized to give the title compound as formate salt 9.53 mg.

ESI-MS(m/z):377.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)8.50(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),0.65m,1H).

Example two: synthesis of N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-2-amine

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (75mg,0.289mmol) and 1,2,3, 4-tetrahydronaphthalen-2-amine (75.55mg,0.289mmol) were added to dichloromethane (15mL) under nitrogen protection, anhydrous magnesium sulfate (348.09mg,2.89mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (90.87mg,1.45mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. The raw materials are not completely reacted and products are generated by LC-MS detection. Direct post-treatment, adding diatomite, filtering, concentrating the filtrate under reduced pressure, adding 100mL of water, extracting with ethyl acetate (30 mL. times.3), combining organic phases, drying with anhydrous sodium sulfate, concentrating, purifying with a preparative liquid phase (the preparative liquid phase is purified by the method B), and freeze-drying to obtain 22.9mg of the trifluoroacetate salt of the title compound.

ESI-MS(m/z):391.56[M+H]⁺；

¹H NMR(400MHz,CDCl₃)9.34(d,J＝66.3Hz,2H),8.66(t,J＝6.8Hz,1H),8.06(d,J＝7.8Hz,1H),7.63(d,J＝8.0Hz,1H),7.52(t,J＝6.2Hz,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＝15.9Hz,2H),2.87(s,3H),2.73–2.52(m,1H),2.20(d,J＝14.8Hz,2H),2.02(d,J＝13.8Hz,1H),1.93–1.74(m,3H),0.81–0.65(m,1H).

Example three: synthesis of 2- ((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) -2, 3-dihydro-1H-inden-1-ol

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (75mg,0.289mmol) and 2-amino-2, 3-dihydro-1H-inden-1-ol (51.77mg,0.347mmol) were added to dichloromethane (15mL) under nitrogen protection, anhydrous magnesium sulfate (208.86mg,1.75mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (21.81mg,0.347mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. Methanol (15mL) was added to the system to quench the reaction, filtered and the solvent was evaporated under reduced pressure to give the crude product. Purification by preparative liquid phase (preparative liquid phase purification using method B) followed by lyophilization afforded the trifluoroacetate salt of the title compound.

ESI-MS(m/z):393.53[M+H]⁺；

¹H NMR(400MHz,CDCl₃)8.68(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＝13.9Hz,1H),1.85(d,J＝11.4Hz,2H),1.67(m,1H),1.62-1.36(m,4H),1.15(s,3H).

Example four: synthesis of 5-fluoro-N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-indene-2-amine

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (75mg,0.289mmol) and 5-fluoro-2, 3-dihydro-1H-inden-2-amine (52.46mg,0.347mmol) were added to dichloromethane (15mL) under nitrogen, anhydrous magnesium sulfate (208.86mg,1.75mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (21.81mg,0.347mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. Methanol (15mL) was added to the system to quench the reaction, filtered and the solvent was evaporated under reduced pressure to give the crude product. Purification by preparative liquid phase (preparative liquid phase purification using method B) followed by lyophilization afforded the trifluoroacetate salt of the title compound.

ESI-MS(m/z):395.52[M+H]⁺；

1H NMR(400MHz,CDCl₃)8.56(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＝14.0Hz,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 five: 2- ((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) -2, 3-dihydro-1H-indene-5-carbonitrile

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (75mg,0.289mmol) and 2-amino-2, 3-dihydro-1H-indene-5-carbonitrile (54.9mg,0.347mmol) were added to dichloromethane (15ml) under nitrogen, anhydrous magnesium sulfate (208.86mg,1.75mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (21.81mg,0.347mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. Methanol (15mL) was added to the system to quench the reaction, filtered and the solvent was evaporated under reduced pressure to give the crude product. Purification by preparative liquid phase (preparative liquid phase purification using method B) followed by lyophilization afforded the trifluoroacetate salt of the title compound.

ESI-MS(m/z):402.54[M+H]⁺；

¹H NMR(400MHz,CDCl₃)8.69(s,1H),8.27–8.07(m,1H),7.76–7.57(m,2H),7.47(m,1H),7.41(d,J＝3.9Hz,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＝12.0Hz,1H),2.37(m,3H),2.20(m,1H),2.02(d,J＝13.5Hz,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 six: synthesis of (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-inden-2-amine

The method comprises the following steps: synthesis of (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1.00g,3.90mmol) was added to dry toluene (35mL), cooled to-78 ℃ under nitrogen and diisobutylaluminum hydride (0.83g,5.85mmol) was added dropwise. After the addition, the mixture was stirred at-78 ℃ for 2 hours, and after completion of the reaction was monitored by LCMS, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 1 hour. 6N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 6 hours while the temperature was raised to 85 ℃. The reaction solution was cooled to room temperature, sodium bicarbonate was added thereto, PH was adjusted to 8, liquid separation was performed, the aqueous phase was concentrated to dryness, dichloromethane and anhydrous sodium sulfate were added thereto, stirring was performed for 30 minutes, filtration was performed, and concentration was performed to obtain 1.21g of a crude product. Pre-HPLC purification gave 0.30g of (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde.

Step two: synthesis of (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-inden-2-amine

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (88.0mg,0.34mmol) and 2-aminoindene hydrochloride (69.1mg,0.41mmol) were added to dichloromethane (15mL) under nitrogen, anhydrous magnesium sulfate (245.06mg,2.04mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (25.59mg,0.41mmol) and methanol (5mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. The reaction was quenched by addition of methanol (15mL), filtered, and the solvent was evaporated under reduced pressure to give 150mg of crude product. Purification by preparative liquid phase (preparative liquid phase purification using method B) followed by lyophilization afforded 12.6mg of the trifluoroacetate salt of the title compound.

ESI-MS(m/z):377.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d6)8.62-8.58(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 seven: synthesis of N- (2- ((R) -9- (pyridin-2-yl-6-oxaspiro [4.5] decan-9-yl) ethyl) -5-morpholin-2, 3-dihydro-1H-inden-2-amine

The method comprises the following steps: synthesis of N- (2- ((R) -9- (pyridin-2-yl-6-oxaspiro [4.5] decan-9-yl) ethyl) -5-morpholin-2, 3-dihydro-1H-inden-2-amine

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (88.0mg,0.34mmol) and 5-morpholine-2, 3-dihydro-1H-inden-2-amine (89.0mg,0.41mmol) were added to dichloromethane (15mL) under nitrogen protection, anhydrous magnesium sulfate (490mg,4.07mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (107mg,1.70mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. Adding methanol (15mL) into the system, performing extraction and quenching reaction, filtering, and evaporating the solvent under reduced pressure to obtain a crude product. Purification by preparative liquid phase (preparative liquid phase purification using method C) and lyophilisation gave 3.7mg of the title compound.

ESI-MS(m/z):462.2[M+H]⁺；

¹H NMR(400MHz,CD₃OD)8.63(dd,J＝4.9,1.7Hz,1H),7.99-7.94(m,1H),7.65(d,J＝8.1Hz,1H),7.47–7.39(m,1H),7.20(dd,J＝8.3,2.1Hz,1H),7.06–6.97(m,2H),3.91–3.84(m,4H),3.77(dd,J＝7.7,2.8Hz,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),1.17-1.05(m,1H).

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

The method comprises the following steps: synthesis of (S) -N- (2- ((R) -9- (pyridin-2-yl-6-oxaspiro [4.5] decan-9-yl) ethyl-1, 2,3, 4-tetrahydronaphthalen-2-amine

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (80.0mg,0.31mmol) and (S) -1,2,3, 4-tetrahydronaphthalen-2-amine (90.8mg,0.62mmol) were added to dichloromethane (15mL) under nitrogen protection, anhydrous magnesium sulfate (186mg,1.54mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (97.0mg,1.54mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. Adding methanol (15mL) into the system, performing extraction and quenching reaction, filtering, and evaporating the solvent under reduced pressure to obtain a crude product. After purification of the preparative liquid phase (preparative liquid phase purification using method C), the title compound was lyophilized, dissolved in acetonitrile, added 1mol/L dilute hydrochloric acid and stirred for 30 minutes and lyophilized again to give 29.6mg of the hydrochloride salt of the title compound.

ESI-MS(m/z):391.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)8.65–8.59(m,1H),7.94-7.90(m,1H),7.61(d,J＝8.1Hz,1H),7.40-7.37(m,1H),7.18–7.03(m,4H),3.61(t,J＝11.6Hz,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 nine: synthesis of (R) -N- (2- ((R) -9- (pyridin-2-yl-6-oxaspiro [4.5] decan-9-yl) ethyl) chroman-3-amine

The method comprises the following steps: synthesis of (R) -N- (2- ((R) -9- (pyridin-2-yl-6-oxaspiro [4.5] decan-9-yl) ethyl) chroman-3-amine

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (60.0mg, 0.23mmol) and (R) -chroman-3-amine (43.0mg,0.23mmol) were added to dichloromethane (15mL) under nitrogen protection, anhydrous magnesium sulfate (139mg,1.16mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (93.1mg,1.16mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. Adding methanol (15mL) into the system, performing extraction and quenching reaction, filtering, and evaporating the solvent under reduced pressure to obtain a crude product. Purification by preparative liquid phase (preparative liquid phase purification using method C), lyophilization afforded the title compound, which was dissolved in acetonitrile and stirred for 30 minutes with 1mol/L dilute hydrochloric acid and lyophilized again to afford 13.5mg of the hydrochloride salt of the title compound.

ESI-MS(m/z):393.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)8.63(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＝7.8Hz,1H),4.22–4.15(m,2H),3.58(t,J＝11.1Hz,4H),3.17–3.04(m,1H),2.94–2.78(m,2H),2.44(d,J＝13.9Hz,3H),2.16–2.06(m,1H),1.97(t,J＝11.1Hz,1H),1.86(d,J＝13.7Hz,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 ten: synthesis of (S) -N- (2- ((R) -9- (pyridin-2-yl-6-oxaspiro [4.5] decan-9-yl) ethyl) chroman-3-amine

The method comprises the following steps: synthesis of (S) -N- (2- ((R) -9- (pyridin-2-yl-6-oxaspiro [4.5] decan-9-yl) ethyl) chroman-3-amine

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (60.1mg,0.23mmol) and (S) -chroman-3-amine (43.0mg,0.23mmol) were added to dichloromethane (15mL) under nitrogen protection, anhydrous magnesium sulfate (139mg,1.16mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (93.2mg,1.16mmol) and methanol (3mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. Adding methanol (5mL) into the system, performing extraction and quenching reaction, filtering, and evaporating the solvent under reduced pressure to obtain a crude product. Purification by preparative liquid phase (preparative liquid phase purification using method C), lyophilization afforded the title compound which was dissolved in acetonitrile and stirred for 30 minutes with 1mol/L dilute hydrochloric acid and lyophilized again to afford 23.4mg of the hydrochloride salt of the title compound.

ESI-MS(m/z):393.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)8.63(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＝7.8Hz,1H),4.22–4.15(m,2H),3.58(t,J＝11.1Hz,4H),3.17–3.04(m,1H),2.94–2.78(m,2H),2.44 (d,J＝13.9Hz,3H),2.16–2.06(m,1H),1.97(t,J＝11.1Hz,1H),1.86(d,J＝13.7Hz,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 eleven: synthesis of (R) - (2- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) -2, 3-dihydro-1H-inden-2-yl) methanol

The method comprises the following steps: synthesis of (2-amino-2, 3-dihydro-1H-inden-2-yl) methanol

2-amino-2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester hydrochloride (50.3mg,0.21mmol) was dissolved in THF (35mL) and LiAlH was added₄(24.5mg, 0.64mmol), and reacted at 25 ℃ for 2 hours. After completion of the reaction was monitored by LCMS, the reaction mixture was quenched by addition of water and 15% NaOH solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 30.5mg of crude (2-amino-2, 3-dihydro-1H-inden-2-yl) methanol.

ESI-MS(m/z):164.22[M+H]⁺。

Step two: synthesis of (R) - (2- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) -2, 3-dihydro-1H-inden-2-yl) methanol

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (50.2mg,0.19mmol) and (2-amino-2, 3-dihydro-1H-inden-2-yl) methanol (39.7mg,0.19mmol) were added to MeOH (5mL) under nitrogen and stirred at room temperature for 0.5H. Sodium cyanoborohydride (123.6mg,1.93mmol) was added, and the reaction was continued at room temperature for 4 hours. Through LC-MS detection, the raw materials disappear and the target product is generated. Filtration, concentration of the filtrate to remove some of the solvent, and lyophilization of the residue after purification of the preparative liquid phase (preparative liquid phase purification using method C) gave 12.34mg of the title compound.

¹H NMR(400MHz,CD₃OD)8.48(d,J＝4.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.21(dd,J＝7.2,5.2Hz,1H),7.11–6.99(m,4H),3.78–3.66(m,2H),3.38(d,J＝11.2Hz,1H),3.34(d,J＝11.2Hz,1H),2.80(dd,J＝16.4,10.8Hz,2H),2.68(dd,J＝16.0,14.4Hz,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＝13.6,8.8Hz,1H).

Example twelve: synthesis of (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -6,7,8, 9-tetrahydro-5H-benzo [7] cyclopenten-7-amine

The method comprises the following steps: synthesis of (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -6,7,8, 9-tetrahydro-5H-benzo [7] cyclopenten-7-amine

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (44.5mg,0.17mmol) and 6,7,8, 9-tetrahydro-5H-benzo [7] cyclopenten-7-amine (35.2mg,0.17mmol) were added to MeOH (5mL) under nitrogen and stirred at room temperature for 0.5H. Sodium cyanoborohydride (39.5mg,1.72mmol) was added and the reaction was continued at room temperature for 4 hours. Through LC-MS detection, the raw materials disappear and the target product is generated. Filtration, concentration of the filtrate to remove some of the solvent, and lyophilization of the residue after purification of the preparative liquid phase (preparative liquid phase purification using method C) gave 11.2mg of the title compound.

ESI-MS(m/z):405.3[M+H]⁺；

¹H NMR(400MHz,CD₃OD)8.62–8.53(m,1H),7.81(td,J＝8.0,2.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.28(ddd,J＝7.6,4.8,0.8Hz,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＝14.0,2.0Hz,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＝13.6,9.2Hz,1H).

Example thirteen: synthesis of (R) -2-methyl-N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-inden-2-amine

The method comprises the following steps: synthesis of (R) -2-methyl-N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-inden-2-amine

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (60.2mg,0.23mmol) and 2-methyl-2, 3-dihydro-1H-inden-2-amine (43.8mg,1.23mmol) were added to MeOH (5mL) under nitrogen and stirred at room temperature for 0.5H. Sodium cyanoborohydride (148.4mg,2.31mmol) was added and the reaction was continued at room temperature for 4 hours. Through LC-MS detection, the raw materials disappear and the target product is generated. Filtration, concentration of the filtrate to remove some of the solvent, and lyophilization of the residue after purification of the preparative liquid phase (preparative liquid phase purification using method C) gave 9.3mg of the title compound.

ESI-MS(m/z):391.3[M+H]⁺；

¹H NMR(400MHz,CD₃OD)8.52–8.47(m,1H),7.75(td,J＝8.0,2.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.23(ddd,J＝7.6,4.8,0.8Hz,1H),7.10–7.03(m,4H),3.79–3.68(m,2H),2.79(dd,J＝15.6,6.4Hz,2H),2.67(dd,J＝15.6,11.6Hz,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＝13.6,8.8Hz,1H).

Example fourteen: synthesis of 3- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) thiochroman 1, 1-dioxide

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (30.0mg,0.12mmol) and 3-aminothiochroman 1, 1-dioxide (22.8mg,0.12mmol) were added to MeOH (5mL) under nitrogen and stirred at room temperature for 0.5 h. Sodium cyanoborohydride (74.2mg,1.16mmol) was added and the reaction was continued at room temperature for 4 hours. Through LC-MS detection, the raw materials disappear and the target product is generated. Filtration, concentration of the filtrate to remove some of the solvent, and lyophilization of the residue after purification by preparative liquid phase (preparative liquid phase purification using method C) gave 8.4mg of the title compound.

ESI-MS(m/z):441.2[M+H]⁺；

¹H NMR(400MHz,CD₃OD)8.54(d,J＝4.4Hz,1H),7.84–7.71(m,2H),7.58–7.48(m,2H),7.45(t,J＝7.6Hz,1H),7.31(d,J＝8.0Hz,1H),7.28–7.21(m,1H),3.83–3.69(m,2H),3.48(t,J＝13.6Hz,1H),3.40–3.31(m,1H),3.19–3.04(m,2H),2.75(ddd,J＝16.4,10.8,5.2Hz,1H),2.66–2.50(m,2H),2.43(d,J＝13.2Hz,1H),2.19–2.08(m,1H),2.04–1.97(m,1H),1.91(d,J＝13.3Hz,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 fifteen: synthesis of (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2-vinyl-2, 3-dihydro-1H-indene-2-amine

The method comprises the following steps: synthesis of 2-aminoindan-2-carboxylic acid hydrochloride

To N-tert-butoxycarbonyl-2-aminoindan-2-carboxylic acid (1.13g,4.07mmol) was added a 4M dioxane hydrochloride solution (10mL) and the mixture was reacted at room temperature for 2 hours, and after completion of the reaction was monitored by LC-MS, the mixture was concentrated to give the title compound as a white solid (0.85 g).

Step two: synthesis of 2-amino-2, 3-dihydro-1H-indene-2-methanol

2-aminoindan-2-carboxylic acid hydrochloride (0.85g, 3.98mmol) was dissolved in THF (50mL), lithium aluminum hydride (0.40mg,11.9mmol) was slowly added under ice bath conditions, and the reaction was slowly warmed to room temperature for 3 hours. After the completion of the reaction was monitored by LC-MS, the reaction was quenched with water (0.4mL), 15% aqueous NaOH (0.4mL), and water (1.2mL), and stirred for 30min with anhydrous sodium sulfate, and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography with DCM/MeOH ═ 10/1 to give the title compound 292mg as a pale yellow solid.

Step three: synthesis of tert-butyl-N- (2 (hydroxymethyl) indol-2-yl) carbamate

2-amino-2, 3-dihydro-1H-indene-2-methanol (0.15g,0.92mmol) was dissolved in DCM (10mL), and triethylamine (1.38mmol,0.19mL) and di-tert-butyl dicarbonate (1.01mmol,0.23mL) were added to react at 25 ℃ for 2 hours.

The reaction was monitored by LC-MS to endpoint and purified by DCM/MeOH 10/1pre-TLC to afford the title compound as a white solid, 207 mg.

Step four: synthesis of tert-butyl-N- (2-formylindol-2-yl) carbamate

Oxalyl chloride (0.15g,1.18mmol) was dissolved in DCM (5mL) and reacted at-78 deg.C under nitrogen protection with DMSO (0.12g,1.57mmol,0.11mL) in DCM (5mL) and at that temperature for 1 hour, tert-butyl-N- (2 (hydroxymethyl) indol-2-yl) carbamate (0.21g,0.79mmol) in DCM (5mL) was added dropwise and at that temperature for 1 hour, and finally triethylamine (0.32g,3.14mmol) was added and allowed to warm to room temperature for 2 hours. TLC monitored the reaction to endpoint. The solvent was spun dry and PE/EA 2/1pre-TLC afforded 136mg of the title compound as a colorless oily liquid.

Step five: synthesis of tert-butyl N- (2-vinyl indol-2-yl) carbamate

Methyltriphenylphosphonium iodide (556mg,1.38mmol) was dissolved in THF (10mL) to give a dark yellow solution, N-BuLi (2.5M in hexane) (1.38mmol,0.55mL) was added under ice-bath conditions, the solution was reacted at this temperature for 30 minutes to give a pale yellow solution, and a solution of tert-butyl-N- (2-formylindol-2-yl) carbamate (45mg,0.17mmol) in THF (5mL) was added dropwise. Slowly raising the temperature to room temperature for reaction for 2 hours. The reaction was detected by LC-MS to the end point. After dilution with water (20mL), liquid was separated, EA (20mL × 3) was extracted, dried over anhydrous sodium sulfate, filtered, concentrated, and PE/EA 5/1pre-TLC separated and purified to give the title compound as a colorless oily liquid, 34 mg.

Step six: synthesis of 2-vinyl indole-2-amine hydrochloride

To tert-butyl N- (2-vinylindol-2-yl) carbamate (30mg,0.12mmol) was added hydrochloric acid (4M dioxane solution, 12.0mmol, 3mL) and the mixture was reacted at room temperature for 1 hour. The reaction was monitored by LC-MS to endpoint. Concentration afforded the title compound as a pale yellow solid, 22 mg.

Step seven: synthesis of (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2-vinyl-2, 3-dihydro-1H-indene-2-amine

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (32mg,0.12mmol) and 2-ethylindole-2-amine hydrochloride (22mg,0.11mmol) were dissolved in MeOH (5mL) under nitrogen, reacted at 50 ℃ for 1h, glacial acetic acid (8.74mmol,0.5mL) and sodium cyanoborohydride (25.9mg,1.12mmol) were added and the reaction was continued for 18 h. The reaction was terminated by LC-MS detection, filtered, concentrated, purified by preparative liquid phase (preparative liquid phase purification using method C), and lyophilized to give 18.4mg of the title compound.

ESI-MS(m/z):403.2[M+H]⁺；

¹H NMR(400MHz,CD₃OD)8.55–8.46(m,1H),7.75(td,J＝7.6,2.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.27-7.18(m,1H),7.13–7.01(m,4H),5.72(dd,J＝17.2,10.8Hz,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 sixteen: synthesis of 5- ((2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) -4H-cyclopenta [ b ] thiophen-6 (5H) -one

The method comprises the following steps: (E) synthesis of (E) -5- (oximido) -4H-cyclopentano [ b ] thiophen-6 (5H) -one

4H-Cyclopenta [ b ] thiophen-6 (5H) -one (0.60g,4.34mmol) was added to methanol (7.5mL), and the mixture was stirred at 40 ℃ with warming. N-butyl nitrite (0.90g,8.68mmol) was added dropwise to the reaction system, and after completion of the addition, concentrated hydrochloric acid (1mL) was added dropwise. After further stirring at 40 ℃ for 1.5 hours, LC-MS shows that 50% of the raw material is not converted, the mixture is cooled to room temperature, and the mixture is concentrated, purified (the preparation liquid phase is purified by a method C) and lyophilized to obtain 0.38g of (E) -5- (hydroxyimino) -4H-cyclopenta [ b ] thiophene-6 (5H) -ketone.

Step two: synthesis of 5-amino-4H-cyclopenta [ b ] thiophen-6 (5H) -one

(E) -5- (hydroxyimino) -4H-cyclopenta [ b ] thiophen-6 (5H) -one (70mg,0.42mmol) was added to methanol (25mL) and HCl (0.5mL), palladium on carbon (8.8mg,0.07mmol) was added, and the mixture was stirred overnight with hydrogen substitution 3 times. LC-MS showed the raw material reaction was complete, and direct filtration and concentration gave 65 mg of hydrochloride of 5-amino-4H-cyclopenta [ B ] thiophen-6 (5H) -one. The crude product was used directly in the next step.

Step three: synthesis of 5- ((2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) -4H-cyclopenta [ b ] thiophen-6 (5H) -one

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (82.0mg, 0.32mmol) and hydrochloride salt of 5-amino-4H-cyclopenta [ b ] thiophen-6 (5H) -one (60.1mg,0.32mmol) were added to dichloromethane (25mL) under nitrogen, anhydrous magnesium sulfate (0.23g,1.90mmol) and sodium cyanoborohydride (23.9mg,0.38mmol) were added. Stirring for 18 hours, LC-MS tracing the reaction, product formation, incomplete conversion of the raw material, celite filtration through pad, methanol elution, reduced pressure spin-drying, preparative purification (preparative liquid phase purification using method C) lyophilization yielded 3.8mg of 5- ((2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) -4H-cyclopenta [ b ] thiophen-6 (5H) -one.

ESI-MS(m/z):397.54[M+H]⁺；

¹H NMR(400MHz,CD₃OD)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＝4.8Hz,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＝13.8Hz,1H),1.80–1.36(m,10H),0.76–0.67(m,1H).

Example seventeen: synthesis of N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -5, 6-dihydro-4H-cyclopenta [ b ] thiophen-5-amine

The method comprises the following steps: synthesis of tert-butyl (6-oxo-5, 6-dihydro-4H-cyclopenta [ b ] thiophen-5-yl) carbamate

Di-tert-butyl dicarbonate (50mg,0.23mmol) and (E) -5- (hydroxyimino) -4H-cyclopenta [ B ] thiophen-6 (5H) -one (38.3mg,0.23mmol) were added to methanol (6mL), and after palladium on charcoal (27.8mg,0.23mmol) was added, hydrogen gas was substituted for 3 times and the mixture was stirred overnight. LC-MS showed the starting material reacted completely, filtered directly and concentrated to give 58mg of tert-butyl (6-oxo-5, 6-dihydro-4H-cyclopenta [ b ] thiophen-5-yl) carbamate. The crude product was used directly in the next step.

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

Sodium borohydride (19.4mg,0.52mmol) was added to tetrahydrofuran (15mL), and tert-butyl (6-oxo-5, 6-dihydro-4H-cyclopenta [ b ] thiophen-5-yl) carbamate (65.2mg,0.26mmol) in methanol (5mL) was added dropwise to the reaction mixture, and stirred at room temperature overnight. LC-MS shows that the raw materials completely react, the reaction solution is concentrated to be dry, water and DCM are added for liquid separation, the water phase is extracted for 2 times by DCM, organic phases are combined, and the tert-butyl (6-hydroxy-5, 6-dihydro-4H-cyclopenta [ B ] thiophen-5-yl) carbamate is obtained by drying and concentration after 35.5mg of tert-butyl (6-hydroxy-5, 6-dihydro-4H-cyclopenta [ B ] thiophen-5-yl) carbamate is.

Step three: synthesis of 5, 6-dihydro-4H-cyclopenta [ b ] thiophene-5-amine

Tert-butyl (6-hydroxy-5, 6-dihydro-4H-cyclopenta [ b)]Thien-5-yl) carbamate (35.1mg,0.14mmol) was dissolved in dichloromethane (17mL) and trifluoroacetic acid (1.7mL,0.14mmol) and Et were added sequentially₃SiH (1.7mL,0.14mmol), 0.5 h at 0 ℃. LC-MS shows that the reaction is complete, and the 5, 6-dihydro-4H-cyclopentano [ b ] is directly obtained by concentration]30.5mg of thiophene-5-amine. The crude product was used directly in the next step.

Step four: synthesis of N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -5, 6-dihydro-4H-cyclopenta [ b ] thiophen-5-amine

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (74.5mg,0.29mmol) and 5, 6-dihydro-4H-cyclopenta [ b ] thiophen-5-amine (40.2mg,0.29mmol) were added to dichloromethane (5mL) under nitrogen, anhydrous magnesium sulfate (207.5mg,1.72mmol) and sodium cyanoborohydride (21.7mg,0.34mmol) were added. Stirring for 18H, performing LC-MS tracking reaction to generate a product, incompletely converting the raw material, filtering with diatomite, eluting with methanol, performing reduced pressure spin-drying, and performing preparative purification (liquid phase purification is performed by method C) and freeze-drying to obtain 4.8mg of N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -5, 6-dihydro-4H-cyclopenta [ b ] thiophene-5-amine.

ESI-MS(m/z):383.2[M+H]⁺；

¹H NMR(400MHz,CD₃OD)8.54–7.53(m,1H),7.80–7.76(m,1H),7.53–7.51(m,1H),7.26–7.23(m,1H),7.18–7.17(m,1H),6.73–6.72(m,1H),3.86–3.72(m,2H),3.06–3.00(m,1H),2.94–2.84(m,1H),2.61–2.48(m,3H),2.46–2.34(m,2H),2.08–1.95(m,2H),1.91(d,J＝13.7Hz,1H),1.79–1.36(m,9H),1.14–1.05(m,1H),0.76–0.68(dt,J＝13.6,8.8Hz,1H).

Example eighteen: synthesis of (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-inden-2-amine

The method comprises the following steps: (R) -N- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -2, 3-dihydro-1H-indene-2-amine (hydrochloride)

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (235.0mg,0.91mmol) and 2-aminoindene hydrochloride (153.7mg,0.91mmol) were added to dichloromethane (50mL) under nitrogen, anhydrous magnesium sulfate (654.4mg,5.44mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (68.3mg,1.09mmol) and methanol (10mL) were added, and the reaction was stirred at room temperature overnight. Through LC-MS detection, the raw materials disappear and the target product is generated. The reaction was quenched by adding methanol (15mL), filtered, and the solvent was evaporated under reduced pressure to give 377mg of crude product. The free compound (107 mg) was obtained by preparative liquid phase purification (preparative liquid phase purification using method C) followed by lyophilization. This compound was added to 35mL of dilute hydrochloric acid (1N), stirred for 30 minutes, and lyophilized again to give 106mg of the hydrochloride of the title compound.

ESI-MS(m/z):377.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d6)9.35(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＝13.8Hz,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 compounds for agonism at the mu opioid receptor (mu OR) G protein signaling pathway.

1.2 principle of the test

Activation of the G protein signaling pathway of the μ OR can regulate intracellular cAMP levelsThe method of phase time resolved fluorescence (HTRF) measures changes in intracellular cAMP levels, which may reflect agonistic activity of the compound. Maximum Effect E on changes in cAMP levels according to the Compound_max(maximum effect of 1. mu.M of the full agonist DAMGO (H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH) is 100%) and the concentration of compound EC which causes half of the maximum effect₅₀The compounds were evaluated for in vitro activity.

1.3 test methods

1.3.1 test materials and instruments

1.3.2 test procedure

Samples of test compounds at serial dilution concentrations were prepared on 384-well LDV plates and the sample dilution sequences were transferred to an experimental plate (Corning-3824) using an Echo machine, corresponding to 30nL per well, together with 30nL of the positive control damgo (hpe) and the negative control dmso (zpe) to the corresponding wells. Then 5. mu.L of stimulation buffer (STB) and 5. mu.L of hMOR/CHO cell suspension (10000 cells/well) were added to each well of the plate in sequence, with the final concentrations of IBMX and NKH477 compounds in the 10. mu.L system being 100. mu.M and 1.5. mu.M, respectively. The experimental plate is placed in a constant-temperature incubator at 37 ℃ for incubation for 40 min. cAMP levels were then detected according to the cAMP Dynamic 2 kit instructions.

1.4 test results

The level of agonism of the μ OR G protein signaling pathway by the test compounds is determined by the above assay, and the EC measured₅₀And E_maxThe results are shown in Table 1 (100% maximal effect with 1. mu.M full agonist DAMGO).

TABLE 1 EC for test compounds agonizing the μ OR G protein signaling pathway affecting cAMP levels₅₀And E_max

Examples	EC ₅₀(nM)	E _max(％)
Example one	1.0	83.4
Example two	7.2	68.3
EXAMPLE III	12.4	63.5
Example four	13.7	67.1
EXAMPLE six	0.1	61.7
EXAMPLE seven	97.2	100.9
Example eight	9.3	71.3
Example nine	8.5	81.1
Example ten	17.6	74.9

EXAMPLE eleven	57.5	79.4
Example twelve	15.3	73.6
EXAMPLE thirteen	21.4	63.4
Example fifteen	22.5	100.8
Example sixteen	23.0	70.3
Example seventeen	1.0	65.8
EXAMPLE eighteen	1.3	63.9

And (4) conclusion: the compounds of the application have strong agonistic activity on the mu opioid receptor (mu OR) G protein signaling pathway.

Experimental example 2

2.1 purpose of the test

The purpose of this assay is to test the activity of recruiting β arrestin2 following activation of μ opioid receptors (μ OR) by the compounds of the present application.

2.2 principle of the test

The activity of recruiting β arrestin2 after activation of μ opioid receptors (μ OR) by compounds was examined by enzyme fragment complementation method (EFC). The agonist, when bound to a mu opioid receptor (mu OR) overexpressing a coupled beta-gal fragment, recruits the beta-gal complementary fragment coupled to the beta-arrestin to form an intact catalytically active enzyme, which catalyzes the substrate to produce chemiluminescence. The maximum effect Emax (100% of the maximum effect with the 1 μ M full agonist DAMGO) on the level of β arrestin2 recruitment with the compound.

2.3 test methods

2.3.1 test materials and instruments

2.3.2 test procedure

Samples of test compounds at serial dilution concentrations were prepared on 384-well LDV plates, and the sample dilution sequences were transferred to an experimental plate (PerkinElmer) using an Echo machine, corresponding to 60nL per well, while transferring 60nL of the positive control damgo (hpe) and the negative control dmso (zpe) to the corresponding wells. 20 μ L U2OS/OPRM1 cell suspension (7500 cells/well) was then added to each well of the plate, centrifuged at 300rpm for 30s, and incubated at room temperature for 2 hours. Then 6. mu.L PathHunter detection reagent was added to each well of the plate as per PathHunter detection kit instructions and read on Envision after standing for 60 minutes at room temperature.

2.4 test results

Levels of recruitment of beta-arrestin 2 following activation of μ OR by the test Compounds were determined by the above assay, E_maxThe results are shown in Table 2 (100% maximal effect with 1. mu.M full agonist DAMGO).

TABLE 2 recruitment of beta-arrestin 2 levels of E following activation of μ OR by test Compounds_max。

Examples	E _max(％)
Example one	<3
Example two	<3
EXAMPLE six	<3
Example eight	<3
Example ten	<3
Example fifteen	<3
Example sixteen	N/A
Example seventeen	N/A
EXAMPLE eighteen	<3

Note: "N/A" means no agonist activity.

And (4) conclusion: the level of recruitment of beta arrestin2 following activation of the mu opioid receptor (mu OR) by the compounds of the present application was shown to be weak.

Experimental example 3 Effect on respiratory System of conscious non-restraint C57 mice

3.1 purpose of the experiment

The compound of example eighteen was administered in a single subcutaneous injection to conscious unbound C57 mice in this experiment to evaluate its effect on the respiratory system of conscious unbound C57 mice.

3.2 Experimental methods

In this test, 4 groups of six animals each having half of a sex were administered with PBS (vehicle control group), eighteen examples (1.2 mg/kg), eighteen examples (2.4 mg/kg) and morphine hydrochloride injection (10 mg/kg). Respiratory system indicators (respiratory rate, RR; tidal volume, TV; minute ventilation, MV) were recorded and analyzed using a systemic plethysmography system at 0.25, 0.75, 2, and 4 hours before and after administration, respectively.

3.3 results of the experiment

And (3) displaying a respiratory index detection result: there was no abnormality at each time point after vehicle control administration compared to pre-administration, and under the present experimental conditions, eighteen examples given at doses of 1.2mg/kg and 2.4mg/kg by single subcutaneous injection had no inhibitory effect on the respiratory system of conscious non-restraint C57 mice.

In summary, the compounds of the present application have selective agonism at the mu opioid receptor (mu OR) G protein signaling pathway.

While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure, and that such modifications are intended to be included within the scope of the disclosure. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

A compound shown in a formula (I), a solvate, a stereoisomer, a crystal form, a pharmaceutically acceptable salt or ester thereof, or any combination of the compound,

wherein R is¹Selected from hydroxy, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or, R¹Form a ring with ring A;

R²selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

R³Selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or, R³And R²Connecting to form a ring;

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

R^band R^cIndependently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, sulfonyl is optionally substituted with 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)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-NR^f-、-(CR^dR^e)_m1-C(＝O)-、-(CR^dR^e)_m1-S(O)_q-、-C(＝O)-NR^f-and-C (═ O) -;

v is selected from C and N;

R^d、R^eand R^fIndependently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, and heterocycloalkyl; or, R^dAnd R^eForm a ring with the attached carbon atom;

m₁selected from 1,2,3 and 4;

ring a is selected from the group consisting of aromatic, heteroaromatic, aliphatic carbocycle, and lipoheterocycle;

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.
The compound of claim 1, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, having a structure according to formula (II),

wherein R is¹Selected from hydroxy, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or, R¹Form a ring with ring A;

R²selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

R³Selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or, R³And R²Connecting to form a ring;

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

R^band R^cIndependently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, sulfonyl is optionally substituted with 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)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-NR^f-；

R^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, alkyl and alkoxy; or, R^dAnd R^eForm a ring with the attached carbon atom;

m₁selected from 1,2,3 and 4;

ring a is selected from the group consisting of aromatic, heteroaromatic, aliphatic carbocycle, and lipoheterocycle;

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 of claim 1 or 2, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, having a structure represented by formula (III),

wherein the groups and substituents are as defined in claim 1 or 2.
The compound of any one of claims 1-3, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, having a structure represented by formula (III-1) or formula (III-2),

wherein the groups and substituents are as defined in claim 1 or 2.
The compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination of the foregoing of any one of claims 1-4, wherein,

w is selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; m is₁Is 1 or 2; x is selected from 1,2 and 3;

preferably, W is selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1 or 2; x is selected from 1,2 and 3;

preferably, W is selected from the group consisting ofCR^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; x is 1 or 2;

preferably, W is selected from-CH₂-and-CH₂CH₂-; x is 1 or 2.
The compound of any one of claims 1-4, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof,

wherein W is selected from- (CR)^dR^e)_m1-O-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; x is 1,2 or 3;

preferably, W is selected from- (CR)^dR^e)_m1-O-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; x is 1,2 or 3;

preferably, W is selected from
Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1 or 2; x is 1,2 or 3;

preferably, W is selected from
Wherein, the 1 position is connected with the 3 position in the general formula, and the 2 positionTo position 4 in the general formula; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; x is 1 or 2;

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

wherein W is selected from- (CR)^dR^e)_m1-NR^f-、-(CR^dR^e)_m1-C(＝O)-、-(CR^dR^e)_m1-S(O)_q-, -C (═ O) -, and-C (═ O) -NR^f-；R^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1,2 or 3;

preferably, W is selected from- (CR)^dR^e)_m1-NR^f-、-(CR^dR^e)_m1-C(＝O)-、-(CR^dR^e)_m1-S(O)_q-, -C (═ O) -, and-C (═ O) -NR^f-；R^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; or, R^dAnd R^eForm a 3-7 membered heterocyclic ring with the carbon atom to which it is attached; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1,2 or 3;

preferably, W is selected from

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1,2 or 3;

preferably, W is selected from

Wherein, the position 1 is connected with the position 3 in the general formula, and the position 2 is connected with the position 4 in the general formula; r^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1 or 2;

preferably, W is selected from

Wherein the 1 position is connected with the 3 position in the general formula, and the 2 position is connected with the 4 position in the general formula；R^d、R^eAnd R^fIndependently selected from hydrogen, hydroxy, fluoro, chloro, methyl and ethyl; m is₁Is 1 or 2; q is 0, 1 or 2; x is 1 or 2;

connecting at the position; x is 1 or 2;

preferably, W is selected from
and-C (═ O) -, where the 1 position is attached to the 3 position in the formula and the 2 position is attached to the 4 position in the formula; x is 1.
The compound of any one of claims 1-4, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof,

wherein W is selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-S(O)_q-and-C (═ O) -; r^dAnd R^eEach independently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; or, R^dAnd R^eTo the carbon atom to which it is attached to form a 3-7 membered heterocyclic ring; m is₁Selected from 1 and 2; q is selected from 0, 1 and 2; x is selected from 1,2 and 3;

preferably, W is selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-SO₂-and-C (═ O) -; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl and 3-6 membered heterocycloalkyl; m is₁Is 1 or 2; x is selected from 1,2 and 3;

preferably, W is selected from- (CR)^dR^e)_m1-、-(CR^dR^e)_m1-O-、-(CR^dR^e)_m1-SO₂-and-C (═ O) -; r^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; x is 1 or 2;

preferably, W is selected from-CH₂-、-CH₂CH₂-、-CH₂-O-、-CH₂-SO₂-and-C (═ O) -; x is 1.
The compound of any one of claims 1-8, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof,

wherein U is selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl and 4-8 membered heterocycloalkyl; m is₁Is 1 or 2; y is selected from 1,2 and 3;

preferably, U is selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-6Alkyl and C_1-6An alkoxy group; m is₁Is 1 or 2; y is selected from 1,2 and 3;

preferably, U is selected from- (CR)^dR^e)_m1-；R^dAnd R^eIndependently selected from hydrogen, hydroxy, halogen, C_1-4Alkyl and C_1-4An alkoxy group; m is₁Is 1 or 2; y is 1 or 2;

preferably, U is selected from-CH₂-and-CH₂CH₂-; y is 1 or 2.
The compound of any one of claims 1-9, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof,

wherein R is¹Selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl、C_6-10Aryl, 5-10 membered heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or R¹Form a fused ring with ring a, said fused ring being a ring a and 5-6 membered lipoheterocyclic ring or a ring a and 5-6 membered heteroaromatic ring;

R^aselected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

R^band R^cIndependently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6An alkylsulfonyl group; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6Alkylsulfonyl is optionally substituted with one or more substituents selected from: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

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

preferably, R¹Selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl, 5-10 membered heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c(ii) a Or R¹Form a fused ring with ring a, said fused ring being a ring a and 5-6 membered lipoheterocyclic ring or a ring a and 5-6 membered heteroaromatic ring;

R^aselected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10A membered heteroaryl group; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

R^band R^cIndependently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6An alkylsulfonyl group; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6Alkylsulfonyl is optionally substituted with one or more substituents selected from: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

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

preferably, R¹Selected from cyano, halogen and 3-6 membered heterocycloalkyl;

m is 0, 1 or 2;

preferably, R¹Selected from cyano, halogen and 5-6 membered heterocycloalkyl;

m is 0, 1 or 2;

preferably, R¹Selected from cyano, fluoro and morpholinyl;

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

wherein R is²Selected from hydroxy, cyano, halogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Hydroxyalkyl, -C_1-4alkyl-O-C_1-4Alkyl radical, C_3-8Cycloalkyl, 4-8 membered heterocycloalkyl, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_6-10Aryl, 5-10 membered heteroaryl, -OR^a、-NR^bR^c、-SR^a、-CO₂R^aand-C (O) NR^bR^c；

R^aSelected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

R^band R^cIndependently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl radical, C_1-6An alkylsulfonyl group; wherein, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 membered heteroaryl, C_1-6Alkanoyl and C_1-6Alkylsulfonyl is optionally substituted with one or more substituents selected from: halogen, hydroxy, amino, cyano, carboxy, C_1-6Alkyl and halo C_1-6An alkyl group;

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

preferably, R²Selected from hydroxy, C_1-6Alkyl radical, C_1-6Hydroxyalkyl and C_2-6An alkenyl group;

n is 0, 1 or 2;

preferably, R²Selected from hydroxy, C_1-4Alkyl radical, C_1-4Hydroxyalkyl and C_2-4An alkenyl group;

n is 0, 1 or 2;

preferably, R²Selected from the group consisting of hydroxy, methyl, hydroxymethyl, and vinyl;

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

wherein ring A is selected from C_6-10Aromatic ring, 5-10 membered heteroaromatic ring, C_3-8Aliphatic carbocycles and 3-8 membered aliphatic heterocycles;

preferably, ring A is selected from C_6-10Aromatic rings and 5-10 membered heteroaromatic rings;

preferably, ring A is selected from a phenyl ring and a 5-6 membered heteroaromatic 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, a 1,2, 4-1H-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.
The compound of any one of claims 1-12, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof,

wherein R is³Selected from hydrogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl and 5-10 membered heteroaryl;

preferably, R³Selected from hydrogen, hydroxy, C_1-6Alkyl and halo C_1-6An alkyl group;

preferably, R³Selected from hydrogen and C_1-4An alkyl group;

preferably, R³Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl;

preferably, R³Selected from hydrogen, methyl, ethyl, n-propyl and isopropyl;

preferably, R³Is hydrogen.
The compound, solvate, stereoisomer, crystalline form, 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:

preferably, said compound is selected from:

preferably, said compound is selected from:
a pharmaceutical composition comprising a compound of any one of claims 1-14, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination of the foregoing; optionally, it further contains one or more pharmaceutical excipients.
Use of a compound of any one of claims 1-14, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition of claim 15, for the manufacture of a medicament for activating the activity of an opioid receptor (e.g., a μ -opioid receptor).
Use of a compound of any one of claims 1-14, a solvate, stereoisomer, crystal form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition of claim 15, for the manufacture of an analgesic medicament.
The compound of any one of claims 1-14, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or the pharmaceutical composition of claim 15 for use in activating opioid receptor (e.g., μ -opioid receptor) activity.
A compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof according to any one of claims 1 to 14 or any combination of the foregoing, or a pharmaceutical composition according to claim 15 for use in analgesia.
A method of activating the activity of an opioid receptor (e.g., a μ -opioid receptor) in a subject, comprising the step of administering to the subject an effective amount of a compound of any one of claims 1-14, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition of claim 15.
A method of analgesia comprising the step of administering to a subject in need thereof an effective amount of a compound of any one of claims 1-14, a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or the pharmaceutical composition of claim 15.
A process for the preparation of a compound according to claim 1 or 2, comprising the steps of:

wherein R is¹、R²、R³W, U, V, A, m, n, x, y are as described in claim 1;

carrying out reductive amination reaction on a compound shown in a formula I-A and a compound shown in a formula I-B to prepare a compound shown in a formula I;

preferably, the first and second electrodes are formed of a metal,

wherein R is¹、R²、R³W, U, A, m, n, x, y are as described in claim 2;

carrying out reductive amination reaction on the compound of the formula I-A and the compound of the formula II-B to prepare a compound of the formula II;

preferably, the reductive amination reaction is carried out with addition of an acid and/or a reducing agent; preferably, the acid is selected from AcOH and TFA; preferably, the reducing agent is selected from NaBH₄、NaCNBH₃And NaBH (OAc)₃。