CN109206417B

CN109206417B - Opioid receptor agonists and uses thereof

Info

Publication number: CN109206417B
Application number: CN201810702595.3A
Authority: CN
Inventors: 范江; 朱凤飞; 陈清平; 汪成涛
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Tibet Haisike Pharmaceutical Co ltd
Priority date: 2017-07-04
Filing date: 2018-07-02
Publication date: 2023-01-03
Anticipated expiration: 2038-07-02
Also published as: CN109206417A; CN115124520A

Abstract

Compounds and salts thereof that may be used as opioid receptor ligands, as well as methods of making and compositions containing the compounds, and their use as mu opioid receptor agonists for the treatment of mu opioid receptor-mediated related disorders, such as pain and pain-related disorders, are described.

Description

Opioid receptor agonists and uses thereof

Technical Field

The present invention relates to compounds useful as opioid receptor ligands, or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts or compositions thereof, and to the use of the compounds of the invention for the treatment of pain.

Background

The opioid receptor is a G Protein Coupled Receptor (GPCR) and is a target for combining endogenous opioid peptide and opioid drugs. Various opioid receptors are present in the human body and are widely distributed in peripheral tissues such as the central nervous system, heart, digestive tract, blood vessels, kidney, etc. The opioid receptors mainly include three types, i.e., mu Opioid Receptor (MOR), delta Opioid Receptor (DOR), and Kappa Opioid Receptor (KOR). Endogenous Nociceptin is the 4 th member of the opioid receptor family, found relatively late, and is called the opioid receptor like 1 (ORL 1). The mu receptor has two subtypes of mu 1 and mu 2, the delta receptor has two subtypes of delta 1 and delta 2, and the kappa receptor has three subtypes of kappa 1, kappa 2 and kappa 3. The research shows that the Mu Opioid Receptor (MOR) has the strongest binding capacity with the morphpeptide, and the mu receptor is also the receptor protein site of main effect of analgesics such as morphine, fentanyl and the like. In recent years, studies show that the mu receptors of hypothalamus, frontal cortex, hippocampus and striatum show different degrees of down regulation after morphine addiction of rats, and simultaneously, the gene expression of the mu receptors is reduced.

Several studies on MOR agonists have been reported in the literature.

(1) CN106588899 discloses compounds of the following structure as MOR agonists,

wherein,

R ₁ selected from alkyl, heterocyclyl, alkoxy and alkenyl. The specific description in this patent is not considered to be part of the present invention.

(2) CN 103702561 discloses compounds of the following structure as MOR agonists,

R ₂₁ and R ₂₂ Independently is H or CH ₃ ，A ₄ Is of the formula C (CH) ₂ ) _n Wherein n =2-5; b ₃ Is H or optionally substituted alkyl, B ₄ Is C ₁ -C ₆ Alkyl radical, D ₁ Is optionally substituted aryl, B ₅ Is an optionally substituted aryl group. The specific description in this patent is not considered to be part of the present invention.

(3) WO2017063509 discloses compounds of the structure as MOR agonists,

wherein ring A is selected from cycloalkyl or heterocyclyl, R is selected from aryl and heteroaryl, R is ₁ The same or different, and each is independently selected from hydrogen atom, alkyl group, alkoxy group, haloalkyl group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, and the like. The specific description in this patent is not considered to be part of the present invention.

In clinical analgesic treatment, opioids are mainly used to treat severe acute pain and cancer pain. Because opioid drugs have a plurality of adverse reactions such as nausea, vomiting, constipation, pruritus and the like, tolerance can be generated after long-term use, and side effects such as respiratory depression, constipation, addiction and the like are generated, so that the development of a novel small-molecule selective MOR agonist which has small side effect or no side effect, better activity and smaller dosage is urgently needed for effectively treating pain.

Disclosure of Invention

The invention aims to provide a small-molecule selective MOR agonist with higher activity, smaller dosage and small side effect.

The invention relates to a compound shown in a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or pharmaceutically acceptable salt thereof,

wherein

A is selected from

And further substituted by 0 to 5R ₄ Substitution;

b is phenyl, pyridyl, alkynyl or benzyl optionally further substituted with 0 to 5R ₂ Substitution;

C ₁ and C ₂ Form a ring together with the carbon atom to which it is attached, said ring being selected from

R ₁ Selected from H, halogen or C _1-6 An alkyl group;

R ₂ selected from F, cl, -CF ₃ 、-CHF ₂ 、-CH ₂ F. Hydroxy, cyano or C _1-6 An alkyl group;

R ₃ selected from H, C _1-6 Alkyl or C _3-6 A cycloalkyl group;

R ₄ selected from halogen, hydroxy, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyl, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b 、-NR _c R _d 、-C(＝O)NR _e R _f 、-C(＝O)OR _g 、C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 10-membered aryl, 5-to 10-membered heteroaryl, -O- (3-to 6-membered heterocycloalkyl), -O- (5-to 10-membered aryl), -O- (5-to 10-membered heteroaryl), -CH ₂ ) _q -S-C _1-6 Alkyl or-S (= O) ₂ -C _1-6 An alkyl group;

R _a selected from hydroxy, C _1-6 Alkoxy, acetoxy, acetamido, -O-C _3-6 A cycloalkyl group;

R _b is selected from- (CH) ₂ ) _p C _3-6 Cycloalkyl, halogen substituted C _1-6 An alkyl group;

R _c and R _d Each independently selected from H or

R _d1 Selected from H, C _1-6 An alkyl group;

R _e and R _f Each independently selected from H or C _1-6 An alkyl group;

R _g is selected from H or C _1-6 An alkyl group;

alternatively, R ₄ 、R ₁ Together with ring a, form a heterocycle;

q is selected from 1 or 2;

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

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

n is selected from 1 or 2;

with the proviso that the following compounds are excluded:

in some embodiments, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

A is selected from

Is preferably selected from

Further preferred is from

Even further preferred from

R ₂₁ Is selected from C _1-6 Alkoxy, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b or-NR _c R _d Preferably selected from methoxy, ethynyl, cyclopropyloxy, ethynyl, n-propyloxy cyclobutyloxy, methoxymethyl, hydroxymethyl,

More preferably from ethynyl, cyclopropyloxy, cyclobutyloxy,

R ₂₂ 、R ₂₃ 、R ₂₄ 、R ₂₅ 、R ₂₆ And R ₂₇ Each independently selected from halogen, hydroxy, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyl, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b 、-NR _c R _d 、-C(＝O)NR _e R _f 、-C(＝O)OR _g 、C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl5-to 10-membered aryl, 5-to 10-membered heteroaryl, -O- (3-to 6-membered heterocycloalkyl), -O- (5-to 10-membered aryl), -O- (5-to 10-membered heteroaryl), -CH ₂ ) _q -S-C _1-6 Alkyl or-S (= O) ₂ -C _1-6 Alkyl, preferably C _1-6 An alkoxy group;

R ₂₈ is selected from-O-C _3-6 Cycloalkyl, preferably cyclopropyloxy;

R _c and R _d Each independently selected from H or

R _d1 Selected from H, C _1-6 An alkyl group;

R _e and R _f Each independently selected from H or C _1-6 An alkyl group;

R _g is selected from H or C _1-6 An alkyl group;

alternatively, R ₂₁ 、R ₁ And A ring form

q is selected from 1 or 2;

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

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

with the proviso that the following compounds are excluded:

A is selected from

B is

1-propynyl or substituted by 0 to 5R ₂ Substituted benzyl, preferably

4-fluorobenzyl or 1-propynyl, and more preferably

In some embodiments, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is included, wherein C ₁ And C ₂ Form a ring together with the carbon atom to which it is attached, said ring being selected from

R ₃ Selected from H, C _1-6 Alkyl or C _3-6 A cycloalkyl group.

In some embodiments, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II)

Wherein

A is selected from

Preference is given to

Further preferred is from

Even further preferred from

R ₂₁ Is selected from C _1-6 Alkoxy, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b or-NR _c R _d Preferably selected from methoxy, ethynyl, cyclopropyloxy, cyclobutyloxy, methoxymethyl, hydroxymethyl,

More preferably from ethynyl, cyclopropyloxy, cyclobutyloxy,

R ₂₂ 、R ₂₃ 、R ₂₄ 、R ₂₅ 、R ₂₆ And R ₂₇ Each independently selected from halogen, hydroxy, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyl, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b 、-NR _c R _d 、-C(＝O)NR _e R _f 、-C(＝O)OR _g 、C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 10-membered aryl, 5-to 10-membered heteroaryl, -O- (3-to 6-membered heterocycloalkyl), -O- (5-to 10-membered aryl), -O- (5-to 10-membered heteroaryl), -CH ₂ ) _q -S-C _1-6 Alkyl or-S (= O) ₂ -C _1-6 Alkyl, preferably C _1-6 An alkoxy group;

R ₂₈ is selected from-O-C _3-6 Cycloalkyl, preferably cyclopropyloxy;

R _a selected from hydroxy, C _1-6 Alkoxy, acetoxy, acetamido, -O-C _3-6 A cycloalkyl group; hydroxy, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, acetoxy, acetylamino, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl or-O-cyclohexyl;

R _b is selected from- (CH) ₂ ) _p C _3-6 Cycloalkyl, halogen substituted C _1-6 Alkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CF ₃ 、-CHF ₂ or-CH ₂ F ₁ Further preferred are cyclopropyl, cyclobutyl and-CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl or-CHF ₂ ；

R _c And R _d Each independently selected from H or

R _d1 Selected from H, C _1-6 Alkyl, preferably methyl or ethyl;

R _e and R _f Each independently selected from H or C _1-6 Alkyl, preferably H or methyl;

R _g is selected from H or C _1-6 Alkyl, preferably H or methyl;

alternatively, R ₂₁ 、R ₁ And A ring form

q is selected from 1 or 2, preferably 1;

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

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

with the proviso that the following compounds are excluded:

in some embodiments, the compound of structural formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein

A is selected from

Preference is given to

B is

1-propynyl or substituted by 0 to 5R ₃ Substituted benzyl, preferably

4-fluorobenzyl or 1-propynyl, and more preferably

R ₁ Selected from H or methyl;

R ₂₁ selected from methoxy, ethynyl, cyclopropyloxy, cyclobutyloxy, methoxymethyl, hydroxymethyl,

R ₂₂ 、R ₂₃ 、R ₂₄ 、R ₂₅ 、R ₂₆ And R ₂₇ Each independently selected from F, cl, hydroxy, methyl, methoxy, ethynyl, hydroxymethyl, methoxymethyl, cyclopropyloxy, cyclobutyloxy,

Substituted with the substituent(s);

alternatively, R ₂₁ 、R ₁ And A ring form

R ₂₈ Selected from cyclopropoxy;

R ₃ selected from F or Cl;

n is selected from 1 or 2;

with the proviso that the following compounds are excluded:

in some embodiments, the compound of structural formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

A is

Preference is given to

Further preferred is

Still further preferred

B is

4-fluorobenzyl or 1-propynyl, preferably

R ₁ Is selected from H orMethyl, preferably H;

n is selected from 2;

with the proviso that the following compounds are excluded:

the invention relates to a compound shown in a general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or pharmaceutically acceptable salt thereof,

Wherein

A is selected from

R ₁ selected from H, halogen or C _1-6 An alkyl group;

R ₂₁ is selected from C _1-6 Alkoxy, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b or-NR _c R _d ；

R ₂₂ 、R ₂₃ 、R ₂₄ 、R ₂₅ 、R ₂₆ And R ₂₇ Each independently selected from halogen, hydroxy, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyl, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b 、-NR _c R _d 、-C(＝O)NR _e R _f 、-C(＝O)OR _g 、C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 10-membered aryl, 5-to 10-membered heteroaryl, -O- (3-to 6-membered heterocycloalkyl), -O-, (5-to 10-membered aryl), -O- (5-to 10-membered heteroaryl), -CH ₂ ) _q -S-C _1-6 Alkyl or-S (= O) ₂ -C _1-6 An alkyl group;

R ₂₈ is selected from-O-C _3-6 Cycloalkyl, halogen or C _1-6 An alkyl group;

R _c and R _d Each independently selected from H or

R _d1 Selected from H, C _1-6 An alkyl group;

R _e and R _f Each independently selected from H or C _1-6 An alkyl group;

R _g is selected from H or C _1-6 An alkyl group;

alternatively, R ₂₁ 、R ₁ And A ring form

q is selected from 1 or 2;

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

n is selected from 1 or 2;

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

with the proviso that,

when A is selected from

B is selected from pyridyl or phenyl, when n is selected from 2, m is not 0 and R is ₂₁ Is other than C _1-6 An alkoxy group;

When A is selected from

B is selected from benzene ring or pyridineWhen it is basic, R ₂₈ Is selected from-O-C _3-6 A cycloalkyl group; and does not include the following compounds:

in some embodiments, a is selected from

B is

1-propynyl or substituted by 0 to 5R ₃ A substituted benzyl group;

R ₁ selected from H or methyl;

Substituted with the substituent(s);

alternatively, R ₂₁ 、R ₁ And A ring form

R ₂₈ Selected from cyclopropoxy;

R ₃ selected from F or Cl;

n is selected from 1 or 2;

with the proviso that,

when A is selected from

B is selected from pyridyl, when n is selected from 2, m is not 0 and R ₂₁ Is not methoxy or

And does not include the following compounds:

in some embodiments, a is

B is

4-fluorobenzyl or 1-propynyl;

R ₁ selected from H or methyl;

n is selected from 2;

provided that when B is selected from

When A is not

And does not include the following compounds:

in some embodiments, a compound of structural formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

In some embodiments, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (III)

In some embodiments, a compound according to the structure of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

A is selected from

And further substituted by 0 to 5R ₄ Substitution; preference is given to

Further preferred is

It is still further preferred

Further preferred is

More preferably

B is pyridyl;

R ₁ is selected from H or C _1-6 Alkyl, preferably H or methyl, further preferably H;

R ₄ selected from halogen, hydroxy, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyl, alkynyl, - (CH) ₂ ) _q R _a 、-OR _b 、-NR _c R _d 、-C(＝O)NR _e R _f 、-C(＝O)OR _g 、C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 10-membered aryl, 5-to 10-membered heteroaryl, -O- (3-to 6-membered heterocycloalkyl), -O- (5-to 10-membered aryl), -O- (5-to 10-membered heteroaryl), -CH ₂ ) _q -S-C _1-6 Alkyl or-S (= O) ₂ -C _1-6 Alkyl, preferably halogen, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _1-6 Alkoxy, - (CH) ₂ ) _q R _a 、-OR _b -O- (3-to 6-membered heterocycloalkyl), -O- (5-to 10-membered aryl) or-O- (5-to 10-membered heteroaryl), further preferably halogen, C _1-6 Alkoxy, -OR _b -O- (3-to 6-membered heterocycloalkyl), -O- (5-to 10-membered aryl) or-O- (5-to 10-membered heteroaryl), more preferably halogen or C _1-6 An alkoxy group;

R _a selected from hydroxy, C _1-6 Alkoxy, acetoxy, acetamido, -O-C _3-6 Cycloalkyl, preferably hydroxy or C _1-6 An alkoxy group;

R _b is selected from- (CH) ₂ ) _p C _3-6 Cycloalkyl or halogen substituted C _1-6 Alkyl, preferably- (CH) ₂ ) _p C _3-6 A cycloalkyl group;

R _c and R _d Each independently selected from H or

Preferably H;

R _d1 selected from H, C _1-6 Alkyl, preferably H or methyl;

R _g is selected from H or C _1-6 Alkyl, preferably methyl or ethyl；

q is selected from 1 or 2, preferably 1;

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

n is selected from 2.

In some embodiments, a compound according to the structure of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

A is selected from

And further substituted by 0 to 5R ₄ Substitution;

R _c and R _d Each independently selected from H or

R _d1 Selected from H, C _1-6 An alkyl group;

R _e and R _f Each independently selected from H or C _1-6 An alkyl group;

R _g is selected from H orC _1-6 An alkyl group;

q is selected from 1 or 2;

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

A is selected from

And further substituted by 0 to 5R ₄ Substitution;

R ₄ selected from halogen or C _1-6 An alkoxy group.

In some embodiments, a compound according to the structure of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

in some embodiments, a compound having the structure of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (IV)

A is selected from

And further substituted by 0 to 5R ₄ Substituted, preferably

Further preferred is

Further preferred is

C ₁ And C ₂ Together with the carbon atom to which they are attached form a ring selected from

R ₃ Selected from H, C _1-6 Alkyl or C _3-6 Cycloalkyl, preferably methyl, ethyl, propyl, isopropyl, 3-pentyl, cyclopentyl, cyclopropyl, cyclobutyl or cyclohexyl;

R _c and R _d Each independently selected from H or

Preferably H;

R _d1 is selected from H or C _1-6 Alkyl, preferably H or methyl;

R _g is selected from H or C _1-6 Alkyl, preferably methyl or ethyl;

q is selected from 1 or 2, preferably 1;

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

n is selected from 2.

In some embodiments, a compound according to the structure of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

A is selected from

And further substituted by 0 to 5R ₄ Substitution;

R ₄ selected from halogen or C _1-6 An alkoxy group.

In a preferred embodiment of the present invention, the compound having the structure of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

A is selected from

And further substituted by 0 to 5R ₄ Substitution;

C ₁ and C ₂ To be connected withThe carbon atoms together forming a ring selected from

R ₃ Selected from H, methyl, ethyl, isopropyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R ₄ selected from F, cl, methoxy or ethoxy;

n is selected from 2.

In some embodiments, a compound according to the structure of formula (IV) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from one of the following structures:

the present invention also relates to a compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein

Is a single bond or a double bond;

R ₁₁ selected from H, phenyl or pyridyl, said phenyl or pyridyl being optionally further substituted by 0 to 3 substituents selected from F, cl, br, I, -CF ₃ 、-CHF ₂ 、-CH ₂ F、C _1-4 Alkyl or C _1-4 Alkoxy radicalSubstituted with a substituent of the group;

R ₁₂ each independently selected from H or

R ₁₃ Each independently selected from H,

R ₁₄ Selected from H, phenyl or C _1-6 Alkyl, said phenyl, alkyl being optionally further substituted by 0 to 2 substituents selected from F, cl, br, I, -CF ₃ 、-CHF ₂ 、-CH ₂ F or C _1-4 Substituted by a substituent of an alkyl group;

R ₁ is selected from H or C _1-4 An alkyl group;

a is selected from

Substituted with a substituent of (1);

R ₂₈ selected from F, cl or C _1-6 An alkyl group;

m is selected from 0, 1 or 2;

provided that R is ₁₁ 、R ₁₂ And R ₁₃ Cannot be both H and R ₁₂ And R ₁₃ And only one is H.

In some embodiments, the compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

R ₁₁ Selected from H, phenyl or pyridyl, said phenyl or pyridyl being optionally further substituted with 0 to 3 substituents selected from F, cl or methoxy;

R ₁₂ each independently selected from H or

R ₁₃ Each independently selected from H,

R ₁₄ Selected from H or phenyl, said phenyl optionally further substituted with 0 to 1 substituents selected from F, cl or methyl;

R ₁ is selected from H;

a is selected from

R ₂₁ Selected from methoxy;

R ₂₈ selected from Cl or methyl;

m is selected from 0 or 1;

In some embodiments, a compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from one of the following structures:

In another aspect of the invention, a compound according to the following structure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

another aspect of the invention relates to the compound or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the salt comprises hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, fumarate, hemi-fumarate, maleate, malate, citrate, succinate, benzenesulfonate or p-toluenesulfonate salt.

The invention also relates to a pharmaceutical composition comprising: an effective dose of the compound, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or further comprising one or more additional therapeutic agents and a pharmaceutically acceptable carrier or excipient. The composition may further comprise at least one additional analgesic, anti-faecal agent.

The invention also relates to the application of the compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt thereof or the composition in preparing a medicament for preventing or treating pain, wherein the pain can be postoperative pain, cancer-caused pain, neuropathic pain, traumatic pain, inflammation-caused pain and the like.

The present invention also relates to a method for preventing or treating pain, which comprises administering to a subject an effective amount of said compound or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or said composition.

The mu opioid receptor-mediated related disorder of the present invention is selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urological and reproductive disorders, cardiovascular disorders, and respiratory disorders.

The terms used in the specification and claims have the following meanings.

Carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention include isotopes thereof, and carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include ¹² C、 ¹³ C and ¹⁴ c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including ¹⁶ O、 ¹⁷ O and ¹⁸ isotopes of O, sulfur including ³² S、 ³³ S、 ³⁴ S and ³⁶ isotopes of S, nitrogen including ¹⁴ N and ¹⁵ isotopes of N, fluorine include ¹⁷ F and ¹⁹ isotopes of F, chlorine including ³⁵ Cl and ³⁷ cl, isotopes of bromine including ⁷⁹ Br and ⁸¹ Br。

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment.

"alkoxy" means-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

"acetoxy" refers to-O- (C = O) -CH ₃ Wherein methyl may be further substituted;

"acetylamino" means-NR' - (C = O) -CH ₃ Wherein methyl may be further substituted and R' may be H or alkyl;

"amino" means-NH ₂ 。

By "cyano" is meant

"Nitro" means-NO ₂ 。

"hydroxy" means-OH.

"carboxyl" means-COOH.

"carbonyl" means- (C = O) -.

"carboxylate" refers to the group-COOR ^19a Wherein R is ^19a Is C _1-6 An alkyl group.

"amido" means a-CONR ^20a R ^21a Wherein R is ^20a And R ^21a Each independently selected from H, alkyl or carbocyclyl, said alkyl or carbocyclyl may be further substituted.

"hydroxyalkyl" is an alkyl group substituted with 1,2 or 3 hydroxyl groups, preferably C _1-4 An alkyl group. Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxypropyl, 1, 3-dihydroxypropyl and 2, 3-dihydroxypropyl.

"cycloalkyl" means a saturated or unsaturated monocyclic cycloalkyl group, which may be substituted or unsubstituted, and the ring carbon atoms include 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 5-cyclooctadienyl, 1, 4-cyclohexadienyl, cycloheptatrienyl and the like.

"Heterocycloalkyl" means a substituted or unsubstituted saturated or unsaturated compound containing at least 1 to 5 substituents selected from N, O, S (= O) or S (= O) ₂ A non-aromatic ring system of heteroatoms or groups, the non-aromatic ring system comprising 3 to 20 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms. Optionally substituted N, S in the heterocyclyl ring may be oxidized to various oxidation states. Non-limiting examples include oxacyclopropane, oxetanyl, oxocyclopentyl, oxocyclohexyl, oxooctyl, aziridinyl, azetidinyl, azacyclohexyl, azacyclopropenyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxacyclohexyl, 1, 3-dithiocyclohexyl, azepinyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyranyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 2, 5-dihydrothienyl,

And the like.

"aryl" refers to substituted or unsubstituted 6 to 14 membered cyclic aromatic groups, including monocyclic aromatic groups and fused ring aromatic groups. Preferably 6 to 14-membered aromatic ring, further preferably 6 to 10-membered aromatic ring, non-limiting examples of which include phenyl, naphthyl, anthryl, phenanthryl and the like. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

"heteroaryl" refers to a substituted or unsubstituted 5 to 14 membered aromatic ring containing 1 to 5 substituents selected from N, O or S (= O) _n A hetero atom or group, preferably a 5-to 10-membered heteroaromatic ring, further preferably 5-to 6-membered. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholine, thiomorpholine, 1, 3-dithiane, benzimidazole, perindopyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together to the parent structure is a heteroaryl ring, non-limiting examples of which include

"alkenyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, containing a carbon-carbon double bond. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-3-yl.

"alkynyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group containing carbon-carbon triple bonds and consisting of 2 to 20 carbon atoms, preferably alkynyl of 2 to 12 carbon atoms, more preferably alkynyl of 2 to 8 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undec-3-yl, dodecyn-4-yl.

"benzyl" means-CH ₂ -phenyl, said phenyl being substituted or unsubstituted, non-limiting examples of which include-CH ₂ -phenyl, -CH ₂ P-methylphenyl, and the like.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of a compound of the present invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, or a non-toxic inorganic or organic acid. Non-limiting examples of the inorganic base include Al, ca, li, mg, K, na, and Zn; non-limiting examples of the organic base include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tetramethylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzaminum, ethylenediamine, glucosamine, N-methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins; non-limiting examples of the inorganic and organic acids include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, and trifluoromethanesulfonic acid.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

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

Detailed Description

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

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS), and Supercritical Fluid Chromatography (SFC) resolves the chiral structure.

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

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

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

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100x 4.6 mm).

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

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

The known starting materials of the present invention can be synthesized by methods known in the art or purchased from Chengdu Kelong chemical industry, chengdu Xiong chemical industry, chengdu chemical industry, aister (Chengdu) pharmaceutical technology GmbH, shaoshan far chemical technology (Shanghai) GmbH, pharmaceutical industry GmbH of the national medicine group, bailinghi Technology GmbH, etc.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 2L.

The hydrogenation reaction is usually carried out by vacuum pumping, hydrogen filling and repeated operation for 3 times.

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

In the examples, the reaction temperature is, unless otherwise specified, room temperature, which is 20 ℃ to 30 ℃.

Brief description:

THF: tetrahydrofuran;

DMF is N, N-dimethylformamide;

me: a methyl group;

PE is petroleum ether;

EA ethyl acetate

THP 2-tetrahydropyran.

Intermediate 1: (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1)

(R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

The first step is as follows: 6-oxaspiro [4.5] decan-9-ol (1 b)

6-oxaspiro[4.5]decan-9-ol

3-buten-1-ol (8.39g, 116.5mmol) and cyclopentanone (1 a) (14.6g, 174.0 mmol) were added to the reaction flask and the temperature was reduced to 0 ℃. 75% concentrated sulfuric acid (33.1g, 337mmol) was added dropwise to the reaction mixture, the temperature of which did not exceed 5 ℃. Naturally raising the temperature to room temperature after the addition is finished, and reacting for 12 hours. At 0 ℃, water (100 mL) was added to the reaction solution, the pH was adjusted to about 8 with sodium hydroxide solution, the product was extracted with ethyl acetate (100 mL × 4), and the combined organic phases were washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. After sample stirring, purification by column chromatography using (ethyl acetate: petroleum ether =1 = 20-1) gave 6-oxaspiro [4.5] decan-9-ol (1 b) as an oily liquid (7.2 g, yield: 40%).

Ms m/z(ESI):139.3[M-OH]；

¹ H NMR(400MHz,CDCl ₃ )δ4.13-4.11(m,2H),3.56-3.50(m,1H),1.86-1.71(m,4H),1.64-1.56(m,2H),1.46-1.36(m,6H).

The second step: 6-oxaspiro [4.5] decan-9-one (1 c)

6-oxaspiro[4.5]decan-9-one

6-oxaspiro [4.5] decan-9-ol (1 b) (5.5g, 35.25mmol) and dichloromethane (120 mL) were added to the reaction flask and the temperature was reduced to 0 ℃. Desmatin oxidant (30g, 70.5 mmol) was added to the reaction mixture in portions at 0 ℃ at a temperature not exceeding 5 ℃. After the addition, the reaction was allowed to naturally warm to room temperature for 12 hours. Sodium bicarbonate solution (80 mL) was added dropwise to the reaction solution to adjust PH =8, filtered, the filter cake was washed with dichloromethane (40 mL × 2), the filtrates were combined, the product was extracted with dichloromethane (50 mL × 2), and the organic phases were combined and washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. After sample stirring, column purification was performed using (ethyl acetate: petroleum ether =1: 30-1).

Ms m/z(ESI):155.3[M+H]；

¹ H NMR(400MHz,CDCl ₃ )δ3.97-3.94(m,2H),2.47-2.42(m,4H),1.85-1.76(m,2H),1.65-1.61(m,2H),1.60-1.53(m,4H).

The third step: 2-cyano-2- [ 6-oxaspiro [4.5] decan-9-ylidene ] acetic acid methyl ester (E/Z) (1 d)

(E/Z)methyl 2-cyano-2-(6-oxaspiro[4.5]decan-9-ylidene)acetate

6-oxaspiro [4.5] decan-9-one (1 c) (25.0g, 0.162mol), methyl cyanoacetate (19.3g, 0.194mol), ammonium acetate (3.75g, 48.64mmol) and acetic acid (1.95g, 32.43mmol) were successively added to toluene (70 mL) at room temperature, heated under reflux to dehydrate and react for 6 hours. After completion of the reaction, water (120 mL) was added to extract the product with ethyl acetate (50 mL. Times.2), the combined organic phases were washed with saturated brine (30 mL. Times.2), and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. After sample stirring, purification by column chromatography using (ethyl acetate: petroleum ether =1 = 80-1) gave methyl 2-cyano-2- [ 6-oxaspiro [4.5] decan-9-ylidene ] acetate (E/Z) (1 d) as an oily liquid (30.0 g, yield: 78.65%).

Ms m/z(ESI):258.2[M+Na]；

¹ H NMR(400MHz,CDCl ₃ )δ3.88-3.86(m,1H),3.84(s,3H),3.81-3.78(m,1H),3.16-3.12(m,2H),2.76-2.72(m,2H),1.82-1.76(m,4H),1.68-1.53(m,4H).

The fourth step: methyl 2-cyano-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) carboxylate (1 e)

methyl 2-cyano-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetate

A solution of 2-bromopyridine (48.0 g,0.3 mol) in THF (150 mL) was added dropwise to a solution of isopropyl magnesium chloride (150 mL, 2M in tetrahydrofuran) at 0 ℃ under nitrogen at 0 ℃ and then stirred at room temperature for 3 hours, ketone iodide (3.5 g) was added and stirred at room temperature for 0.5 hours, and then a mixture of E and Z isomers of methyl 2-cyano-2- [ 6-oxaspiro [4.5] decan-9-ylidene ] acetate (1 d) (47g, 0.2 mol) in tetrahydrofuran (200 mL) was added dropwise to the reaction solution. After the addition, the reaction mixture was heated to 55 ℃ and stirred for 8 hours. The reaction mixture was poured into a mixture of 200g ice/1N HCl (200 mL). The product was extracted with ethyl acetate (500 mL. Times.4), and the combined organic phases were washed with saturated brine (200 mL. Times.1), dried over anhydrous sodium sulfate and concentrated. After sample stirring, purification by column chromatography using (EA: PET =1 = 80-1) gave methyl 2-cyano-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) carboxylate (1 e) (44.0 g, yield: 70.1%) as an oily liquid.

Ms m/z(ESI):315.1[M+H]；

¹ H NMR(400MHz,CDCl ₃ )δ8.62-8.59(m,1H),7.74-7.70(m,1H),7.70-7.68(m,1H),7.21-7.19(m,1H),4.15-4.11(m,3H),3.81-3.66(d,3H),2.67-2.60(m,2H),2.11-2.04(m,1H),1.61-1.28(m,9H).

The fifth step: 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1 f)

2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile

Ethylene glycol (20 mL) was added to methyl 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetate (1 e) (1.57g, 4.99mmol) followed by potassium hydroxide (0.56g, 9.99mmol), and after the addition the reaction was heated to 120 ℃ for 5 hours, the reaction mixture was cooled to room temperature and water (60 mL) was added, the product was extracted with ethyl acetate (50 mL. Times.4), the combined organic phases were washed with saturated brine (40 mL. Times.1), dried over anhydrous sodium sulfate and concentrated. After sample stirring, column purification was performed using (EA: PET =1 = 80-1 50) to give 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1 f) (0.8 g, yield: 60%) as an oily liquid.

Ms m/z(ESI):257.3[M+H]；

And a sixth step: (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1 g-1)

(R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile

(S) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1 g-2)

(S)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile

Resolution of the compound 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (30 g) was taken for resolution to obtain, after separation, two optical isomer compounds (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1 g-1) (4.04min, 10.79g, white solid, ee% = 99.7%) and compound (S) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1 g-2) (retention time: 2.00min,11.17g, white solid, ee% = 99.6%).

Splitting conditions are as follows: apparatus, thar 350 preparatory SFC (SFC-9); column Chiralpak AD,300 × 50mm I.D.,10 μm; mobile phase A: CO2, B: methanol; gradient B45%; the flow rate is 200mL/min; back pressure is 100bar; the column temperature is 38 ℃; the wavelength is 220nm; the period is 7min; compound (1F) was dissolved in methanol to give 60mg/ml; injection, 15 ml/needle.

The seventh step: (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1)

(R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

Lithium aluminum hydride (0.56g, 15.0 mmol) was dissolved in tetrahydrofuran (30 mL), and the temperature was reduced to 0 ℃ to add (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (1 g-1) (1.0 g,3.9 mmol) in tetrahydrofuran (30 mL) to complete the reaction at room temperature overnight. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (1.2 mL), dried with anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (1.0 g, yield: 98%).

Ms m/z(ESI):261.2[M+H ⁺ ]；

Example 1

2- (6-Fluorospiro [ chroman-2, 1' -cyclopentanyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 1)

2-(6-fluorospiro[chroman-2,1'-cyclopentan]-4-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine hydrochloride

The first step is as follows: 6-Fluorospiro [ chroman-2, 1' -cyclopentylalkyl ] compounds]-4-one (1B)

6-fluorospiro[chroman-2,1'-cyclopentan]-4-one

1- (5-fluoro-2-hydroxyphenyl) ethanone 1A (10g, 65mmol) was dissolved in toluene (110 mL), and cyclopentanone (6.6g, 78mol) and pyrrole (14.1g, 198mol) were added to the solution, and the mixture was heated under reflux for 20 hours, cooled to room temperature, added with water (100 mL), extracted with ether (100 mL. Times.2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether/ethyl acetate = 20) to give 6-fluoropirocyclo [ chroman-2, 1' -cyclopentanyl ] -4-one 1B (12.1 g, yield 92%) as a pale yellow oily product

The second step is that: (Z) -2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-methylene) acetonitrile (1C)

(Z)-2-(6-fluorospiro[chroman-2,1'-cyclopentan]-4-ylidene)acetonitrile

Sodium hydride (1.14g, 47.7mmol) was dissolved in tetrahydrofuran (70 mL), and cyanomethyl ethyl phosphate (6.75g, 38.15mmol) was added to the system at zero degrees to conduct a reaction for 60min. The reaction system was cooled to 0 ℃ and 6-fluorospiro [ chroman-2, 1' -cyclopentanyl ] -4-one 1B (7 g, 31.8mmol) was added thereto, and after reacting for 15min, the temperature was raised to room temperature overnight. Water (20 mL) was added to the reaction, and the aqueous phase was extracted with ether (30 mL × 2), washed with a saturated saline solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 50).

Ms m/z(ESI):266.1[M+Na ⁺ ]。

The third step: 2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) ethylamine (1D)

2-(6-fluorospiro[chroman-2,1'-cyclopentan]-4-yl)ethanamine

(Z) -2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-methylene) acetonitrile 1C (2g, 8.22mmol) was dissolved in methanol (40 mL) and sodium borohydride (3.1g, 82.2mmol) was added in portions. Cobalt dichloride (2.14g, 6.4mmol) was then added slowly and the reaction was carried out for 12h at room temperature. The solvent methanol was removed under reduced pressure, extracted with dichloromethane (15 mL × 2), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (dichloromethane/methanol (v/v) = 20) to give 2- (6-fluoropyclospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) ethylamine 1D (0.4 g, yield: 80%) as a light yellow oil.

Ms m/z(ESI):250.2[M+H ⁺ ]。

The fourth step: 2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (1E)

2-(6-fluorospiro[chroman-2,1'-cyclopentan]-4-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine

2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) ethylamine 1D (0.3g, 1mmol) was dissolved in dichloromethane (10 mL) at room temperature, and 3-methoxythiophene-2-aldehyde (0.2g, 1mmol) and sodium sulfate (1g, 10mmol) were added in this order and stirred at room temperature overnight. Methanol (3 mL) was added, sodium borohydride (0.05g, 1mmol) was added, reaction was carried out for 2h, water (20 mL) was added to the system, extraction was carried out with dichloromethane (30 mL × 3), organic phases were combined, washed with a saturated saline solution (50 mL × 1), dried over anhydrous sodium sulfate, the filtrate was concentrated, and column chromatography purification (dichloromethane/methanol (v/v) = 1) was carried out to obtain a yellow liquid product, 2- (6-fluoropirocyclo [ benzofuran-2, 1' -cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine 1E (0.4 g, yield 75%).

Ms m/z(ESI):376.1[M+H ⁺ ]。

Resolution of Compound 1E

2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine 1E (728 mg) was taken for resolution, and after separation, two optical isomers, compound 1E-1 (retention time: 5.36s,336.25mg, light yellow oil,% ee = 100%), compound 1E-2 (retention time: 5.76s,274.37mg, light yellow oil,% ee = 98.9%) were obtained.

Splitting conditions are as follows: apparatus, thar analytical SFC (SFC-A); a column, chiralPak AD,150 × 4.6mm I.D.,3 μm; mobile phase A: carbon dioxide, B: isopropyl alcohol; gradient B25%; the flow rate is 200mL/min; back pressure is 100bar; the column temperature is 38 ℃; wavelength is 220nm; the period is 12min; sample preparation Compound 1E was dissolved in methanol to 18mg/ml; injection, 6ml per needle.

The fifth step: 2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 1)

2- (6-Fluorospiro [ benzofuran-2, 1 '-cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine 1E (0.28g, 0.75mmol) was dissolved in ethyl acetate (8 mL), a solution of hydrogen chloride in ethyl acetate (2mL, 4N) was added, reacted for 0.5h, and the solvent was removed under reduced pressure to give the product 2- (6-Fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride compound 1 (0.31 g, 100% yield) as a pale yellow oil.

Ms m/z(ESI):376.1[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ7.42(d,1H),6.96(d,1H),6.89(t,1H),6.70(m,1H),6.61-6.59(m,1H),4.22(s,2H),3.82(s,3H),3.00-2.95(m,3H),2.21-2.17(m,1H),1.83-1.81(m,4H),1.67-1.60(m,7H).

Compound 1E-1 and compound 1E-2 salt formation methods according to compound 1 gave (R) -2- (6-fluorospiro [ benzofuran-2, 1 '-cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (compound 1-1) and (S) -2- (6-fluorospiro [ benzofuran-2, 1' -cyclopentyl ] -4-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (compound 1-2), respectively.

Example 2

(S) -N- ((3-Methoxythien-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (Compound 2)

(S)-N-((3-methoxythiophen-2-yl)methyl)-N-methyl-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

The first step is as follows: (S) -N- ((3-Methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (2A) (S) -N- ((3-methoxythiopen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxapiro [4.5]

(S) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (1.0 g, 3.62mmol) was dissolved in dichloromethane (15 mL), and sodium sulfate (2.57g, 18.1 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.64g, 4.52mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.17g, 4.52mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was subjected to column chromatography (dichloromethane/methanol (v/v) =50

Ms m/z(ESI):387.2[M+H ⁺ ]；

The second step is that: (S) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (2B)

(S) -N- ((3-Methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (2A) (0.216g, 0.51mmol) and formaldehyde (0.06g, 2.04mmol) were added to 1, 2-dichloroethane (20 mL) at room temperature. After the addition, the reaction was carried out at room temperature for 3 hours. Sodium triacetoxyborohydride (0.16g, 0.77mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 16 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (15 mL), the aqueous phase was extracted with ethyl acetate (25 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (S) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (2B) (0.18 g, yield: 88.2%) as an oily liquid.

Ms m/z(ESI):401.2[M+H ⁺ ]；

The third step: (S) -N- ((3-Methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 2) (S) -N- ((3-methoxythiopen-2-yl) methyl) -N-methyl-2- (9- (pyridine-2-yl) -6-oxapiro [4.5] ]dec-9-yl) ethylamine hydrochloride

(S) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (2B) (0.18g, 0.39mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction was directly spin dried to give (S) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 2) as a yellow solid (0.16 g, 98% yield).

Ms m/z(ESI):401.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD)δ8.73-8.71(d,1H),8.56-8.52(m,1H),8.09-7.92(d,1H),7.90-7.89(m,1H),7.87(d,1H),7.31-7.29(m,1H),7.02-7.01(d,1H),6.90-6.88(m,1H),4.48(m,1H),4.29(m,1H),4.28(s,1H),3.87(s,3H),3.05(m,1H),2.91(m,1H),2.63-2.59(m,1H),1.30-1.17(d,6H).

Example 3

(R) -N- ((3-Methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 3)

(R)-N-((3-methoxythiophen-2-yl)methyl)-N-methyl-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: (R) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (3B)

(R)-N-((3-methoxythiophen-2-yl)methyl)-N-methyl-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -N- ((3-Methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (3A, synthesized according to patent CN201280021050.7, example 15) (0.216g, 0.51mmol) and formaldehyde (0.06g, 2.04mmol) were added to 1, 2-dichloroethane (20 mL) at room temperature. After the addition, the reaction was carried out at room temperature for 3 hours. Sodium triacetoxyborohydride (0.16g, 0.77mmol) was added to the reaction solution, and after the addition, the reaction was carried out at room temperature for 16 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (15 mL), the aqueous phase was extracted with ethyl acetate (25 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (R) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (3B) (0.18 g, yield: 88.2%) as an oily liquid.

Ms m/z(ESI):401.2[M+H ⁺ ]；

The second step is that: (R) -N- ((3-Methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 3) (R) -N- ((3-methoxythiopen-2-yl) methyl) -N-methyl-2- (9- (pyridine-2-yl) -6-oxapiro [4.5] ]dec-9-yl) ethylamine hydrochloride

(R) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (3B) (0.18g, 0.39mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction was directly spin dried to give (R) -N- ((3-methoxythiophen-2-yl) methyl) -N-methyl-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 3) (0.16 g, 98% yield) as a yellow solid.

Ms m/z(ESI):401.2[M+H ⁺ ]；

Example 4

(R) -N- ((3- (cyclopropylmethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 4)

(R)-N-((3-(cyclopropylmethoxy)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 3-methoxythiophene-2-carboxaldehyde (4B)

3-methoxythiophene-2-carbaldehyde

Under the protection of nitrogen, 3-methoxythiophene (4A) (5g, 43.8mmol) was dissolved in tetrahydrofuran (30 mL), the temperature was reduced to-78 ℃, N-butyllithium (19.3mL, 48.2mmol) was added dropwise to the reaction, the reaction was warmed to room temperature for 1 hour, N-dimethylformamide (4.8g, 65.7mmol) was added dropwise to the reaction, and the reaction was continued at room temperature for 1.5 hours. The reaction solution was quenched with saturated ammonium chloride (30 mL), water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and after concentrating the filtrate, the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 20.

¹ H NMR(400MHz,CDCl ₃ )δ9.99(d,1H),7.64(dd,1H),6.87(d,1H),3.99(s,3H).

The second step is that: 3-Hydroxythiophene-2-carbaldehyde (4C)

3-hydroxythiophene-2-carbaldehyde

3-methoxythiophene-2-carboxaldehyde (4B) (3.5g, 25mmol) is dissolved in trichloromethane (40 mL), the temperature is reduced to-10 ℃, then trichloromethane (20 mL) solution of boron tribromide (7.4g, 30mmol) is dripped into the reaction, and the reaction is carried out for 1 hour at 50 ℃ after the addition. Cooling, quenching the reaction with water (50 mL) and 2M hydrochloric acid (20 mL), extraction of the aqueous phase of the separated liquid with dichloromethane (30 mL × 2), combining the organic phases, washing with saturated sodium chloride solution (50 mL), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and column chromatography of the crude product (petroleum ether/ethyl acetate (v/v) = 3) gave 3-hydroxythiophene-2-carbaldehyde (4C) as a yellow solid (1.5 g, yield: 48%).

¹ H NMR(400MHz,CDCl ₃ )δ10.71(s,1H),9.64(d,1H),7.59(d,1H),6.77(dd,1H).

The third step: 3- (cyclopropylmethoxy) thiophene-2-carbaldehyde (4D) 3- (cyclopropropylmethoxy) thiophene-2-carbaldehyde

3-Hydroxythiophene-2-carbaldehyde (4C) (1.4g, 11mmol) was dissolved in N, N-dimethylformamide (20 mL), and potassium carbonate (1.8g, 13mmol) and bromocyclopropane (1.75g, 13mmol) were added thereto, followed by completion of the reaction at 100 ℃ for 2 hours. Water (80 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5) to obtain 3- (cyclopropylmethoxy) thiophene-2-carbaldehyde (4D) as an oily liquid (1.8 g, yield: 90%).

¹ H NMR(400MHz,CDCl ₃ )δ10.21-9.85(m,1H),7.73-7.47(m,1H),6.82(d,1H),3.99(d,2H),1.47-1.16(m,1H),0.85-0.55(m,2H),0.38(q,2H).

The fourth step: (R) -N- ((3- (cyclopropylmethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (4E)

(R)-N-((3-(cyclopropylmethoxy)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.3g, 1.1 mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.8g, 5.5 mmol) and 3- (cyclopropylmethoxy) thiophene-2-carbaldehyde (4D) (0.3g, 1.7 mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.07g, 1.7mmol) was added to the reaction and stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (20 mL), the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):427.2[M+H ⁺ ]；

The fifth step: (R) -N- ((3- (cyclopropylmethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 4)

(R) -N- ((3- (cyclopropylmethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (4E) (0.18g, 0.42mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((3- (cyclopropylmethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 4) as a yellow solid (0.2 g, yield: 100%).

Ms m/z(ESI):427.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.89(d,1H),8.63(d,1H),8.24-7.95(m,2H),7.48(d,1H),6.99(d,1H),4.26(s,2H),3.94(d,2H),3.90-3.80(m,1H),3.79-3.67(m,1H),3.02(dd,1H),2.62-2.44(m,3H),2.27(ddd,3H),2.01-1.82(m,2H),1.72-1.47(m,5H),1.25-1.17(m,2H),0.85(d,1H),0.70-0.57(m,2H),0.46-0.30(m,2H).

Example 6

N- ((3-Methylthion-2-yl) methyl) -2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 6-1)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 2, 6-dioxaspiro [4.5] decan-9-ol (6B)

2,6-dioxaspiro[4.5]decan-9-ol

To a mixture of 3-buten-1-ol (6A) (5g, 69.3mmol) and tetrahydrofuran-3-one (7.6g, 90.1mmol) was added dropwise a 75% sulfuric acid solution (20.4 g,208.0 mmol) at 0 ℃. After the addition was completed, the reaction was allowed to warm to room temperature for 5 hours. At low temperature, water (50 mL) was added to the reaction solution, PH ≈ 8 was adjusted with sodium hydroxide solid, the aqueous phase was extracted with ethyl acetate (50 mL × 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and after the filtrate was concentrated, the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10) to obtain 2, 6-dioxaspiro [4.5] decan-9-ol (6B) as an oily liquid (4.2 g, yield: 38%).

Ms m/z(ESI):159.2[M+H ⁺ ]；

The second step: 2, 6-dioxaspiro [4.5] decan-9-one (6C)

2,6-dioxaspiro[4.5]decan-9-one

2, 6-dioxaspiro [4.5] decan-9-ol (6B) (4.2g, 27mmol) was dissolved in dichloromethane (50 mL), cooled to 0 ℃ and pyridinium chlorochromate (8.7 g,40.5 mmol) was added to the reaction, and the reaction was completed at room temperature overnight. To the reaction solution was added methyl tert-butyl ether (80 mL), and filtered with celite, the filtrate was directly spun dry, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =20: 1. About.2) to give 2, 6-dioxaspiro [4.5] decan-9-one (6C) (4 g, yield: 94%) as a yellow oily liquid.

The third step: 2-cyano-2- (2, 6-dioxaspiro [4.5] decan-9-ylidene) acetic acid methyl ester (6D)

methyl 2-cyano-2-(2,6-dioxaspiro[4.5]decan-9-ylidene)acetate

2, 6-dioxaspiro [4.5] decan-9-one (6C) (4 g,25.6 mmol), methyl cyanoacetate (3g, 30.7 mmol), ammonium acetate (0.72g, 7.7 mmol), acetic acid (0.3g, 5.1 mmol) and toluene (50 mL) were charged into a reaction flask and heated to reflux for 4 hours. After cooling, a sodium hydrogencarbonate solution (50 mL) was added to the reaction solution, and aqueous ethyl acetate (30 mL × 3) was extracted, the organic phases were combined, washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =1 to 2).

Ms m/z(ESI):238.2[M+H ⁺ ]；

The fourth step: 2-cyano-2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) acetic acid methyl ester (6E)

methyl 2-cyano-2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)acetate

Isopropyl magnesium chloride (15.6 mL,31.6 mmol) was charged into a reaction flask, the temperature was lowered to 0 ℃ and a solution of 2-bromopyridine (5g, 31.6 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction, after reaction at room temperature for 3 hours, cuprous iodide (0.4 g,2.1 mmol) was added to the reaction, the reaction was stirred for 0.5 hours, and a solution of methyl 2-cyano-2- (2, 6-dioxaspiro [4.5] decan-9-ylidene) acetate (6D) (5g, 21mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction and allowed to react at room temperature for 18 hours. The reaction was quenched by adding ice water (30 mL) and 1N hydrochloric acid (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =10: 1-1) to give methyl 2-cyano-2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) acetate (6E) (4 g, yield: 60%) as an oily liquid.

Ms m/z(ESI):317.1[M+H ⁺ ]；

The fifth step: 2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) acetonitrile (6F)

2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)acetonitrile

Ethylene glycol (40 mL) was added to methyl 2-cyano-2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) acetate (6E) (4.2g, 13mmol), potassium hydroxide (1.5g, 26mmol) was added thereto, and the mixture was heated to 120 ℃ to react for 3 hours. The reaction solution was cooled, water (80 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL × 4), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =4: 1-1) to give 2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) acetonitrile (6F) as a yellow oily liquid (2.8 g, yield: 82%).

Ms m/z(ESI):259.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.63(ddd,1H),7.78-7.64(m,1H),7.41(dd-1H),7.26-7.14(m,1H),3.97-3.64(m,4H),3.56(d,0.5H),3.21(d,0.5H),2.90-2.46(m,4H),2.16-1.81(m,4H),1.41(ddd,0.5H),1.13(dt,0.5H).

And a sixth step: 2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine (6G)

2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)ethanamine

Lithium aluminum hydride (0.58g, 15.4 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 ℃ and 2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) acetonitrile (6F) (2g, 7.7 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (0.8 mL) in that order, dried by addition of anhydrous sodium sulfate, stirred for 20 min, the solid filtered and washed with tetrahydrofuran (20 mL. Times.3). The combined organic phases were concentrated to give 2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine (6G) (1.6G, yield: 79%).

Ms m/z(ESI):263.1[M+H ⁺ ]；

The seventh step: n- ((3-Methylthion-2-yl) methyl) -2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine (6H)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)ethanamine

2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine (6G) (1.6G, 6.1mmol) was dissolved in methylene chloride (15 mL), and sodium sulfate (4.3G, 30.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (1.3G, 9.1mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.35g, 9.1mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product which was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):389.2[M+H ⁺ ]；

The compound N- ((3-methylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine (6H) (1.3 g) was isolated by two SFC preparations to obtain four optical isomers, compound 6H-1 (retention time: 5.41min,0.28g, oily liquid, ee% = 98.2%), compound 6H-2 (retention time: 6.99min,0.38g, oily liquid, ee% = 99.4%), compound 6H-3 (retention time: 7.78min,0.31g, oily liquid, ee% = 99.5%), compound 6H-4 (retention time: 11.15min,0.24g, oily liquid, ee% = 99.0%).

First SFC preparation conditions:

MG II preparatory SFC (SFC-1);

column, cellulose-2, 250X 30mm I.D.,5 μm;

mobile phase A: carbon dioxide, B: methanol (0.1% ammonia);

gradient B40%;

the flow rate is 60mL/min;

back pressure is 100bar;

the column temperature is 38 ℃;

the wavelength is 220nm;

the period is 16min;

sample preparation, compound is dissolved in methanol to make 26mg/ml; injection 1 ml/needle. Pure compound 6-1,6-4 and mixtures 6-2 and 6-3 were obtained.

Second SFC preparation conditions:

MG II preparatory SFC (SFC-14);

a column, chiralPak AD,250 × 30mm i.d.,5 μm;

mobile phase A: carbon dioxide, B: ethanol;

Gradient B40%;

the flow rate is 50mL/min;

back pressure is 100bar;

the column temperature is 38 ℃;

wavelength is 220nm;

the period is 4.5min;

eighth step: n- ((3-Methylthion-2-yl) methyl) -2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethanamine (Compound 6)

N-((3-methoxythiophen-2-yl)methyl)-2-9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

Compound 6H (0.18g, 0.39mmol) was dissolved in ethyl acetate (5 mL), to which a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction was directly spin-dried to give N- ((3-methylthiophen-2-yl) methyl) -2- ((5R, 9R) -9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 6) as a white solid (0.16 g, 98% yield).

The compound 6H-1, the compound 6H-2, the compound 6H-3 and the compound 6H-4 are salified according to the steps to obtain the compound 6-1, the compound 6-2, the compound 6-3 and the compound 6-4:

compound 6-1:

Ms m/z(ESI):389.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.86(d,1H),8.58(d,1H),8.11(t,1H),8.00(d,1H),7.46(d,1H),7.00(d,1H),4.19(s,2H),3.97-3.67(m,7H),3.44-3.32(m,1H),3.13-2.86(m,2H),2.60-2.15(m,7H),2.12-1.87(m,2H).

compound 6-2:

Ms m/z(ESI):389.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.85(t,1H),8.64-8.44(m,1H),8.22-7.80(m,2H),7.47(d,1H),7.00(d,1H),4.19(s,2H),4.02-3.66(m,8H),3.59(d,1H),3.08-2.89(m,1H),2.66-2.43(m,3H),2.34-2.07(m,3H),2.00(d,1H),1.60-1.47(m,1H),1.30(dt,1H).

compound 6-3:

Ms m/z(ESI):389.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.93-8.82(m,1H),8.58(dd,1H),8.16(t,1H),7.99(dd,1H),7.49(d,1H),7.03(d,1H),4.21(s,2H),3.99-3.66(m,8H),3.61(d,1H),3.00(td,1H),2.62-2.45(m,3H),2.38-2.10(m,3H),2.00(ddd,1H),1.56(dd,1H),1.32(dt,1H).

compounds 6-4:

Ms m/z(ESI):389.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.74(dd,1H),8.45(dt,1H),8.04-7.78(m,2H),7.37(d,1H),6.90(d,1H),4.10(s,2H),3.90-3.61(m,7H),3.27-3.22(m,1H),2.98-2.78(m,2H),2.49-2.02(m,7H),2.01-1.78(m,2H).

example 9

N- ((3-Methylthioen-2-yl) methyl) -2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine hydrochloride (Compound 9)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 2-cyano-2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) acetic acid methyl ester (9B)

methyl 2-cyano-2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decan-9-yl)acetate

Under the protection of nitrogen, propynyl magnesium bromide (102mL, 51mmol) was charged into a reaction flask, the temperature was reduced to 0 ℃ and cuprous iodide (0.32g, 1.7 mmol) was added to the reaction, and the reaction was stirred for 0.5 hour, and then a solution of methyl 2-cyano-2- (6-oxaspiro [4.5] decan-9-ylidene) acetate (1 d) (4g, 17mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction and allowed to react at 50 ℃ for 4 hours. The reaction was quenched by adding 1N hydrochloric acid (40 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 5).

Ms m/z(ESI):276.1[M+H ⁺ ]；

The second step is that: 2- (9- (Prop-1-yn-1-yl) -6-dioxaspiro [4.5] decan-9-yl) acetonitrile (9C)

2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile

Ethylene glycol (20 mL) was added to methyl 2-cyano-2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) acetate (9B) (2g, 7.2mmol), potassium hydroxide (0.81g, 14.4 mmol) was further added thereto, and the mixture was heated to 120 ℃ to react for 3 hours. The reaction solution was cooled, water (80 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 5) to give 2- (9- (prop-1-yn-1-yl) -6-dioxaspiro [4.5] decan-9-yl) acetonitrile (9C) as a yellow oily liquid (1.2 g, yield: 76%).

Ms m/z(ESI):218.1[M+H ⁺ ]；

The third step: 2- (9- (prop-1-yn-1-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (9D)

2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

Lithium aluminum hydride (0.42g, 11mmol) was dissolved in tetrahydrofuran (15 mL), the temperature was lowered to 0 ℃ and 2- (9- (prop-1-yn-1-yl) -6-dioxaspiro [4.5] decan-9-yl) acetonitrile (9C) (1.2g, 5.5 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction, and the reaction was allowed to proceed overnight at room temperature. The reaction was cooled to 0 deg.C, quenched with water (0.4 mL), sodium hydroxide solution (10%, 0.8 mL) and water (1.2 mL) in that order, dried by addition of anhydrous sodium sulfate, stirred for 20 minutes, filtered, and the solid washed with tetrahydrofuran (20 mL. Times.3). The organic phase was concentrated to give 2- (9- (prop-1-yn-1-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (9D) (0.8 g, yield: 70%) as a yellow oily liquid.

Ms m/z(ESI):222.1[M+H ⁺ ]；

The fourth step: n- ((3-Methylthioen-2-yl) methyl) -2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (9E)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

2- (9- (prop-1-yn-1-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (9D) (0.6 g,2.7 mmol) was dissolved in dichloromethane (15 mL), and sodium sulfate (1.9g, 13.5mmol) and 3-methoxythiophene-2-carboxaldehyde (0.57g, 4 mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.15g, 4 mmol) was added to the reaction mixture, and the reaction mixture was stirred for 20 minutes, followed by addition of methanol (15 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude N- ((3-methylthiophen-2-yl) methyl) -2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (9E) (0.4 g, yield: 40%) as a yellow oily liquid by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):348.2[M+H ⁺ ]；

The fifth step: n- ((3-Methylthioen-2-yl) methyl) -2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine hydrochloride (Compound 9)

N- ((3-Methylthioen-2-yl) methyl) -2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (9E) (0.4g, 1.1mmol) was dissolved in ethyl acetate (8 mL), a solution of hydrogen chloride in ethyl acetate (2mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give N- ((3-methylthiophen-2-yl) methyl) -2- (9- (prop-1-yn-1-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (compound 9) (0.44 g, yield: 100%) as a white solid.

Ms m/z(ESI):348.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ7.51(d,1H),7.06(d,1H),4.31(s,2H),3.98-3.83(m,4H),3.66-3.62(m,1H),3.22(dd,2H),2.34-2.21(m,1H),1.80-1.43(m,16H).

Example 10

N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (3-methoxythiophen-2-yl) methylamine hydrochloride (Compound 10)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methyl)-1-(3-methoxythiophen-2-yl)methanamine hydrochloride

The first step is as follows: 9-hydroxy-6-oxaspiro [4.5] dec-8-ene-8-carboxylic acid methyl ester (10B)

methyl 9-hydroxy-6-oxaspiro[4.5]dec-8-ene-8-carboxylate

The compound sodium hydride (12.45g, 0.311mol) was charged into a 2000mL three-substance reaction flask, washed with n-hexane (30 mL. Times.3) under nitrogen, tetrahydrofuran (600 mL) was added to the reaction flask, and 6-oxaspiro [4.5] decan-9-one (40g, 0.259mol) (1 c) in tetrahydrofuran (60 mL) was added dropwise with stirring overnight, and after the addition, the mixture was stirred at room temperature for 0.5 hour, and then a solution of dimethyl carbonate (98g, 1.090mol) was added dropwise and stirred at 80 ℃ under reflux for 4 hours. The reaction solution was cooled to room temperature, poured into 600 g of an ice-water mixture under stirring, acidified to pH1-2 with 5% hydrochloric acid, extracted with dichloromethane (150 mL × 3), the organic phases were combined and washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 10/1) to give methyl 9-hydroxy-6-oxaspiro [4.5] dec-8-ene-8-carboxylate (10B) as a yellow oily compound (51 g, yield: 92.64%).

Ms m/z(ESI):213.1[M+H ⁺ ]；

¹ HNMR(400MHz,CDCl ₃ )δ11.72(s,1H),4.26(t,2H),3.76(s,3H),2.35-2.34(t,2H),1.88-1.85(m,2H),1.80-1.73(m,2H),1.69-1.60(m,2H),1.53-1.45(m,2H).

The second step is that: 9- (((trifluoromethyl) sulfonyl) oxy) -6-oxaspiro [4.5] dec-8-ene-carboxylic acid methyl ester (10C)

methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6-oxaspiro[4.5]dec-8-ene-8-carboxylate

Methyl 9-hydroxy-6-oxaspiro [4.5] dec-8-ene-8-carboxylate (10B) (51g, 0.243mol) was dissolved in methylene chloride (500 mL), stirred and cooled to-78 ℃, diisopropylethylamine (34.1g, 0.264mol) was added and trifluoromethanesulfonic anhydride (101.680g, 0.360mol) was added dropwise, and stirring was completed at room temperature for 3 hours. The reaction mixture was poured into 500mL of a saturated sodium bicarbonate solution, subjected to liquid separation, the aqueous phase was extracted with dichloromethane (200 mL × 3), the organic phases were combined, washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 82g of a crude brown oil, and silica gel column chromatography using petroleum ether/ethyl acetate (V/V) =30/1 gave a brown oil of 9- (((trifluoromethyl) sulfonyl) oxy) -6-oxaspiro [4.5] dec-8-ene-carboxylic acid methyl ester (10C) (51 g, yield: 61.47%).

Ms m/z(ESI):367.0[M+Na ⁺ ]。

The third step: 9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene-8-carboxylic acid methyl ester (10D)

methyl 9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-ene-8-carboxylate

Compound 9- (((trifluoromethyl) sulfonyl) oxy) -6-oxaspiro [4.5] dec-8-ene-carboxylic acid methyl ester (10C) (32.8g, 95.266mmol) was dissolved in toluene (328 mL), p-fluorobenzeneboronic acid (17.34g, 127.54mmol), tetratriphenylphosphine palladium (6.083g, 5.264mmol), sodium carbonate (22.24g, 209.8mmol), ethanol (82 mL), water (82 mL) were added, the reaction solution was bubbled with nitrogen for 10 minutes and replaced with nitrogen 3 times, and stirring and refluxing were carried out at 120 ℃ for 4 hours, the reaction solution was cooled to room temperature, water 500mL was added, extraction was carried out with diethyl ether (200 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, silica gel 200-300 mesh (petroleum ether/ethyl acetate (V/V) = 25/1) to give 9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene-carboxylic acid methyl ester (4.5: 52 g, yield: 52.52%).

Ms m/z(ESI):313.3[M+Na ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ7.12-7.07(m,2H),7.05-6.99(m,2H),4.46-4.45(t,2H),3.51(s,3H),2.45-2.43(t,3H),1.96-1.90(m,2H),1.84-1.76(m,2H),1.69-1.63(m,2H),1.58-1.45(m,2H).

The fourth step: (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methanol (10E)

(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methanol

The compound lithium aluminum tetrahydroborate (2.6g, 41.05mmol) and tetrahydrofuran (70 mL) were sequentially charged into a three-necked reaction flask, and a solution of methyl 9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene-8-carboxylate (10D) (7.00g, 24.111mmol) in tetrahydrofuran (10 mL) was added dropwise with stirring at room temperature, followed by reaction at room temperature for 2 hours. The reaction solution was cooled to 0 ℃ or lower with an ice salt bath, and water (2.6 mL), a 20% sodium hydroxide solution (5.2 mL), water (2.6 mL), and celite were added to the reaction solution in this order while stirring, and the cake was washed with tetrahydrofuran (10 mL. Times.3) and filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and then petroleum ether/ethyl acetate (V/V) =10/1-3/1 was purified by silica gel 200-300 mesh column chromatography to give a colorless oily product (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methanol (10E) (5.83 g, yield: 92.27%).

Ms m/z(ESI):285.1[M+Na ⁺ ]；

¹ HNMR(400MHz,CD ₃ OD)δ7.25-7.20(m,2H),7.10-7.04(m,2H),4.34-4.33(t,2H),3.94(s,2H),2.37-2.36(t,2H),1.95-1.89(m,2H),1.84-1.75(m,2H),1.72-1.63(m,2H),1.61-1.53(m,2H).

The fifth step: 8- (chloromethyl) -9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene (10F)

8-(chloromethyl)-9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-ene

The compound (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methanol (10E) (2.000g, 7.625 mmol) was dissolved in methylene chloride (20 mL), triethylamine (1.54g, 15.26mmol) was added thereto, the mixture was stirred and cooled to 0 ℃ and a solution of methanesulfonyl chloride (0.962g, 8.40mmol) was added dropwise thereto, and the reaction was completed at room temperature for 4 hours. To the reaction solution was added a saturated ammonium chloride solution (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined and washed with a saturated ammonium chloride solution (50 mL × 1), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 8- (chloromethyl) -9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene (10F) (2.14 g, yield: 99.86%) as a yellow oily product.

Ms.m/z(ESI):303.1[M+Na ⁺ ]；

¹ HNMR(400MHz,CD ₃ OD)δ7.26-7.20(m,2H),7.09-7.00(m,2H),4.34-4.33(t,2H),3.93(s,2H),2.40-2.39(t,2H),1.96-1.90(m,2H),1.85-1.76(m,2H),1.71-1.62(m,2H),1.57-1.48(m,2H).

And a sixth step: 8- (Azidomethyl) -9- (4-tetrafluorophenyl) -6-oxaspiro [4.5] dec-8-ene (10G)

8-(azidomethyl)-9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-ene

The compound 8- (chloromethyl) -9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene (10F) (2.000g, 7.12mmol) was dissolved in DMF (20 mL), and sodium azide (0.92g, 14.25mmol) was added and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, and 100 mL of saturated brine was added, extraction was performed with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and silica gel column chromatography was performed using petroleum ether/ethyl acetate (V/V) =20/1 to give 8- (azidomethyl) -9- (4-tetrafluorophenyl) -6-oxaspiro [4.5] dec-8-ene (10G) (1.4G, yield: 68.63%) as a colorless oily product.

¹ HNMR(400MHz,CD ₃ OD)δ7.14-7.09(m,2H),7.08-7.01(m,2H),4.28-4.27(t,2H),3.68(s,2H),2.40(s,2H),1.97-1.91(m,2H),1.87-1.77(m,2H),1.71-1.61(m,2H),1.57-1.50(m,2H).

The seventh step: (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methylamine (10H)

(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methanamine

The compound 8- (azidomethyl) -9- (4-tetrafluorophenyl) -6-oxaspiro [4.5] dec-8-ene (10G) (0.320g, 1.11mmol) was dissolved in tetrahydrofuran (3 mL), water (0.3 mL) was added, triphenylphosphine (0.436G, 1.66mmol) was added with stirring, and the mixture was stirred at room temperature overnight. To the reaction solution, 20mL of 1N hydrochloric acid was added and extracted with diethyl ether (10 mL. Times.3), the aqueous phase was adjusted to pH8 with a saturated sodium bicarbonate solution and extracted with ethyl acetate (10 mL. Times.3), and the ethyl acetate was combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the product (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methylamine (10H) (270 mg, yield: 92.8%) as a colorless oily product.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.30-7.25(m,2H),7.18-7.12(m,2H),4.21(s,2H),2.97(s,2H),2.26(s,2H),1.82-1.74(m,2H),1.71-1.55(m,4H),1.51-1.44(m,4H).

Eighth step: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (3-methoxythien-2-yl) methylamine (10I)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methyl)-1-(3-methoxythiophen-2-yl)methanamine

The compound (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methylamine (10H) (0.250g, 0.957mmol), 3-methoxythiophene-2-carbaldehyde (0.204g, 1.430mmol) was dissolved in dichloromethane (10 mL), and anhydrous sodium sulfate (0.679g, 4.780mmol) was added thereto, followed by stirring at room temperature overnight. Sodium borohydride (0.060g, 1.600mmol) was added and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added and stirred for 2 hours. Water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (3-methoxythiophen-2-yl) methylamine (10I) (220 mg, yield: 59.3%) as a yellow oily product.

Ms.m/z(ESI):388.1[M+H ⁺ ]；

The ninth step: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (3-methoxythien-2-yl) methanamine hydrochloride (Compound 10)

The compound N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (3-methoxythien-2-yl) methylamine (10I) (0.200g, 0.516 mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.135mL, 0.540 mmol) was added and stirred at room temperature for 2 hours. Filtration afforded the product N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (3-methoxythiophen-2-yl) methylamine hydrochloride (compound 10) as a yellow solid (210 mg, yield: 96%).

Ms.m/z(ESI):388.2[M+H ⁺ -HCl]；

¹ HNMR(400MHz,CD ₃ OD)δ7.47-7.46(d,1H),7.15-7.04(m,4H),6.96-6.94(d,1H),4.28(s,2H),4.12(s,2H),3.81(s,3H),3.56(s,2H),2.42(s,2H),1.97-1.91(m,2H),1.85-1.76(m,2H),1.74-1.66(m,2H),1.61-1.53(m,2H).

Example 11

N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl-1- (3-methoxythiophen-2-yl) methylamine hydrochloride (Compound 11)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)methyl)-1-(3-methoxythiophen-2-yl)methanamine hydrochloride

The first step is as follows: (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methylamine (11B)

(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)methanamine

The compound 8- (azidomethyl) -9- (4-tetrafluorophenyl) -6-oxaspiro [4.5] dec-8-ene (10G) (0.500g, 1.74mmol) was dissolved in methanol (10 mL), palladium carbon (0.2g, 10%, water content 50%) was added, and the mixture was replaced with hydrogen gas 3 times, stirred at room temperature overnight (normal pressure), filtered with celite, the filter cake was washed with anhydrous methanol (10 mL. Times.2), and the filtrate was evaporated to dryness to obtain colorless oily product (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-yl) methylamine (11B) (300 mg, yield: 61.7%).

Ms.m/z(ESI):264.2[M+H ⁺ ]。

The second step is that: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl-1- (3-methoxythiophen-2-yl) methylamine (11C)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)methyl)-1-(3-methoxythiophen-2-yl)methanamine

The compound (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-yl) methylamine (11B) (0.400g, 1.83mmol) and 3-methoxythiophene-2-carbaldehyde (0.389g, 2.74mmol) were dissolved in methylene chloride (10 mL), and anhydrous sodium sulfate (1.295g, 9.12mmol) was added thereto, followed by stirring at room temperature overnight. Sodium borohydride (0.104g, 2.740 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour, and then 3 ml of anhydrous methanol was added thereto, and the mixture was stirred for 2 hours. To the reaction solution was added 20mL of water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-yl) methyl-1- (3-methoxythiophen-2-yl) methylamine (11C) (270 mg, yield: 38%) as a yellow oily product.

Ms.m/z(ESI):390.2[M+H ⁺ ]。

The third step: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl-1- (3-methoxythiophen-2-yl) methylamine hydrochloride (Compound 11)

The compound N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl-1- (3-methoxythiophen-2-yl) methylamine (11C) (0.200g, 0.513mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.135mL, 0.54mmol) was added and stirred at room temperature for 2 hours, and filtration gave N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl-1- (3-methoxythiophen-2-yl) methylamine hydrochloride (compound 11) (207 mg, yield: 94.6%) as a white solid.

Ms.m/z(ESI):390.2[M+H ⁺ -HCl]；

¹ HNMR(400MHz,CD ₃ OD)δ7.44-7.43(d,1H),7.25-7.22(dd,2H),7.09-7.04(m,2H),6.96-6.95(d,1H),4.13-4.12(d,2H),3.95-3.92(d,1H),3.84(s,3H),3.83-3.80(d,1H),3.39-3.27(m,2H),2.53-2.50(d,1H),2.15-2.00(m,3H),1.86-1.52(m,8H).

Example 12

(R) -N- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 12)

(R)-N-((3-(difluoromethoxy)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 3- (Difluoromethoxy) thiophene-2-carbaldehyde (12A)

3-(difluoromethoxy)thiophene-2-carbaldehyde

3-Hydroxythiophene-2-carbaldehyde (4C) (0.35g, 2.7 mmol) and potassium hydroxide (3.1g, 55mmol) were dissolved in acetonitrile (10 mL) and water (10 mL) at room temperature, the temperature was reduced to 0 deg.C, diethyl bromofluoromethylphosphonate (1.5g, 5.5 mmol) was added dropwise to the reaction, and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =20: 1-10) to give 3- (difluoromethoxy) thiophene-2-carbaldehyde (12A) (0.4 g, yield 80%) as an oily liquid product.

Ms m/z(ESI):178.9[M+H ⁺ ]；

The second step is that: (R) -N- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (12B) (R) -N- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridine-2-yl) -6-oxapiro [4.5]

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (0.3g, 1.1 mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.8g, 5.5 mmol) and 3- (difluoromethoxy) thiophene-2-carbaldehyde (12A) (0.3g, 1.7 mmol) were added to the reaction mixture, and the reaction was allowed to proceed at room temperature overnight. Sodium borohydride (0.07g, 1.7 mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):423.2[M+H ⁺ ]；

The third step: (R) -N- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 12)

(R) -N- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (12B) (0.3 g, 0.71mmol) was dissolved in ethyl acetate (8 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 12) as a yellow solid (0.32 g, yield: 100%).

Ms m/z(ESI):423.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.63(dd,1H),8.00(t,1H),7.67(d,1H),7.59(d,1H),7.47-7.44(m,1H),7.03(t,1H),6.77(d,1H),4.25(s,2H),3.77-3.74(m,2H),2.99-2.96(m,1H),2.51-2.42(m,3H),2.22-2.10(m,1H),1.98-1.90(m,2H),1.82-1.71(m,2H),1.66-1.40(m,5H),1.17-1.02(m,1H),0.75-0.72(m,1H).

Example 14

N- ((3-Methoxythien-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine hydrochloride (Compound 14)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-9-yl)ethanamine hydrochloride

The first step is as follows: ethyl 9-oxo-6-oxaspiro [4.6] decane-10-carboxylate (14B-1)

ethyl 9-oxo-6-oxaspiro[4.6]undecane-10-carboxylate

Ethyl 10-oxo-6-oxaspiro [4.6] decane-9-carboxylate (14B-2)

ethyl 10-oxo-6-oxaspiro[4.6]undecane-9-carboxylate

6-oxaspiro [4.6] decan-9-one (14A) (15.4 g, 0.1mol) was dissolved in methylene chloride (100 mL), cooled to-40 ℃ and then a boron trifluoride diethyl etherate solution (17.0 g, 0.12mol) and ethyl diazoacetate (14.8g, 0.13mol) were added dropwise to the reaction mixture, followed by reaction at-40 ℃ for 2 hours. The reaction solution was quenched with sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride (80 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 30).

Ms m/z(ESI):263.1[M+Na ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.58-8.57(d,1H),7.65-7.63(td,1H),7.29-7.27(d,1H),7.10-7.09(dd,1H),3.74-3.70(m,1H),3.56-3.54(m,1H),2.52-2.50(m,2H),2.49-2.46(m,2H),1.93-1.18(m,14H).

The second step is that: 6-oxaspiro [4.6] decan-9-one (14C-1)

6-oxaspiro[4.6]undecan-9-one

6-oxaspiro [4.6] decan-10-one (14C-2)

6-oxaspiro[4.6]undecan-10-one

Ethyl 9-oxo-6-oxaspiro [4.6] decane-10-carboxylate ethyl (14B-1) and 9-oxo-6-oxaspiro [4.6] decane-10-carboxylate (14B-2) (24.0 g,0.1 mol) were dissolved in water (200 mL), and potassium carbonate (70.2 g,0.5 mol) was added to the reaction mixture, after which the mixture was heated to 100 ℃ to react for 5 hours. The aqueous phase was extracted with dichloromethane (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (80 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =100

Ms m/z(ESI):169.1[M+H ⁺ ]；

The third step: (Z/E) -methyl 2-cyano-2- (6-oxaspiro [4.6] decan-9-ylidene) carboxylate (14D-1)

(Z/E)-methyl 2-cyano-2-(6-oxaspiro[4.6]undecan-9-ylidene)acetate

(Z/E) -methyl 2-cyano-2- (6-oxaspiro [4.6] decan-10-ylidene) carboxylate (14D-2)

(Z/E)-methyl 2-cyano-2-(6-oxaspiro[4.6]undecan-10-ylidene)acetate

A mixture (10.0g, 0.162mol) of 6-oxaspiro [4.6] decan-9-one (14C-1) and 6-oxaspiro [4.6] decan-10-one (14C-1), methyl cyanoacetate (7.0g, 0.194mol), ammonium acetate (1.4g, 48.64mmol) and acetic acid (0.7g, 32.43mmol) were successively added to toluene (50 mL) at room temperature. After completion of the reaction, water (120 mL) was added to extract the product with ethyl acetate (40 mL. Times.2), and the combined organic phases were washed with saturated brine (30 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Column purification with EA: PET =1 80-1 to give oily liquids (Z/E) -methyl 2-cyano-2- (6-oxaspiro [4.6] decan-9-ylidene) carboxylate (14D-1) and (Z) -methyl 2-cyano-2- (6-oxaspiro [4.6] decan-10-ylidene) carboxylate (14D-2) (30.0 g, yield: 78.65%).

Ms m/z(ESI):272.1[M+Na ⁺ ]；

The fourth step: methyl 2-cyano-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) carboxylate (14E-1)

methyl 2-cyano-2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-9-yl)acetate

Methyl 2-cyano-2- (10- (pyridin-2-yl) -6-oxaspiro [4.5] decan-10-yl) carboxylate (14E-2)

methyl 2-cyano-2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)acetate

A solution of 2-bromopyridine (3.2 g,20.0 mmol) in THF (15 mL) was added dropwise to a solution of isopropylmagnesium chloride (10 mL, 2M in THF) at 0 ℃ under nitrogen at room temperature, followed by stirring for 3 hours, ketone iodide (0.34g, 1.8 mmol) was added thereto and stirring at room temperature for 0.5 hour, and then a mixture of E and Z isomers of methyl 2-cyano-2- [ 6-oxaspiro [4.5] decan-9-ylidene ] acetate (4.7 g,20.0 mmol) in THF (20 mL) was added dropwise to the reaction mixture. After the addition, the reaction mixture was heated to 55 ℃ and stirred for 8 hours. The reaction mixture was poured into a mixture of 200g ice/1N HCl (100 mL). The product was extracted with ethyl acetate (50 mL. Times.4), and the combined organic phases were washed with saturated brine (40 mL. Times.1), dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography with EA: PET =1 80-1 to give methyl 2-cyano-2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) carboxylate (14E-1) and methyl 2-cyano-2- (10- (pyridin-2-yl) -6-oxaspiro [4.5] decan-10-yl) carboxylate (14E-2) as oily liquids (2.0 g, yield: 32.0%).

Ms m/z(ESI):329.1[M+H ⁺ ]；

The fifth step: 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] undecan-9-yl) acetonitrile (14F)

2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-9-yl)acetonitrile

2- (10- (pyridin-2-yl) -6-oxaspiro [4.5] undecan-10-yl) acetonitrile (33A)

2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)acetonitrile

Ethylene glycol (50 mL) was added to methyl 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetate (14E-1) and methyl 2-cyano-2- (10- (pyridin-2-yl) -6-oxaspiro [4.5] decan-10-yl) carboxylate (14E-2) (5.0 g, 15.24mmol), then potassium hydroxide (1.7g, 30.4 mmol) was added, after which the reaction liquid was heated to 120 ℃ for 5 hours, the reaction mixture was cooled to room temperature and water (100 mL) was added, the product was extracted with ethyl acetate (50 mL. Times.4), the combined organic phases were washed with saturated brine (40 mL. Times.1), dried over anhydrous sodium sulfate and concentrated. Purification on a column with EA: PET =1 80-1 to give 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (14F) and 2- (10- (pyridin-2-yl) -6-oxaspiro [4.5] undecan-10-yl) acetonitrile (33A) as oily liquids (0.8 g, yield: 19.4%). And 2- (10- (pyridin-2-yl) -6-oxaspiro [4.5] undecan-10-yl) acetonitrile (1.08 g, yield: 26.2%).

Ms m/z(ESI):271.1[M+H ⁺ ]；

Compound (14F) ¹ H NMR(400MHz,CDCl ₃ )δ8.63-8.62(d,1H),7.72-7.70(m,1H),7.39-7.37(d,1H),7.21-7.19(m,1H),3.83-3.68(m,1H),3.59-3.57(m,1H),2.77-2.69(m,2H),2.65-2.61(m,1H),2.43-2.37(m,1H),1.96-1.94(m,4H),1.92-1.48(m,8H).

Compound (33A) ¹ H NMR(400MHz,CDCl ₃ )δ8.63-8.61(d,1H),7.72-7.70(m,1H),7.42-7.39(d,1H),7.21-7.19(m,1H),3.71-3.68(m,1H),3.57-3.53(m,1H),2.77-2.65(m,2H),2.62-2.61(m,1H),2.54-2.43(m,1H),1.90-1.48(m,12H).

And a sixth step: 2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine (14G)

2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-9-yl)ethanamine

Lithium aluminum hydride (0.56g, 15.0 mmol) was dissolved in tetrahydrofuran (30 mL), and the temperature was reduced to 0 ℃ to add 9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) acetonitrile (14F) (0.9g, 3.0 mmol) in tetrahydrofuran (10 mL) to complete the reaction at room temperature overnight. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (1.2 mL), dried with anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give 9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine (14G) (0.5G, yield: 50%).

Ms m/z(ESI):275.2[M+H ⁺ ]；

The seventh step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine (14H)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-9-yl)ethanamine

9- (pyridin-2-yl) -6-oxaspiro [4.6] undec-9-yl) ethylamine (14G) (0.5g, 2.0mmol) was dissolved in methylene chloride (15 mL), and sodium sulfate (1.3g, 7.5mmol) and 3-methoxythiophene-2-carboxaldehyde (0.28g, 3.0mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.09g, 2.0 mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =50

Ms m/z(ESI):401.2[M+H ⁺ ]；

The eighth step: n- ((3-Methoxythien-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine hydrochloride (Compound 14)

N- ((3-Methoxythien-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine (14G) (0.2g, 0.42mmol) was dissolved in ethyl acetate (3 mL), a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction was directly spun dry to give N- ((3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine hydrochloride (compound 14) (0.185 g, 85.7% yield) as an off-white solid.

Ms m/z(ESI):401.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.63-8.62(d,1H),7.95(s,1H),7.57-7.56(d,1H),7.44-7.43(d,1H),7.29-7.28(s,1H),7.05-7.04(d,1H),4.06-4.04(m,2H),3.80(s,3H),3.58-3.56(m,2H),2.67-2.66(m,2H),2.20-1.99(m,2H),1.98-1.36(m,12H).

Resolution of the compound N- ((3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine hydrochloride (Compound 14)

(compound 14) (170 mg) was taken for resolution to obtain, after separation, two optical isomers of the free base compound, compound 14H-1 (retention time: 4.12min,49.26mg, oily liquid, ee% = 99.6%), compound 14H-2 (retention time: 5.29min,43.63mg, oily liquid, ee% = 99.0%).

Splitting conditions are as follows: MG II preparatory SFC (SFC-13); column P Cellulose-2,250 × 30mm i.d.,5 μm. Mobile phase a: carbon dioxide, B: methanol (0.1% ammonia); gradient B60%; the flow rate is 60mL/min; back pressure is 100bar; the column temperature is 38 ℃; wavelength is 220nm; the period is 5.5min; sample preparation Compound 14 was dissolved in methanol to 8mg/ml; injection 2 ml/needle.

Compound 14H-1 and compound 14H-2 Compound 14-1 and compound 14-2 can be obtained by a salt-forming method of Compound 14:

compound 14-1:

Ms m/z(ESI):401.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.58-8.57(d,1H),7.83(s,1H),7.56-7.55(d,1H),7.44-7.43(d,1H),7.29-7.28(s,1H),7.05-7.04(d,1H),4.06-4.04(m,2H),3.80(s,3H),3.58-3.57(m,1H),3.41-3.39(m,1H),2.67-2.66(m,2H),2.20-1.99(m,2H),1.98-1.36(m,12H).

compound 14-2:

Ms m/z(ESI):401.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.59-8.58(d,1H),7.86(s,1H),7.56-7.48(d,1H),7.46-7.43(d,1H),7.32-7.28(s,1H),7.05-7.04(d,1H),4.07-4.04(m,2H),3.79(s,3H),3.58-3.56(m,2H),2.67-2.66(m,2H),2.27-2.20(m,2H),1.99-1.36(m,12H).

example 15

2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 15)

2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine hydrochloride

The first step is as follows: 2-cyano-2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) acetic acid methyl ester (15B)

methyl 2-cyano-2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)acetate

The compound magnesium powder (0.450g, 18.80mmol) and diethyl ether (10 mL) were charged into a three-necked reaction flask, 4-fluorobenzyl chloride (1.200g, 8.300mmol) in diethyl ether (10 mL) was added dropwise under nitrogen protection, and the mixture was stirred at room temperature for 1 hour, and further cuprous iodide (0.400g, 2.090mmol) was added into the reaction flask under ice bath and stirred for 10 minutes, and a solution of methyl 2-cyano-2- (6-oxaspiro [4.5] decan-9-ylidene) acetate (1 d) (1.500g, 6.37mmol) in diethyl ether (20 mL) was added dropwise and stirred at room temperature overnight. The reaction mixture was added to 100mL of a stirred ice-water mixture, 6N hydrochloric acid was added to dissolve it, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined and washed with saturated brine (50 mL. Times.1), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, evaporation was performed, silica gel column chromatography was performed, and petroleum ether/ethyl acetate (V/V) =10/1 to obtain methyl 2-cyano-2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) acetate (15B) (1.7 g, yield: 73.4%) as a colorless oil

Ms m/z(ESI):346.2[M+H ⁺ ]；

¹ HNMR(400MHz,DMSO-d ₆ )δ7.24-7.07(m,4H),4.34-4.15(d,1H),3.70-3.52(m,4H),3.3(s,1H),2.95-2.85(m,1H),2.76-2.63(dd,1H),1.95-1.33(m,10H).

The second step is that: 2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (15C)

2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile

Methyl 2-cyano-2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) acetate (15B) (1.7g, 4.925 mmol) was dissolved in ethylene glycol (25 mL), potassium hydroxide (0.553 g, 9.86mmol) was added, the mixture was stirred at 120 ℃ for 4 hours, the reaction mixture was cooled to room temperature, 50mL of water was added, ethereal oil (50 mL × 3) was extracted, the organic phases were combined and washed with saturated brine (50 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and petroleum ether/ethyl acetate (V/V) =10/1 by silica gel column chromatography gave 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (15C) as a colorless oily compound (0.963 g, yield: 68.1%).

Ms m/z(ESI):310.1[M+Na ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )：δ7.22-7.12(m,2H),7.04-6.98(m,2H),3.77-3.71(dt,1H),3.60-3.54(ddd,1H),2.81-2.71(q,2H),2.38-2.21(dd,2H),1.99-1.93(ddd,1H),1.89-1.85(m,1H),1.79-1.50(m,8H),1.43-1.34(m,2H).

The third step: 2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (15D)

2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

The compound 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (15C) (0.54g, 1.88mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (0.143g, 3.76mmol) was added with stirring and stirred at room temperature overnight. Water (0.4 mL), a 20% NaOH solution (0.8 mL), and water (0.4 mL) were sequentially added dropwise to the reaction solution in a salt bath with ice, stirred for 1 hour, filtered, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product, 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (15D) (0.45 g, yield: 82.2%) was obtained as a colorless oil.

Ms m/z(ESI):292.2[M+H ⁺ ]。

The fourth step: 2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (15E)

2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine

The compound 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (15D) (0.800g, 2.75mmol), 3-methoxythiophene-2-carbaldehyde (0.600g, 4.22mmol) was dissolved in dichloromethane (10 mL), and anhydrous sodium sulfate (2.000g, 14.080mmol) was added and stirred at room temperature overnight. Sodium borohydride (0.170g, 4.470mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour, and then 3 ml of anhydrous methanol was added thereto, and the mixture was stirred for 2 hours. To the reaction solution was added 20mL of water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1-3).

Ms.m/z(ESI):418.2[M+H ⁺ ]。

The fifth step: 2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 15)

The compound 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (15E) (0.472g, 1.130mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.330mL, 1.320mmol) was added and stirred at room temperature for 2 hours. Filtration gave the product 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (compound 15) as a white solid (500 mg, yield: 97.6%).

Ms.m/z(ESI):418.2[M+H ⁺ -HCl]；

¹ H NMR(400MHz,CD ₃ OD)：δ7.30-7.29(d,1H),7.09-7.06(m,2H),6.99-6.95(m,3H),3.91(s,2H),3.87(s,3H),3.69-3.63(m,2H),2.81-2.68(dtd,2H),2.66-2.62(d,1H),2.55-2.51(d,1H),1.82-1.41(m,14H).

Example 16

2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl-N- (3-methylbenzyl) ethylamine hydrochloride (Compound 16)

2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)-N-(3-methylbenzyl)ethanamine hydrochloride

The first step is as follows: 2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl-N- (3-methylbenzyl) ethylamine (16B)

2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)-N-(3-methylbenzyl)ethanamine

The compound 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (15D) (0.250g, 0.858mmol), 3-methylbenzaldehyde (0.155g, 1.29mmol) was dissolved in methylene chloride (10 mL), and anhydrous sodium sulfate (0.610g, 4.30mmol) was added to stir at room temperature overnight. Sodium borohydride (0.049 g, 1.30mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour, and then 3 ml of anhydrous methanol was added thereto, and the mixture was stirred for 2 hours. To the reaction solution was added 20mL of water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered and evaporated to dryness, and subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1-3).

Ms.m/z(ESI):396.3[M+H ⁺ ]。

The second step is that: 2- (9- (4-Fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl-N- (3-methylbenzyl) ethylamine hydrochloride (Compound 16)

Compound 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl-N- (3-methylbenzyl) ethylamine (16B) (0.062g, 0.160mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.090mL, 0.180mmol) was added and stirred at room temperature for 2 hours, filtration gave 2- (9- (4-fluorobenzyl) -6-oxaspiro [4.5] decan-9-yl-N- (3-methylbenzyl) ethylamine hydrochloride (compound 16) (62 mg, yield: 92%) as a white solid.

Ms.m/z(ESI):396.3[M+H ⁺ -HCl]；

¹ HNMR(400MHz,CD ₃ OD)：δ7.39-7.29(m,4H),7.16-7.12(dd,2H),7.02-6.97(t,2H),4.19(s,2H),3.73-3.65(m,2H),3.21-3.07(m,2H),2.77-2.70(t,1H),2.59-2.55(d,2H),2.03-1.98(m,1H),1.85-1.45(m,13H).

Example 17

N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (m-methylbenzene) methylamine hydrochloride (Compound 17)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methyl)-1-(m-tolyl)methanaminehydrochloride

The first step is as follows: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (m-methyltolyl) methylamine (17B)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methyl)-1-(m-tolyl)methanamine

The compound (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methylamine (17A) (0.630g, 2.395mmol), 3-methylbenzaldehyde (0.432g, 3.593mmol) was dissolved in methylene chloride (10 mL), and anhydrous sodium sulfate (1.700g, 11.975mmol) was added to stir at room temperature overnight. Sodium borohydride (0.136g, 3.593 mmol) was added and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added and stirred for 2 hours. To the reaction solution was added 20mL of water, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 1), dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (m-methyltolyl) methylamine (17B) (500 mg, yield: 56.7%) as a yellow oily product.

Ms.m/z(ESI):366.2[M+H ⁺ ]；

The second step is that: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (m-methyltolyl) methylamine hydrochloride (Compound 17)

The compound N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (m-methylbenzene) methylamine (17B) (0.500g, 1.37mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.700mL, 1.4 mmol) was added and stirred at room temperature for 2 hours. Filtration gave the product, N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (m-methylbenzene) methylamine hydrochloride (compound 17) as a white solid (520 mg, yield: 94.7%).

Ms.m/z(ESI):366.2[M+H ⁺ -HCl]；

¹ HNMR(400MHz,CD ₃ OD)δ7.27-7.21(m,2H),7.10-7.06(m,4H),7.03-6.99(m,2H),4.30(s,2H),3.99(s,2H),3.55(s,2H),2.40(s,2H),2.32(s,3H),1.96-1.90(m,2H),1.84-1.78(m,2H),1.75-1.65(m,2H),1.60-1.54(m,2H).

Example 18

N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine amine hydrochloride (Compound 18)

2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine hydrochloride

The first step is as follows: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) acetonitrile (18B)

2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)acetonitrile

The compound 8- (chloromethyl) -9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene (18A) (2.000g, 7.12mmol) was dissolved in DMF (20 mL), and potassium cyanide (2.40g, 36.86mmol) was added thereto, followed by stirring at 80 ℃ for 4 hours. The reaction mixture was cooled to room temperature, water (200 mL), ethyl acetate (100 mL) were added and stirred, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phases were combined and washed with saturated brine (200 mL × 3), the aqueous phase was treated with sodium hypochlorite and poured into a waste tank, the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, (petroleum ether/ethyl acetate (V/V)) =30/1-10/1 to give 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) acetonitrile (18B) (1.0 g, yield: 25.88%) as a white solid.

Ms.m/z(ESI):294.1[M+Na ⁺ ]。

The second step is that: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) ethylamine (18C)

2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)ethanamine

The compound 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) acetonitrile (18B) (0.500g, 1.84mmol) was dissolved in THF (10 mL), and lithium aluminum hydride (0.140g, 3.68mmol) was added with stirring, and after completion of the addition, the mixture was stirred at room temperature overnight (12 hours). Water (0.5 mL), a 20% NaOH solution (1 mL) and water (0.5 mL) were added dropwise to the reaction mixture in this order under a ice salt bath, stirred for 1 hour, filtered, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) ethylamine (18C) (0.5 g, yield: 98.5%) as a yellow oily product.

Ms.m/z(ESI):276.1[M+H ⁺ ]。

The third step: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- ((3-methoxythien-2-yl) methyl) ethylamine (18D)

2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine

The compound 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) ethylamine (18C) (0.400g, 1.45mmol), 3-methoxythiophene-2-carbaldehyde (0.310g, 2.180mmol) was dissolved in dichloromethane (10 mL), and anhydrous sodium sulfate (1.03g, 7.254mmol) was added, followed by stirring at room temperature overnight. Sodium borohydride (0.083g, 2.200mmol) was added thereto and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added thereto and stirred for 2 hours. To the reaction solution was added 20mL of water, followed by extraction with ethyl acetate (10 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 1), and the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (18D) (66 mg, yield: 11%) as a yellow oily product.

Ms.m/z(ESI):402.1[M+H ⁺ ]。

The fourth step: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- ((3-methoxythien-2-yl) methyl) ethylamine hydrochloride (Compound 18)

The compound 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (18D) (0.066 g, 0.16mmol) was dissolved in ethyl acetate (5 mL), and an ethyl acetate solution of hydrogen chloride (0.100mL, 0.2mmol) was added and stirred at room temperature for 2 hours. Filtration afforded the product 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (compound 18) (70 mg, yield: 97%) as a white solid.

Ms.m/z(ESI):402.1[M+H ⁺ -HCl]；

¹ HNMR(400MHz,CD ₃ OD)δ7.49-7.48(d,1H),7.18-7.07(m,4H),7.04-7.02(d,1H),4.16(s,4H),3.89(s,3H),2.91-2.87(m,2H),2.33-2.27(dd,4H),1.93-1.87(m,2H),1.80-1.77(m,2H),1.72-1.64(m,2H),1.59-1.52(m,2H).

Example 19

2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- (3-methylbenzyl) ethylamine hydrochloride (Compound 19)

2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)-N-(3-methylbenzyl)ethanaminehydrochloride

The first step is as follows: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- (3-methylbenzyl) ethylamine (19B) 2- (9- (4-fluorophenyl) -6-oxapiro [4.5] dec-8-en-8-yl) -N- (3-methyllbenzyl) ethanamine

The compound 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) ethylamine (18C) (0.415g, 1.51mmol), 3-methylbenzaldehyde (0.2.72g, 2.26mmol) was dissolved in dichloromethane (10 mL), and anhydrous sodium sulfate (1.070g, 7.542mmol) was added, followed by stirring at room temperature overnight. Sodium borohydride (0.086g, 2.300mmol) was added thereto and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added thereto and stirred for 2 hours. To the reaction solution was added 20mL of water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered and evaporated to dryness, and subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1-3).

Ms.m/z(ESI):380.2[M+H ⁺ ]；

The second step is that: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- (3-methylbenzyl) ethylamine hydrochloride (Compound 19)

The compound N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methyl) -1- (m-methyltolyl) methylamine (19B) (0.044g, 0.12mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.075mL, 0.15mmol) was added and stirred at room temperature for 2 hours. Filtration gave the product 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) -N- (3-methylbenzyl) ethylamine hydrochloride (compound 19) as a white solid (46 mg, yield: 95%).

Ms.m/z(ESI):380.2[M+H ⁺ -HCl]；

¹ HNMR(400MHz,CD ₃ OD)δ7.33-7.07(m,8H),4.17(m,2H),4.03(s,2H),2.95-2.90(m,2H),2.36(s,3H),2.33-2.29(m,4H),1.93-1.87(m,2H),1.83-1.77(m,2H),1.74-1.64(m,2H),1.59-1.52(m,2H).

Example 20

N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl) -1- (m-methyltolyl) methylamine hydrochloride (Compound 20)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)methyl)-1-(m-tolyl)methanaminehydrochloride

The first step is as follows: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl) -1- (m-methyltolyl) methylamine (20B)

N-((9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)methyl)-1-(m-tolyl)methanamine

Compound (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-yl) methylamine (20A) (0.400g, 1.52mmol), 3-methylbenzaldehyde (0.274g, 2.28mmol) were dissolved in methylene chloride (10 mL), and anhydrous sodium sulfate (1.080g, 7.59mmol) was added, followed by stirring at room temperature overnight. Sodium borohydride (0.087g, 2.28mmol) was added thereto and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added thereto and stirred for 2 hours. To the reaction solution, 20mL of water was added, extraction was performed with ethyl acetate (10 mL × 3), organic phases were combined and washed with saturated brine (30 mL × 1), and the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1-3) to obtain N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-yl) methyl) -1- (m-methyltolyl) methylamine (20B) (230 mg, yield: 41.2%) as a colorless oily product.

Ms.m/z(ESI):368.2[M+H ⁺ ]。

The second step is that: n- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-yl) methyl) -1- (m-methyltolyl) methylamine hydrochloride (Compound 20)

The compound N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl) -1- (m-methyltolyl) methylamine (0.230g, 0.626 mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.400mL, 0.800mmol) was added, followed by stirring at room temperature for 2 hours. Filtration gave the product N- ((9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methyl) -1- (m-methyltolyl) methylamine hydrochloride (compound 20) as a white solid (230 mg, yield: 91%).

Ms.m/z(ESI):368.2[M+H ⁺ -HCl]

¹ HNMR(400MHz,CD ₃ OD)：δ7.26-7.20(m,4H),7.11-7.02(m,4H),4.04-3.84(m,4H),3.39-3.30(m,2H),2.50-2.47(d,1H),2.32(s,3H),2.16-2.01(m,3H),1.87-1.52(m,8H).

Example 21

(R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride (Compound 21)

(R)-5-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride

The first step is as follows: (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde (21B)

(R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetaldehyde

2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] acetonitrile (1 g) (1.28g, 5.0 mmol) was dissolved in dry toluene (20 mL), and diisobutylaluminum hydride (11.0 mmol) was added dropwise to the reaction mixture at-70 ℃ when the temperature of the dry ice acetone bath was lowered to-70 ℃ and the temperature T < -70 ℃ was reached, followed by reaction at-70 ℃ for 3 hours. Ammonium chloride solution (10 mL) was added at-70 ℃ and extracted with ethyl acetate (40 mL. Times.3). The organic phases were combined and washed with saturated saline solution (25 mL. Times.1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =100: 1-50).

Ms m/z(ESI):260.1[M+H ⁺ ]；

The second step: (R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydrothiophene [3,2-C ] pyridine (21C)

(R)-5-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

(R) -2- (9- (pyridin-2-yl) -6-oxa [4.5] decan-9-yl) acetaldehyde (21B) (0.519g, 2.0mmol) was dissolved in methylene chloride (36 mL), and sodium sulfate (1.42g, 5.0mmol) and 4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride (0.44g, 2.5mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.095g, 2.50mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product which was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):383.2[M+H ⁺ ]；

The third step: (R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride (Compound 21)

(R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydrothiophene [3,2-C ] pyridine (21C) (0.10 g, 0.26mmol) was dissolved in ethyl acetate (5 mL), a solution of hydrogen chloride in ethyl acetate (1 mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride (Compound 21) as a white solid (0.09 g, 82% yield).

Ms m/z(ESI):383.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.63(s,1H),7.93(s,1H),7.63(s,1H),7.46-7.45(m,2H),6.86-6.85(m,1H),3.63-3.57(m,4H),3.17-3.06(m,3H),3.11-3.08(m,1H),2.50-2.42(m,2H),2.27(m,1H),2.01(m,1H),1.72(m,1H),1.50-1.04(m,7H).

Example 22

(R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride (Compound 22)

(R)-6-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride

The first step is as follows: (R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydroisothiophene [3,2-c ] pyridine (22A)

(R)-6-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

(R) -2- (9- (pyridin-2-yl) -6-oxa [4.5] decan-9-yl) acetaldehyde (21B) (0.259g, 1.0mmol) was dissolved in methylene chloride (36 mL), and sodium sulfate (1.42g, 5.0mmol) and 4,5,6, 7-tetrahydroisothiophene [3,2-c ] pyridine hydrochloride (0.22g, 1.25mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.048 g, 1.25mmol) was added to the reaction, and the reaction was stirred for 30 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product which was purified by column chromatography (dichloromethane/methanol (v/v) = 40.

Ms m/z(ESI):383.2[M+H ⁺ ]；

The third step: (R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride (Compound 22)

((R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6,7 tetrahydroisothiophene [3,2-c ] pyridine (22A) (0.050g, 0.13mmol) was dissolved in ethyl acetate (5 mL), a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added, the reaction was stirred at room temperature for 0.5 hour, and the reaction mixture was directly spin-dried to give (R) -5- (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -4,5,6,7 tetrahydroisothiophene [3,2-c ] pyridine hydrochloride (Compound 22) (0.05 g, 92% yield) as a white solid.

Ms m/z(ESI):383.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.61-8.60(s,1H),7.87(s,1H),7.43(s,2H),7.33(m,1H),6.92-6.90(m,1H),4.03-4.01(m,3H),3.61-3.58(m,2H),3.18-3.10(m,2H),2.44(m,3H),2.23(m,1H),1.99(m,1H),1.68-155(m,1H),2.01(m,1H),,1.72(m,1H),1.55-1.16(m,9H).

Example 23

(R) -N- ((3-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 23)

(R)-N-((3-ethynylthiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 3- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (23B)

3-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde

3-bromothiophene-2-carbaldehyde (23A) (2g, 10.47mmol) and trimethylsilyne (1.54g, 15.70mmol) were dissolved in tetrahydrofuran (15 mL) and triethylamine (15 mL), and trans-bis (triphenylphosphine) palladium (II) dichloride (0.367 mg, 0.52mmol) and cuprous iodide (0.199mg, 1.05mmol) were added to the reaction under nitrogen, and the reaction was allowed to warm to 60 ℃ for 2 hours. The reaction solution was filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 50) to give 3- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (23B) (2 g, yield: 91%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ10.13(d,1H),7.64(dd,1H),7.17(d,1H),0.28(m,9H).

The second step is that: 3-ethynylthiophene-2-carbaldehyde (23C)

3-ethynylthiophene-2-carbaldehyde

3- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (23B) (2g, 9.6 mmol) was dissolved in methanol (20 mL), and potassium carbonate (2g, 14mmol) was added to the reaction, after which the reaction was carried out at room temperature for 1 hour. The reaction solution was quenched with water (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 20) to obtain 3-ethynylthiophene-2-carbaldehyde (23C) as a yellow solid (1.2 g, yield: 92%).

¹ H NMR(400MHz,CDCl ₃ )δ10.15(d,1H),7.67(dd,1H),7.22(d,1H),3.46(s,1H).

The third step: (R) -N- ((3-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5]

Decan-9-yl) ethylamine (23D)

(R)-N-((3-ethynylthiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.3 g, 1.15mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.818g, 5.76mmol) and 3-ethynylthiophene-2-carbaldehyde (23C) (0.235g, 1.73mmol) were added to the reaction and reacted at room temperature overnight. Sodium borohydride (0.07g, 1.73mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):381.2[M+H ⁺ ]；

The fourth step: (R) -N- ((3-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 23)

(R) -N- ((3-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (23D) (0.03g, 0.078mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrogen chloride in ethyl acetate (0.5mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((3-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 23) as a yellow solid (0.03 g, yield: 91%).

Ms m/z(ESI):381.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.82(dd,1H),8.49(t,1H),8.07(d,1H),7.92-7.89(m,1H),7.58(d,1H),7.13(d,1H),4.42(s,2H),3.92(s,1H),3.84-3.67(m,2H),3.05(td,1H),2.59-2.45(m,3H),2.29(td,1H),2.20-2.10(m,2H),1.94-1.78(m,2H),1.69-1.50(m,5H),1.22-1.15(m,1H),0.85-0.77(m,1H).

Example 24

2- ((3-chlorobenzyl) amino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide hydrochloride (Compound 24)

2-((3-chlorobenzyl)amino)-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acetamide hydrochloride

The first step is as follows: para methylaniline (24B)

p-toluidine

P-methylnitrobenzene (24B) (13.7g, 100mmol) was dissolved in ethanol (100 mL), palladium on carbon (1.37g, wt = 10%) was added, the reaction system was evacuated, hydrogen was introduced to replace three times, and the reaction was carried out under a hydrogen balloon at room temperature for 12 hours. The pad was filtered with suction and filtered, the filter cake was washed with ethanol (20 mL. Times.2), and the filtrate was concentrated to give p-methylaniline (24B) as a yellow solid (10 g, 93.4% yield).

¹ H NMR(400MHz,CDCl ₃ )δ6.95(d,2H),6.67-6.46(m,2H),3.40(s,2H),2.23(s,3H).

The second step is that: n- (p-tolyl) -6-dioxaspiro [4.5] decan-9-amine (24C)

N-(p-tolyl)-6-oxaspiro[4.5]decan-9-amine

P-methylaniline (24B) (2g, 18.7 mmol) was dissolved in methanol (20 mL), 6-dioxaspiro [4.5] decan-9-one (3.45g, 22.4 mmol) and acetic acid (1.5 g, 25mmol) were added to the reaction, and reacted at room temperature for 1 hour, and sodium cyanoborohydride (0.449g, 28mmol) was added to the reaction, and reacted at room temperature overnight. The reaction solution was quenched with saturated sodium bicarbonate solution (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 50.

¹ H NMR(400MHz,CDCl ₃ )δ6.98(d,2H),6.54(d,2H),3.87-3.76(m,1H),3.64(td,1H),3.50(tt,1H),2.23(s,3H),2.06-1.92(m,3H),1.81-1.69(m,3H),1.67-1.43(m,5H),1.44-1.30(m,2H).

Third step 2-chloro-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24D)

2-chloro-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acetamide

N- (p-tolyl) -6-dioxaspiro [4.5] decan-9-amine (24C) (2g, 8.15mmol) and triethylamine (1.23g, 12.22mmol) were dissolved in methylene chloride (40 mL), cooled to 0 ℃ and chloroacetyl chloride (1.1g, 9.78mmol) was added dropwise to the reaction and reacted at room temperature for 1 hour. The reaction solution was quenched with a saturated sodium bicarbonate solution (30 mL), the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10) to obtain 2-chloro-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24D) as an oily liquid (2 g, yield: 76.3%).

¹ H NMR(400MHz,CDCl ₃ )δ7.23(d,2H),6.99(d,2H),4.89(ddd,1H),3.82-3.57(m,4H),2.40(s,3H),2.09-1.93(m,1H),1.74-1.31(m,11H).

The fourth step 2-azido-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24E)

2-azido-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acetamide

2-chloro-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24D) (2g, 6.22mmol) was dissolved in N, N-dimethylformamide (20 mL), and sodium azide (0.81g, 12.44mmol) was added to the reaction, after which the reaction was allowed to react at room temperature for 3 hours. The reaction solution was quenched with water (30 mL), the aqueous phase was extracted with methyl t-butyl ether (30 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2-azido-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24E) (2 g, yield: 98%) as an oily liquid.

The fifth step 2-amino-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24F)

2-amino-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acetamide

2-azido-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24E) (2g, 6.09mmol) was dissolved in tetrahydrofuran (20 mL) and water (5 mL), and triphenylphosphine (3.19g, 12.2mmol) was added to the reaction, after which the reaction was carried out at room temperature for 3 hours. 1M hydrochloric acid solution (20 mL) was added to the reaction, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phase was removed, the aqueous phase was adjusted to pH ≈ 9 with 1M sodium hydroxide solution, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 2-amino-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24F) (1.5 g, yield: 81%) as an oily liquid.

Ms m/z(ESI):303.2[M+H ⁺ ]；

And a sixth step: 2- ((3-chlorobenzyl) amino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24G) 2- ((3-chlorobenzinyl) amino) -N- (6-oxapiro [4.5] ]can-9-yl) -N- (p-tolyl) acetamide

2-amino-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24F) (0.3 g, 0.99mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.7 g,5.0 mmol) and 3-chlorobenzaldehyde (0.21g, 1.5mmol) were added thereto and reacted at room temperature overnight. Sodium borohydride (0.057g, 1.5mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and reaction with stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product which was purified by column chromatography (dichloromethane/methanol (v/v) = 50).

Ms m/z(ESI):427.2[M+H ⁺ ]；

The seventh step: 2- ((3-chlorobenzyl) amino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide hydrochloride (Compound 24)

2- ((3-chlorobenzyl) amino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24G) (0.15g, 0.351mmol) was dissolved in ethyl acetate (5 mL), a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give 2- ((3-chlorobenzyl) amino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide hydrochloride (Compound 24) as a white solid (0.16 g, yield: 98%).

Ms m/z(ESI):427.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ7.57-7.39(m,3H),7.35(t,3H),7.08(d,2H),4.82-4.77(m,1H),4.15(s,2H),3.75-3.64(m,2H),3.49(s,2H),2.41(s,3H),2.12-1.98(m,1H),1.77-1.44(m,9H),1.38-1.27(m,2H).

Example 25

2- (((3-Methylthion-2-yl) methyl) amine) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide hydrochloride (Compound 25)

2-(((3-methoxythiophen-2-yl)methyl)amino)-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acetamide hydrochloride

The first step is as follows: 2- (((3-methylthiophen-2-yl) methyl) amine) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (25A)

2-(((3-methoxythiophen-2-yl)methyl)amino)-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acetamide

2-amino-N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (24F) (0.3g, 0.99mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.7g, 5.0mmol) and 3-methoxythiophene-2-carbaldehyde (0.21g, 1.5 mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.057g, 1.5mmol) was added to the reaction, and the reaction mixture was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude 2- (((3-methylthiophen-2-yl) methyl) amine) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (25A) (0.15 g, yield: 35%) as a yellow oily liquid by column chromatography (dichloromethane/methanol (v/v) = 50).

Ms m/z(ESI):429.2[M+H ⁺ ]；

The second step is that: 2- (((3-Methylthioen-2-yl) methyl) amine) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide hydrochloride (Compound 25)

2- (((3-Methylthion-2-yl) methyl) amine) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide (25A) (0.15g, 0.351mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give 2- (((3-methylthiophen-2-yl) methyl) amine) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acetamide hydrochloride (Compound 25) as a white solid (0.16 g, yield: 98%).

Ms m/z(ESI):429.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ7.48(d,1H),7.34(d,2H),7.07(d,2H),6.98(d,1H),4.81-4.78(m,1H),4.23(s,2H),3.75(s,3H),3.72-3.66(m,2H),3.39(s,2H),2.41(s,3H),2.10-2.00(m,1H),1.78-1.47(m,9H),1.35-1.26(m,2H).

Example 26

2- (2- (6-Oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- (3-chlorophenyl) ethylamine hydrochloride (Compound 26)

2-(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)-N-(3-chlorobenzyl)ethanamine hydrochloride

The first step is as follows: 6-oxaspiro [4.5] dec-8-en-9-yl trifluoromethanesulfonate (26B)

6-oxaspiro[4.5]dec-8-en-9-yl trifluoromethanesulfonate

6-oxaspiro [4.5] decan-9-one (26A) (10.0g, 64.8mmol) was dissolved in a three-necked flask with tetrahydrofuran (120 mL), the temperature was lowered to-78 ℃, lithium diisopropylamide (38.9mL, 77.8mmol) was added dropwise to the reaction mixture, the temperature was maintained at-65 ℃ or lower, stirring was carried out for 20 minutes after the addition was completed, N-phenylbis (trifluoromethanesulfonyl) imide (25.5g, 71.3mmol) was dissolved in tetrahydrofuran (30 mL), and then the mixture was added dropwise to the reaction mixture, and the mixture was allowed to warm to room temperature for reaction for 3 hours. After the reaction was completed, the reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate solution, extracted with methyl t-butyl ether (100 mL. Times.2), the organic phases were combined, washed with 10% aqueous sodium hydroxide (100 mL. Times.2), water (100 mL. Times.1), saturated brine (100 mL. Times.1), filtered and dried, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/100-1/20), and concentrated to dryness to give 6-oxaspiro [4.5] dec-8-en-9-yl trifluoromethanesulfonate (26B) (10.2 g, yield 54.9%) as a yellow oily product.

¹ H NMR(400MHz,CDCl ₃ )δ5.79-5.69(m,1H),4.26-4.24(t,1H),3.85-3.82(q,1H),2.42-2.40(m,1H),1.88-1.78(m,4H),1.68-1.51(m,4H).

The second step is that: 4, 5-tetramethyl-2- (6-oxaspiro [4.5] dec-8-en-9-yl) -1,3, 2-dioxaborane (26C)

4,4,5,5-tetramethyl-2-(6-oxaspiro[4.5]dec-8-en-9-yl)-1,3,2-dioxaborolane

6-oxaspiro [4.5] dec-8-en-9-yl trifluoromethanesulfonate (26B) (7.9g, 28mmol) was dissolved in a single-neck flask with dioxane (80 mL), pinacol diborate (14g, 55mmol), potassium acetate (5.4g, 55mmol) were added, vacuum was applied and nitrogen was replaced 3 times, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (1.0g, 1.4mmol) was added, vacuum was applied and nitrogen was replaced 3 times, and the mixture was heated to 80 ℃ under nitrogen for 7 hours. Methyl tert-butyl ether (100 mL) was added, filtered through celite, rinsed with methyl tert-butyl ether (50 mL. Times.2), the organic phases were combined, concentrated to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/100-1/30) and concentrated to dryness to give 4,4,5,5-tetramethyl-2- (6-oxaspiro [4.5] dec-8-en-9-yl) -1,3, 2-dioxaborane (26C) as a colorless oil (7 g, 96% yield).

¹ H NMR(400MHz,CDCl ₃ )δ6.52-6.38(dt,1H),4.22-4.20(q,1H),3.71-3.69(t,1H),2.22-2.13(m,2H),1.80-1.63(m,8H),1.27-1.26(d,12H).

The third step: 2- (6-oxaspiro [4.5] dec-8-en-9-yl) nicotinaldehyde (26D)

2-(6-oxaspiro[4.5]dec-8-en-9-yl)nicotinaldehyde

4, 5-tetramethyl-2- (6-oxaspiro [4.5] dec-8-en-9-yl) -1,3, 2-dioxaborane (26C) (12.6 g, 47.7mmol), 2-bromo-3-pyridinecarbaldehyde (11.5 g,62.0 mmol), tetrakis (triphenylphosphine) palladium (3.3 g, 2.9mmol), sodium carbonate (11.1g, 105mmol) were dissolved in toluene (80 mL), ethanol (20 mL), water (20 mL), and the mixture was heated to 90 ℃ for 5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL. Times.2), and the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 0/100-1/20) by column flushing and concentrated to dryness to give 2- (6-oxaspiro [4.5] dec-8-en-9-yl) nicotinaldehyde (26D) as a yellow oil (4.5 g, yield 39%).

¹ H NMR(400MHz,CDCl ₃ )δ10.20-10.18(q,1H),8.79-8.77(dt,1H),8.22-8.20(q,1H),7.37-7.28(m,1H),5.80-5.69(dt,1H),4.42-3.94(m,2H),2.76-2.72(m,2H),1.96-1.69(m,8H).

The fourth step: (2- (6-oxaspiro [4.5] dec-8-en-9-yl) pyridin-3-yl) methanol (26E)

(2-(6-oxaspiro[4.5]dec-8-en-9-yl)pyridin-3-yl)methanol

2- (6-oxaspiro [4.5] dec-8-en-9-yl) nicotinaldehyde (26D) (2.5 g, 10mmol) was dissolved in a single-neck flask with tetrahydrofuran (20 mL), the temperature was lowered to 0 ℃, sodium borohydride (0.51g, 13mmol) was added to the reaction mixture in three portions, and after completion of the addition, the reaction was carried out at room temperature for 4 hours. The reaction was quenched by dropwise addition of saturated ammonium chloride, water (50 mL) was added, extraction was performed with ethyl acetate (30 mL × 4), the organic phases were combined, dried by addition of anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 0/100-1/20) by column chromatography, and concentrated to dryness to give (2- (6-oxaspiro [4.5] dec-8-en-9-yl) pyridin-3-yl) methanol (26E) (1.7 g, yield 67%) as a colorless oil.

The fifth step: (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) methanol (26F)

(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)methanol

(2- (6-oxaspiro [4.5] dec-8-en-9-yl) pyridin-3-yl) methanol (26E) (2.0 g, 8.2mmol) was dissolved in methanol (20 mL), palladium on carbon (0.4 g, 20%) was added, and the air in the reaction flask was replaced with hydrogen three times and reacted under hydrogen for 3 hours. The palladium-carbon contained in the reaction mixture was filtered off with Celite, rinsed with ethyl acetate (20 mL. Times.2), and the filtrate was concentrated to dryness to give (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) methanol (26F) (2.0 g, 99% yield) as a colorless oil.

LCMS m/z＝248.1[M+1]；

And a sixth step: (2- (7-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) methyl methanesulfonate (26G)

(2-(7-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)methyl methanesulfonate

(2- (6-Oxaspiro [4.5] decan-9-yl) pyridin-3-yl) methanol (26F) (2.3, 9.3 mmol) was dissolved in methylene chloride (20 mL), triethylamine (1.41g, 14.0 mmol) was added thereto, the temperature was lowered to 0 ℃ and methanesulfonyl chloride (1.38g, 12.1 mmol) was added dropwise to the reaction mixture, and the mixture was allowed to warm to room temperature for 3 hours. Water (50 mL) was added to the reaction mixture, followed by liquid separation, extraction of the aqueous phase with dichloromethane (20 mL), combination of the organic phases, drying with anhydrous sodium sulfate, filtration and concentration, and purification of the crude product by column chromatography (ethyl acetate: petroleum ether (v/v) = 0/100-1/30) column chromatography, and concentration to dryness gave (2- (7-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) methylmethanesulfonate (26G) as a yellow oil (2.1G, 69% yield).

The seventh step: 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) acetonitrile (26H)

2-(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)acetonitrile

(2- (7-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) methylmethanesulfonate (26G) (2.1g, 6.5 mmol), potassium cyanide (1.3g, 19mmol) were dissolved in N, N-dimethylformamide (20 mL) in a single vial and heated to 85 ℃ for 5 hours. Water (50 mL) was added to the reaction solution, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phases were combined and washed with water (50 mL. Times.3), the organic phase was dried, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/100-1/30) using a column punch and concentrated to dryness to give 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) acetonitrile (26H) (1.3 g, yield 79%) as a yellow oil.

¹ H NMR(400MHz,CDCl ₃ )δ8.59-8.57(q,1H),7.67-7.65(dd,1H),7.19-7.16(dd,1H),3.93-3.88(m,1H),3.78-3.71(m,3H),3.14-3.08(m,1H),2.16-2.09(m,4H),1.82-1.57(m,8H).

Eighth step: 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) ethylamine (26I)

2-(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)ethanamine

Aluminum lithium hydride (0.96g, 25mmol) was dissolved in tetrahydrofuran (10 mL), the temperature was reduced to 0 ℃ or lower, 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) acetonitrile (26H) (1.3 g,5 mmol) was dissolved in tetrahydrofuran (5 mL), and the mixture was added dropwise to the reaction mixture, followed by reaction at 0 ℃ for 2 hours. Water (1 mL), 15% aqueous sodium hydroxide (1 mL), water (3 mL) was slowly added dropwise to the reaction, stirred for half an hour and filtered, rinsed with ethyl acetate (10 mL), and the filtrate was dried and concentrated to afford 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) ethylamine (26I) (0.4 g, 30% yield) as a yellow oil.

LCMS m/z＝261.2[M+H ⁺ ]；

The ninth step: 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- (3-chlorophenyl) ethanamine (26J)

2-(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)-N-(3-chlorobenzyl)ethanamine

2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) ethylamine (26I) (0.20g, 0.77mmol), 3-chlorobenzaldehyde (0.16g, 1.15mmol) were dissolved in methylene chloride (10 mL), magnesium sulfate (0.46g, 3.84mmol) was added, the mixture was stirred at room temperature overnight, sodium borohydride (0.05g, 1.15mmol) was added, the mixture was stirred at room temperature for 1 hour, and anhydrous methanol (3 mL) was added and the mixture was stirred for 2 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL), the organic phase was dried over colorless sodium sulfate, filtered to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/10-1/1) cartridge, concentrated to dryness to give 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- (3-chlorophenyl) ethylamine (26J) (0.22 g, 74% yield) as a pale yellow oil.

LCMS m/z＝385.2[M+H ⁺ ]；

The tenth step: 2- (2- (6-Oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- (3-chlorophenyl) ethylamine hydrochloride (Compound 30)

2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- (3-chlorophenyl) ethanamine (26J) (0.22g, 0.57mmol) was dissolved in ethyl acetate (10 mL), an ethyl acetate solution of hydrochloric acid (1mL, 4mol/L) was added dropwise, a white solid precipitated, stirred for half an hour, and concentrated to dryness to give 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- (3-chlorophenyl) ethanamine hydrochloride (Compound 26) (0.23 g, 95% yield).

LCMS m/z＝385.2[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.67-8.66(q,1H),8.51(d,1H),7.95-7.92(dd,1H),7.66(s,1H),7.53-7.48(m,1H),4.33-4.32(d,2H),4.11-4.09(t,1H),3.90-3.88(dd,2H),3.65(m,1H),3.39(s,3H),2.07-1.57(m,13H).

Example 27

2- (2- (6-Oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 27)

2-(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine hydrochloride

The first step is as follows: 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (27A)

2-(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine

2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) ethylamine (26I) (0.20g, 0.77mmol), 3-methoxythiophene-2-carbaldehyde (0.16g, 1.2mmol) were dissolved in methylene chloride (10 mL), magnesium sulfate (0.46g, 3.84mmol) was added, stirring was continued overnight at room temperature, sodium borohydride (44mg, 1.15mmol) was added, stirring was continued at room temperature for 1 hour, and anhydrous methanol (3 mL) was added and stirring was continued for 2 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL), the organic phase was dried over colorless sodium sulfate, filtered to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/10-1/1) cartridge, concentrated to dryness to give 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (27A) (0.22 g, 74% yield) as a pale yellow oil.

LCMS m/z＝387.2[M+H ⁺ ]；

The second step: 2- (2- (6-Oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 27)

2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (27A) (0.10 g, 0.26mmol) was dissolved in ethyl acetate (10 mL), and a solution of hydrochloric acid in ethyl acetate (1mL, 4mol/L) was added dropwise with solid precipitation, stirred for half an hour and concentrated to dryness to give 2- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -N- (3-chlorophenyl) ethylamine hydrochloride (Compound 27) (0.08 g, 70% yield) as an orange solid.

LC-MS m/z＝387.2[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.68-8.67(d,1H),8.53-8.51(d,1H),7.96-7.92(t,1H),7.54-7.53(d,1H),7.08-7.06(d,1H),4.41(s,2H),3.94(s,3H),3.89-3.87(d,2H),3.60-3.57(q,1H),3.37-3.30(m,4H),2.05-1.62(m,13H).

Example 28

(R) -N- ((3- (methoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 28)

(R)-N-((3-(methoxymethyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decn-9-yl)ethanamine hydrochloride

The first step is as follows: 3- (methoxymethyl) thiophene (28B)

3-(methoxymethyl)thiophene

Sodium hydrogen (3.15g, 131.3mmol) was dissolved in tetrahydrofuran (40 mL) at zero degrees, and then thiophene 3-ylmethanol (28A) (5g, 43.7mmol) was added to the solution, and after addition, iodomethane (9.32g, 65.69mmol) was added dropwise, and after addition, 60 degrees reaction was performed for 2h, cooling was performed, water (30 mL) was added, ethyl acetate extraction (50 mL × 3), water washing (50 mL × 1), the organic phases were combined, washed with a saturated saline solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography separation and purification (n-hexane/ethyl acetate = 10) to obtain a yellow liquid product, 3- (methoxymethyl) thiophene (28B) (5.6 g, yield 100%).

¹ H NMR(400MHz,CDCl ₃ ):δ7.31–7.26(m,1H),7.21(m,H),7.08-7.06(m,1H),4.46(s,2H),3.37(s,3H)。

The second step is that: 3- (methoxymethyl) thiophene-2-carbaldehyde (28C)

3-(methoxymethyl)thiophene-2-carbaldehyde

3- (methoxymethyl) thiophene (28B) (2g, 12.8mmol) was dissolved in tetrahydrofuran (10 mL), and then the reaction system was cooled to-78 ℃ and n-butyllithium (6.88mL, 17.2mmol) was added thereto, after which the reaction was completed for 0.5h, and dimethylformamide (1.4g, 20mmol) was added thereto up to zero and the reaction was continued for 2h. Ammonium chloride water (20 mL) was added, extracted with EA (20 mL × 3), and the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography separation and purification (n-hexane/ethyl acetate = 5.

The third step: (R) -N- ((3- (methoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (28D)

(R)-N-((3-(methoxymethyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

3- (methoxymethyl) thiophene-2-aldehyde (28C) (0.2g, 1.27mmol) was dissolved in dichloromethane (10 ml), and (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1), anhydrous sodium sulfate (1.31 g) was added thereto in this order. The reaction was allowed to react overnight at room temperature, sodium borohydride (0.065g, 1.73mmol) was added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography purification (dichloromethane/methanol =20 1) was performed to obtain N- ((3- (methoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine (28D) (0.3g, 70%) as a yellow liquid.

Ms m/z(ESI):401.1[M+H ⁺ ]；

The fourth step: (R) -N- ((3- (methoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 28)

(R) -N- ((3- (methoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine (28D) (0.3g, 0.7 mmol) was dissolved in EA (5 mL) and the solution of ethyl hydrogen chloride acetate (2mL, 4N) was added at 0 ℃ and the reaction was continued for 0.5h, after which the solvent was removed under reduced pressure to give (R) -N- ((3- (methoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine hydrochloride (Compound 28) (0.31g, 100%) as a white solid.

Ms m/z(ESI):401.1[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.83(m,1H),8.83(m,1H),8.52(t,1H),8.10(d,1H),7.95(m,1H),7.49(d,1H),7.04(d,1H),4.53(s,2H),4.36(s,2H),3.77(m,2H),3.40(s,3H),3.04(td,1H),2.52(m,3H),2.30(td,1H),2.15(m,2H),1.91(m,2H),1.59(m,5H),1.34-1.32(m,3H)。

Example 29

(R) -N- (3-Cyclopropylbenzyl) -2- (9- (pyridin-2-yl) -6-oxa [4.5] decan-9-yl) ethylamine hydrochloride (Compound 29)

(R)-N-(3-cyclopropoxybenzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: methyl 3- (2-bromoethoxy) benzoate (29B)

methyl 3-(2-bromoethoxy)benzoate

Methyl 3-phenolic hydroxybenzoate (29A) (7g, 46mmol) was dissolved in DMF (40 mL), potassium carbonate (12.7g, 92mmol), 1, 2-dibromoethane (26g, 184mmol) were added to the solution in this order, reaction was carried out for 24h, cooling, water (150 mL) was added, dichloromethane was extracted (50 mL × 4), washing was carried out with a saturated aqueous salt solution (150 mL × 3), anhydrous sodium sulfate was dried, filtration was carried out, the filtrate was concentrated, and column chromatography separation purification (n-hexane/ethyl acetate = 10) was carried out to obtain methyl 3- (2-bromoethoxy) benzoate (29B) (5 g, yield 50%) as a pale yellow oily product,

¹ H NMR(400MHz,CDCl ₃ ):δ7.68–7.66(m,1H),7.57–7.56(m,1H),7.36-7.26(m,H),7.14-7.11(m,1H),4.36-4.33(t,2H),3.92(s,3H),4.67-4.64(t,2H)。

The second step is that: methyl 3- (vinyl) benzoate (29C)

methyl 3-(vinyloxy)benzoate

3- (2-Bromoethoxy) benzoate (29B) (3g, 11.57mmol) was dissolved in THF (20 mL), potassium tert-butoxide solution (23mL, 23mmol) was added, and the reaction was continued for 5h. Water (100 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with a saturated saline solution (30 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give methyl 3- (vinyl) benzoate 29C as a pale yellow oil product (2.2 g, yield 60%).

Ms m/z(ESI):215.1[M+H ⁺ ]

The third step: methyl 3-cyclopropylbenzoate (29D)

methyl 3-cyclopropoxybenzoate

Methyl 3- (vinyl) benzoate (29C) (2.2g, 12mmol) was dissolved in methylene chloride (40 mL), diiodomethane (13g, 49mmol) was added thereto, followed by cooling to 0 ℃ and diethyl zinc (3.1g, 21mmol) was slowly added dropwise. After 5h reaction at room temperature, 1N aqueous hydrochloric acid (20 mL) was added to clear the solution, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated aqueous saline solution (30 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give methyl 3-cyclopropylbenzoate (29D) (1.9g, 60%) as a crude pale yellow liquid, which was directly used in the next step.

Ms m/z(ESI):215.1[M+H ⁺ ]。

The fourth step: (3-Cyclopropylphenyl) methanol (29E)

(3-cyclopropoxyphenyl)methanol

Methyl 3-cyclopropylbenzoate (29D) (1.9g, 9.9mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature, lithium aluminum hydride (0.75, 20mmol) was added at 0 ℃ and the reaction was continued for 2 hours, then water (0.75 mL), 10% aqueous sodium hydroxide (0.75 mL), water (0.75 mL), anhydrous sodium sulfate (2 g) was added to the reaction mixture, the mixture was stirred for 10 minutes, and the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to obtain (3-cyclopropylphenyl) methanol (29E) (1.3g, 80%) as a colorless oily product.

Ms m/z(ESI):187.1[M+H ⁺ ]。

The fifth step: 3-Cyclopropylbenzaldehyde (29F)

3-cyclopropoxybenzaldehyde

At room temperature, (3-cyclopropylphenyl) methanol (29E) (1.3 g,7.9 mmol) was dissolved in dichloromethane (15 mL), dess-min reagent (5g, 12mmol) was added at 0 ℃, after the addition, the reaction was continued for 0.5h, and extraction was performed with dichloromethane (20 mL × 3), and the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (n-hexane/ethyl acetate = 20) was performed to isolate and purify 3-cyclopropylbenzaldehyde (29F) (0.08g, 10%) as a pale yellow liquid product

Ms m/z(ESI):163.1[M+H ⁺ ]。

And a sixth step: (R) -N- (3-cyclopropylbenzyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (29G)

(R)-N-(3-cyclopropoxybenzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

3-Cyclopropylbenzaldehyde (29F) (0.08g, 0.5 mmol) was dissolved in methylene chloride (10 mL), and (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine (0.2g, 0.6 mmol) and anhydrous sodium sulfate (0.6 g) were added thereto in this order. After reacting overnight at room temperature, sodium borohydride (0.02g, 0.6 mmol) was added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with dichloromethane (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (dichloromethane/methanol =20 = 1) was performed to isolate and purify the product N- (3-cyclopropylbenzyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (29G) as a yellow oily product (0.09g, 60%).

Ms m/z(ESI):407.1[M+H ⁺ ]。

The seventh step: (R) -N- (3-Cyclopropylbenzyl) -2- (9- (pyridin-2-yl) -6-oxa [4.5] decan-9-yl) ethylamine hydrochloride (Compound 29)

(R)-N-(3-cyclopropoxybenzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanaminehydrochloride

Dissolving N- (3-cyclopropylbenzyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine (29G) (0.09g, 0.2mmol) in ethyl acetate (5 mL) at room temperature, adding hydrogen chloride in ethyl acetate (2 mL, 4N) at 0 deg.C, continuing the reaction for 0.5h, and removing the solvent under reduced pressure to obtain (R) -N- ((3- (methoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine hydrochloride (Compound 29) (0.09g, 96%)

Ms m/z(ESI):407.1[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.81(d,1H),8.47(t,1H),8.06(d,1H),7.90(m,1H),7.33(m,1H),7.12(dd,1H),6.99(d,1H),4.06(s,2H),3.78(m,2H),3.03(td,1H),2.51(ddd,2H),2.30(td,1H),2.14(m,2H),1.88(m,2H),1.57(m,5H),0.81(m,2H),0.67(dd,2H)。

Example 30

(R) -N- ((3-Cyclopropoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 30)

(R)-N-((3-cyclopropoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 3- (2-Bromoethoxy) thiophene-2-carboxylic acid methyl ester (30B)

methyl 3-(2-bromoethoxy)thiophene-2-carboxylate

Methyl 3-hydroxythiophene-2-carboxylate (30A) (10g, 63.2mmol) was dissolved in N, N-dimethylformamide (50 mL) at room temperature, and potassium carbonate (34.9g, 252.8mmol) and dibromoethane (95g, 505.7mmol) were added, and the reaction was completed at 80 ℃ for 2 hours. To the reaction solution was added water (200 mL), the aqueous phase was extracted with methyl tert-butyl ether (50 mL × 3), the combined organic phases were washed with a saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 20).

¹ H NMR(400MHz,CDCl ₃ )δ7.41(d,1H),6.84(d,1H),4.43(t,2H),3.85(s,3H),3.65(t,2H).

The second step is that: 3- (ethyleneoxy) thiophene-2-carboxylic acid methyl ester (30C)

methyl 3-(vinyloxy)thiophene-2-carboxylate

3- (2-Bromoethoxy) thiophene-2-carboxylic acid methyl ester (30B) (14g, 52.8mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 ℃ and a solution of sodium bis (trimethylsilyl) amide (39.5 mL, 79mmol) was added dropwise to the reaction and reacted at 0 ℃ for 1 hour. The reaction solution was quenched with a saturated ammonium chloride solution (100 mL), the liquids were separated, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10) to obtain methyl 3- (ethyleneoxy) thiophene-2-carboxylate (30C) as a yellow solid (5.5 g, yield: 57%).

¹ H NMR(400MHz,CDCl ₃ )δ7.42(d,1H),6.87(d,1H),6.67(dd,1H),4.82(dd,1H),4.49(dd,1H),3.86(s,3H).

The third step: 3- (Cyclopropoxy) thiophene-2-carboxylic acid methyl ester (30D)

methyl 3-cyclopropoxythiophene-2-carboxylate

Methyl 3- (vinyloxy) thiophene-2-carboxylate (30C) (5.5g, 29.9 mmol) and diiodomethane (40g, 149mmol) were dissolved in dichloromethane (80 mL) under nitrogen, cooled to 0 deg.C, and diethylzinc (59.5mL, 119mmol) was added dropwise to the reaction, after which the reaction was allowed to proceed overnight at room temperature. The reaction was quenched by adding a saturated ammonium chloride solution (80 mL) to the reaction solution, separating the layers, extracting the aqueous phase with dichloromethane (50 mL × 2), combining the organic phases, washing with a saturated sodium chloride solution (80 mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and then purifying the crude product by column chromatography (petroleum ether/ethyl acetate (v/v) = 1-10) to obtain methyl 3- (cyclopropoxy) thiophene-2-carboxylate (30D) as an oily liquid (3 g, yield: 50.7%).

¹ H NMR(400MHz,CDCl ₃ )δ7.40(d,1H),7.12(d,1H),3.99-3.89(m,1H),3.82(s,3H),1.00-0.87(m,2H),0.84-0.73(m,2H).

The fourth step: (3-Cyclopropoxythiophen-2-yl) methanol (30E)

(3-cyclopropoxythiophen-2-yl)methanol

Lithium aluminum hydride (1.2 g, 30mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0 deg.C, and then a solution of methyl 3- (cyclopropoxy) thiophene-2-carboxylate (30D) (3 g, 15mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction, and the reaction was carried out at room temperature for 2 hours. The reaction was cooled to 0 ℃, and quenched with water (1.2 mL), sodium hydroxide solution (10%, 1.2 mL) and water (3.6 mL) in that order, dried by adding anhydrous sodium sulfate, the solid was filtered and washed with tetrahydrofuran (20 mL × 2), and the combined organic phases were concentrated to give an oily liquid (3-cyclopropoxythiophene-2-yl) methanol (30E) (2.5 g, yield: 97%).

The fifth step: 3-Cyclopropoxythiophene-2-carbaldehyde (30F)

3-cyclopropoxythiophene-2-carbaldehyde

(3-Cyclopropoxythiophen-2-yl) methanol (30E) (1.5g, 8.81mmol) was dissolved in dichloromethane (50 mL), cooled to 0 ℃ and manganese dioxide (7.66g, 88.1mmol) was added to the reaction, and the reaction was carried out at room temperature for 12 hours. The reaction solution was filtered of a solid and washed with dichloromethane (20 mL. Times.2), and the combined organic phases were concentrated to give 3-cyclopropoxythiophene-2-carbaldehyde (30F) (1.4 g, yield: 94%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ9.93(d,1H),7.63(dd,1H),7.10(d,1H),3.97(td,1H),0.95-0.81(m,4H).

And a sixth step: (R) -N- ((3-Cyclopropoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (30G)

(R)-N-((3-cyclopropoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.50g, 1.92mmol) was dissolved in dichloromethane (20 mL), and sodium sulfate (1.36g, 9.60mmol) and 3-cyclopropyloxythiophene-2-carbaldehyde (30F) (0.388g, 2.3mmol) were added to the reaction and reacted overnight at room temperature. Sodium borohydride (0.11g, 2.88mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and the crude product was purified by preparative HPLC (method: acetonitrile/0.1% aqueous ammonia-25% _60% _15 min) to give (R) -N- ((3-cyclopropoxythien-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (30G) (0.5G, yield: 63%) as an oily liquid.

Ms m/z(ESI):413.2[M+H ⁺ ]。

The seventh step: (R) -N- ((3-Cyclopropoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 30)

(R) -N- ((3-Cyclopropoxythen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (30G) (0.50g, 1.21mmol) was dissolved in ethyl acetate (10 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((3-cyclopropoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (compound 30) as a white solid (0.54 g, yield: 99%).

Ms m/z(ESI):413.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.89(d,1H),8.67(d,1H),8.22(d,1H),8.08(t,1H),7.47(d,1H),7.18(d,1H),4.15(s,2H),3.98-3.91(m,1H),3.89-3.80(m,1H),3.75-3.69(m,1H),3.04-2.91(m,1H),2.54-2.45(m,3H),2.39-2.26(m,1H),2.20(t,2H),2.01-1.80(m,2H),1.75-1.41(m,5H),1.24-1.18(m,1H),0.90-0.68(m,5H).

Example 31

3- (benzylamino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) propanamide hydrochloride (Compound 31)

3-(benzylamino)-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)propanamide hydrochloride

First step N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acrylamide (31A)

N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acrylamide

N- (p-tolyl) -6-dioxaspiro [4.5] decan-9-amine (24C) (1.5g, 6.1mmol) and triethylamine (0.93g, 9.2mmol) were dissolved in methylene chloride (20 mL), cooled to 0 ℃ and chloropropionyl chloride (0.93g, 7.3mmol) was added dropwise to the reaction, after which the reaction was carried out at room temperature for 2 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution (30 mL), the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10) to give N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acrylamide (31A) as an oily liquid (1.5 g, yield: 82%).

¹ H NMR(400MHz,CDCl ₃ )δ7.21(t,2H),6.94(d,2H),6.32(dd,1H),5.83(dd,1H),5.44(dd,1H),5.07-4.90(m,1H),3.77-3.59(m,2H),2.43-2.31(m,3H),2.09-1.95(m,1H),1.81-1.30(m,11H).

Second step 3- (benzylamino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) propanamide (31B) 3-

(benzylamino)-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)propanamide

N- (6-dioxaspiro [4.5] decan-9-yl) -N- (p-tolyl) acrylamide (31A) (0.30g, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL), and benzylamine (0.215g, 2.0 mmol) and 1, 8-diazabicycloundec-7-ene (0.305g, 2.0 mmol) were added to the reaction, which was heated to reflux for 12 hours. The reaction solution was quenched with water (30 mL), the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and the crude product was purified by preparative HPLC (method: acetonitrile/0.1% aqueous ammonia-45% _75% _15 min) to give 3- (benzylamino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) propionamide (31B) (0.2 g, yield: 50%).

Ms m/z(ESI):407.3[M+H ⁺ ]。

The third step: 3- (benzylamino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) propanamide hydrochloride (Compound 31)

3- (benzylamino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) propanamide (31B) (0.2g, 0.492mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give 3- (benzylamino) -N- (6-oxaspiro [4.5] decan-9-yl) -N- (p-tolyl) propanamide hydrochloride (compound 31) as a white solid (0.21 g, yield: 96%).

Ms m/z(ESI):407.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ7.59-7.38(m,5H),7.31(d,2H),7.07(d,2H),4.93-4.82(m,1H),4.19(s,2H),3.74-3.61(m,2H),3.18(t,2H),2.46-2.27(m,5H),2.03(d,1H),1.72-1.54(m,9H),1.40-1.28(m,2H).

Example 32

(R) -N- ((4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 32)

(R)-N-((4-ethynylthiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (32B)

4-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde

4-bromothiophene-2-carbaldehyde (32A) (2g, 10.47mmol) and trimethylsilyne (1.54g, 15.70mmol) were dissolved in tetrahydrofuran (15 mL) and triethylamine (15 mL), and trans-bis (triphenylphosphine) palladium (II) dichloride (0.367 mg, 0.52mmol) and cuprous iodide (0.199mg, 1.05mmol) were added to the reaction under nitrogen, and the temperature was raised to 60 ℃ for 2 hours. The reaction solution was filtered, and the organic phase was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 50) to give 4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (32B) (2 g, yield: 91.7%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ9.88(d,1H),7.85-7.68(m,2H),0.25(m,9H).

The second step is that: 4-ethynylthiophene-2-carbaldehyde (32C)

4-ethynylthiophene-2-carbaldehyde

4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (32B) (2g, 9.6 mmol) was dissolved in methanol (20 mL), and potassium carbonate (2g, 14mmol) was added to the reaction, and the reaction was allowed to proceed at room temperature for 1 hour after the addition. The reaction solution was quenched with water (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 20) to obtain 4-ethynylthiophene-2-carbaldehyde (32C) as a yellow solid (1.2 g, yield: 92%).

¹ H NMR(400MHz,CDCl ₃ )δ9.90(d,1H),7.99-7.62(m,2H),3.10(s,1H).

The third step: (R) -N- ((4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (32D)

(R)-N-((4-ethynylthiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.3g, 1.15mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.818g, 5.76mmol) and 4-ethynylthiophene-2-carbaldehyde (32C) (0.235g, 1.73mmol) were added to the reaction and reacted at room temperature overnight. Sodium borohydride (0.07g, 1.73mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =50:1 to 20) to give (R) -N- ((4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (32D) as a yellow oily liquid (0.31 g, yield: 70%).

Ms m/z(ESI):381.2[M+H ⁺ ]；

The fourth step: (R) -N- ((4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 32)

(R) -N- ((4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (32D) (0.3 g, 0.788mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 32) as a white solid (0.32 g, yield: 97%).

Ms m/z(ESI):381.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.87(d,1H),8.64(t,1H),8.19(t,1H),8.11-7.97(m,1H),7.69(s,1H),7.29(s,1H),4.31(s,2H),3.89-3.80(m,1H),3.72(ddd,1H),3.50(s,1H),3.05(td,1H),2.64-2.43(m,3H),2.41-2.28(m,1H),2.28-2.12(m,2H),2.02-1.83(m,2H),1.70-1.51(m,5H),1.27-1.17(m,1H),0.90-0.81(m,1H).

Example 33

N- ((3-Methoxythien-2-yl) methyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine hydrochloride (Compound 33)

N-((3-methoxythiophen-2-yl)methyl)-2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)ethanamine hydrochloride

The first step is as follows: 2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (33B)

2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)ethanamine

Lithium aluminum hydride (0.56g, 15.0 mmol) was dissolved in tetrahydrofuran (30 mL), and the temperature was reduced to 0 ℃ to add 2- (10- (pyridin-2-yl) -6-oxaspiro [4.5] undecan-10-yl) acetonitrile (33A) (1.08g, 4.0 mmol) in tetrahydrofuran (10 mL) to the reaction, followed by reaction at room temperature overnight. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (1.2 mL), dried with anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give 2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (33B) (0.8 g, yield: 72.5%).

Ms m/z(ESI):275.2[M+H ⁺ ]；

The second step is that: n- ((3-Methoxythiophen-2-yl) methyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (33C)

N-((3-methoxythiophen-2-yl)methyl)-2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)ethanamine

2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (33B) (0.5g, 1.82mmol) was dissolved in methylene chloride (15 mL), and sodium sulfate (1.3g, 7.5mmol) and 3-methoxythiophene-2-carboxaldehyde (0.35g, 2.46mmol) were added to the reaction, followed by reaction at room temperature overnight. Sodium borohydride (0.14g, 3.64mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was subjected to column chromatography (dichloromethane/methanol (v/v) =50

Ms m/z(ESI):401.2[M+H ⁺ ]；

The third step: n- ((3-Methoxythien-2-yl) methyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine hydrochloride (Compound 33)

N- ((3-Methoxythien-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine (33B) (0.5g, 1.25mmol) was dissolved in ethyl acetate (3 mL), a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give N- ((3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-9-yl) ethylamine hydrochloride (Compound 33) (0.5 g, 91.6% yield) as an off-white solid.

Ms m/z(ESI):401.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.80(s,1H),8.59-8.58(d,1H),7.89(s,1H),7.57-7.56(d,1H),7.35(s,1H),7.05-7.04(d,1H),3.78(s,3H),3.64-3.61(m,2H),2.67(m,2H),2.28-2.27(m,4H),1.91-1.83(m,3H),1.77-1.47(m,12H).

Example 34

N- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine hydrochloride (Compound 34)

N-(3-chlorobenzyl)-2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)ethanaminehydrochloride

The first step is as follows: n- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (34A)

N-(3-chlorobenzyl)-2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)ethanamine

2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (33B) (0.3 g, 1.09mmol) was dissolved in methylene chloride (15 mL), and sodium sulfate (1.3 g,7.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.23g, 1.64mmol) were added to the reaction and reacted overnight at room temperature. Sodium borohydride (0.083g, 2.18mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was subjected to column chromatography (dichloromethane/methanol (v/v) =50

Ms m/z(ESI):399.2[M+H ⁺ ]；

The second step is that: n- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine hydrochloride (Compound 34)

N- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (34A) (0.23g, 0.57mmol) was dissolved in ethyl acetate (3 mL), a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction was directly spun dry to give N- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine hydrochloride (compound 34) (0.225 g, 97.8% yield) as an off-white solid.

Ms m/z(ESI):399.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.79-8.77(d,1H),8.45-8.44(m,1H),8.11-8.09(d,1H),7.86(s,1H),7.54(s,1H),7.44-7.40(m,3H),3.78(s,3H),3.73-3.66(m,1H),3.63-3.61(m,1H),3.03-3.01(m,1H),2.61-2.56(m,4H),2.24-2.23(m,2H),1.99-1.93(m,2H),1.92-1.91(m,3H)1.60-1.45(m,6H).

Resolution of the Compound N- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine hydrochloride (Compound 34)

(compound 34) (220 mg) was taken for resolution, and after separation, two optical isomers, compound (R) -N- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (compound 34A-1) (retention time: 5.36min,59.68mg, oily liquid, ee% = 100%), compound (S) -N- (3-chlorophenyl) -2- (10- (pyridin-2-yl) -6-oxaspiro [4.6] undecan-10-yl) ethylamine (compound 34A-2) (retention time: 6.01min,70.27mg, oily liquid, ee% = 100%), were obtained.

Splitting conditions are as follows:

MG II preparatory SFC (SFC-15); column ChiralPak AD,250 × 30mm i.d.,5 μm. Mobile phase a: carbon dioxide, B: methanol (0.1% ammonia); gradient B30%; the flow rate is 50mL/min; back pressure is 100bar; the column temperature is 38 ℃; the wavelength is 220nm; the period is 3min; sample preparation, compound is dissolved in methanol to make 7mg/ml; injection 2 ml/needle.

Compound 34A-1 and compound 34A-2 can be obtained by a salt-forming method of compound 34 to obtain compound 34-1 and compound 34-2:

compound 34-1:

Ms m/z(ESI):399.2[M+H ⁺ ]；

compound 34-2:

Ms m/z(ESI):399.2[M+H ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.78-8.76(d,1H),8.43-8.41(m,1H),8.09-8.07(d,1H),7.84(s,1H),7.54(s,1H),7.45-7.40(m,3H),4.12(s,3H),3.73-3.66(m,1H),3.64-3.60(m,1H),3.03-3.01(m,1H),2.61-2.56(m,4H),2.24-2.23(m,2H),2.10–2.05(m,2H),1.97-1.92(m,3H),1.59-1.45(m,6H).

example 35

(R) -N- (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) methyl) thiophen-3-yl) acetamide hydrochloride (Compound 35)

(R)-N-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)acetamide hydrochloride

The first step is as follows: 3-Acetylaminothiophene-2-carboxylic acid methyl ester (35B)

methyl 3-acetamidothiophene-2-carboxylate

Methyl 3-aminothiophene-2-carboxylate (35A) (10g, 63.617mmol) was dissolved in methylene chloride (100 mL), and pyridine (10.06g, 127.23mmol) and acetic anhydride (7.794g, 76.341mmol) were added successively with stirring, and after completion of the addition, the mixture was stirred at room temperature overnight. The reaction mixture was added with a saturated ammonium chloride solution (100 mL) and separated, the aqueous phase was extracted with dichloromethane (20 mL. Times.2), the organic phases were combined and washed with 1N hydrochloric acid and a saturated saline solution (20 mL. Times.2) in this order, the organic phase was dried over anhydrous sodium sulfate, and the mixture was filtered and evaporated to dryness to give methyl 3-acetamidothiophene 2-carboxylate (35B) (12 g, yield: 94.68%) as a yellow solid product.

Ms.m/z(ESI):200.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ10.14(s,1H),8.12(d,1H),7.46-7.45(d,1H),3.89(s,3H),2.23(s,3H).

The second step is that: n- (2- (hydroxymethyl) thiophen-3-yl) acetamide (35C)

N-(2-(hydroxymethyl)thiophen-3-yl)acetamide

The compound lithium aluminum hydride (0.382g, 10.04mmol) and tetrahydrofuran (25 mL) were sequentially charged into a 100mL three-necked reaction flask, and a solution of methyl 3-acetamidothiophene 2-carboxylate (35B) (1.0 g, 5.019mmol) in tetrahydrofuran (5 mL) was added dropwise with stirring at room temperature, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was cooled to 0 ℃ or lower with an ice salt bath, and water (0.6 mL), a 20% sodium hydroxide solution (1.2 mL), water (0.6 mL) and celite were added to the reaction solution in this order while stirring, and the resulting mixture was washed with tetrahydrofuran (10 mL. Times.3) and filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give N- (2- (hydroxymethyl) thiophen-3-yl) acetamide (35C) (0.8 g, yield: 90%) as a yellow oily product.

Ms m/z(ESI):194.0[M+Na ⁺ ]；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.47(s,1H),7.31-7.29(d,1H),7.17(d,1H),5.30(t,1H),4.54-4.52(d,2H),2.01(s,3H).

The third step: n- (2-Methoxymethylenethiophene-3-yl) acetamide (35D)

N-(2-formylthiophen-3-yl)acetamide

The compound N- (2- (hydroxymethyl) thiophen-3-yl) acetamide (35C) (0.58g, 3.39mmol) was dissolved in dichloromethane (20 mL), stirred and cooled to 0 deg.C, and a solution of dess-martin oxidant (0.772g, 1.82mmol) was added, after which the reaction was completed at room temperature for 4 hours. To the reaction solution was added a saturated thiosulfate solution (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined and washed with a saturated carbonic acid inner solution (50 mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow solid product, N- (2-formol thiophen-3-yl) acetamide (35D) (0.40 g, yield: 69.8%).

The fourth step: (R) -N- (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) methyl) thiophen-3-yl) acetamide (35E)

(R)-N-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)acetamide

The compound N- (2-Methoxymethylthien-3-yl) acetamide (35D) (0.422g, 2.50mmol), (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.50g, 1.92mmol) was dissolved in dichloromethane (20 mL), and anhydrous sodium sulfate (1.36g, 9.60mmol) was added and stirred at room temperature overnight. Sodium borohydride (0.109g, 2.88mmol) was added thereto and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added thereto and stirred for 2 hours. Water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give (R) -N- (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) methyl) thiophen-3-yl) acetamide (35E) (400 mg, yield: 50.4%) as a colorless oily product.

Ms.m/z(ESI):414.2[M+H ⁺ ]；

The fifth step: (R) -N- (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) methyl) thiophen-3-yl) acetamide hydrochloride (Compound 35)

The compound (R) -N- (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) methyl) thiophen-3-yl) acetamide (35E) (0.400g, 0.968mmol) was dissolved in ethyl acetate (5 mL), and an ethyl acetate solution of hydrogen chloride (0.968mL, 0.968mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness to give (R) -N- (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amine) methyl) thiophen-3-yl) acetamide hydrochloride (compound 35) as a yellow solid (420 mg, yield: 96.5%).

Ms.m/z(ESI):414.2[M+H ⁺ -HCl]；

¹ H NMR(400MHz,CD ₃ OD)δ8.89(dd,1H),8.67(td,1H),8.23(d,1H),8.12–8.05(m,1H),7.52(d,1H),6.99–6.94(m,1H),4.24–4.13(m,2H),3.87(dt,1H),3.73(ddd,1H),3.05(td,1H),2.59(td,1H),2.53–2.42(m,2H),2.40–2.24(m,2H),2.21(d,1H),2.15(s,3H),2.05–1.96(m,2H),1.93–1.44(m,7H).

Example 36

5- (2- ((3-chlorobenzyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 36)

5-(2-((3-chlorobenzyl)amino)ethyl)-1-methyl-5-(pyridin-2-yl)piperidin-2-one hydrochloride

The first step is as follows: 3- (1, 3-dioxo-2-yl) -2- (pyridin-2-yl) propionitrile (36B)

3-(1,3-dioxolan-2-yl)-2-(pyridin-2-yl)propanenitrile

2- (pyridin-2-yl) acetonitrile (36A) (2.26g, 19.1mmol) was dissolved in tetrahydrofuran (30 ml), and sodium hydride (0.5g, 23mmol) was added to the solution, and after 2 hours of reaction, 2- (bromomethyl) -1, 3-dioxolane (3.51g, 21mmol) was reacted at room temperature for 24 hours. Cooling, addition of water (150 mL), extraction with ethyl acetate (50 mL × 4), washing with a saturated saline solution (150 mL × 3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by column chromatography (n-hexane/ethyl acetate = 10) gave the product 3- (1, 3-dioxo-2-yl) -2- (pyridin-2-yl) propionitrile (36B) (1 g, yield 30%) as a yellow oily substance,

Ms m/z(ESI):205.1[M+H ⁺ ]。

The second step is that: methyl 4-cyano-5- (1, 3-dioxolan-2-yl) -4- (pyridin-2-yl) pentanoate (36C)

methyl 4-cyano-5-(1,3-dioxolan-2-yl)-4-(pyridin-2-yl)pentanoate

3- (1, 3-dioxo-2-yl) -2- (pyridin-2-yl) propionitrile (36B) (0.5g, 2mmol) was dissolved in dichloromethane (20 mL), 1, 5-diazabicyclo [5.4.0] undec-5-ene (0.6 g, 4mmol) and methyl acrylate (0.4g, 4mmol) were added, and the reaction was continued for 15h after completion of the addition. The reaction was concentrated and purified by column chromatography (petroleum ether/ethyl acetate =5: 1) to give methyl 4-cyano-5- (1, 3-dioxolan-2-yl) -4- (pyridin-2-yl) pentanoate (36C) as a yellow oily product (0.7 g, 86% yield).

Ms m/z(ESI):291.1[M+H ⁺ ]；

The third step: 5- ((1, 3-Dioxolan-2-yl) methyl) -5- (pyridin-2-yl) piperidin-2-one (36D)

5-((1,3-dioxolan-2-yl)methyl)-5-(pyridin-2-yl)piperidin-2-one

4-cyano-5- (1, 3-dioxolan-2-yl) -4- (pyridin-2-yl) pentanoate (36C) (0.23g, 0.8mmol) was dissolved in methanol (10 ml), raney nickel (0.047 g, 0.08mmol) was added and reacted at 60 ℃ for 10h under a hydrogen balloon atmosphere. 15mL of dichloromethane was added to clear the reaction solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and column chromatographed (dichloromethane/methanol =30: 1) to isolate and purify 5- ((1, 3-dioxolan-2-yl) methyl) -5- (pyridin-2-yl) piperidin-2-one (36D) (0.19g, 60%) as a yellow oily product.

Ms m/z(ESI):263.1[M+H ⁺ ]。

The fourth step: 5- ((1, 3-Dioxolan-2-yl) methyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one (36E)

5-((1,3-dioxolan-2-yl)methyl)-1-methyl-5-(pyridin-2-yl)piperidin-2-one

At room temperature, 5- ((1, 3-dioxolan-2-yl) methyl) -5- (pyridin-2-yl) piperidin-2-one (36D) (0.3 g, 1mmol) was dissolved in tetrahydrofuran (15 mL), and at 0 ℃, sodium hydride (0.04g, 2mmol), methyl iodide (0.2g, 2mmol) were added, after the addition was completed, the reaction was continued for 2h, 2mL of water was added to the reaction solution, anhydrous sodium sulfate was added and dried, the filtrate was filtered, the solvent was removed by concentration under reduced pressure, and column chromatography (dichloromethane/methanol =30

Ms m/z(ESI):277.2[M+H ⁺ ]。

The fifth step: 2- (1-methyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (36F)

2-(1-methyl-6-oxo-3-(pyridin-2-yl)piperidin-3-yl)acetaldehyde

5- ((1, 3-Dioxolan-2-yl) methyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one (36E) (0.3g, 1.1mmol) was dissolved in tetrahydrofuran (5 mL) and concentrated hydrochloric acid (8 mL) at room temperature, stirred overnight at room temperature, and the reaction mixture was concentrated to give 2- (1-methyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (36F) (0.26g, 100%) as a black oily product, which was directly charged into the next step.

Ms m/z(ESI):233.1[M+H ⁺ ]。

And a sixth step: 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one (36J)

5-(2-((3-chlorobenzyl)amino)ethyl)-1-methyl-5-(pyridin-2-yl)piperidin-2-one

2- (1-methyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (36F) (0.14g, 0.6 mmol) was dissolved in methylene chloride (10 ml), and m-chlorobenzylamine (0.11g, 0.78mmol), anhydrous sodium sulfate (0.6 g) were added thereto in this order. After reaction at room temperature overnight, sodium borohydride (0.036g, 0.9mmol) was added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated brine solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (dichloromethane/methanol =30: 1) was performed to isolate and purify the product 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one (36J) (0.03g, 10%) as a pale yellow oil.

Ms m/z(ESI):358.2[M+H ⁺ ]。

The seventh step: 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 36)

5- (2- ((3-chlorobenzyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one 36J (0.03g, 0.2mmol) was dissolved in EA (5 mL) at room temperature, ethyl hydrogen chloride solution (2mL, 4N) was added at 0 deg.C, the reaction was continued for 0.5h, and the solvent was removed under reduced pressure to give 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 36) as a white solid (0.03g, 96%).

Ms m/z(ESI):358.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.93(d,1H),8.64(t,1H),8.08(dd,2H),7.57(s,1H),7.43(m,3H),3.85(d,1H),3.31(s,2H),3.05(d,2H),3.01(m,1H),2.85(td,1H),2.65(m,1H),2.52(m,2H),2.36(ddd,2H),2.12(m,1H),2.00(d,3H)。

Example 37

(2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanolic acid hydrochloride (Compound 37)

(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methanolhydrochloride

The first step is as follows: 2- (Thien-3-ylmethoxy) tetrahydro-2H-pyran (37B)

2-(thiophen-3-ylmethoxy)tetrahydro-2H-pyran

Thiophen-3-ylmethanol (28A) (5g, 60mmol) was dissolved in tetrahydrofuran (40 mL), and dihydropyran (5g, 60mmol) and a hydrochloric acid solution (0.5ml, 3n) were sequentially added, reacted for 3H, cooled, added with water (50 mL), extracted with dichloromethane (50 mL × 4), washed with a saturated saline solution (150 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography separation and purification (n-hexane/ethyl acetate =10 1) to obtain 2- (thiophen-3-ylmethoxy) tetrahydro-2H-pyran (37B) (11 g, yield 90%) as a pale yellow liquid product.

¹ H NMR(400MHz,CDCl ₃ ):δ7.30–7.26(m,2H),7.23–7.11(m,1H),7.10–7.08(m,1H),4.75(t,2H)，4.68(d,2H),4.56(d,2H)，3.91–3.88(m,1H),3.57-3.51(m,1H),1.72–1.43(m,8H).

The second step is that: 3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-aldehyde (37C)

3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiophene-2-carbaldehyde

2- (thien-3-ylmethoxy) tetrahydro-2H-pyran 37B (1g, 5 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction was cooled to-78 deg.C, n-butyllithium (0.354g, 5.54mmol) was added, the reaction was raised to zero degrees for 0.5H after completion of the addition, dimethylformamide (0.55g, 7.58mmol) was added and the reaction was continued for 2H. Ammonium chloride solution (20 mL) was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography separation and purification (n-hexane/ethyl acetate =5: 1) to obtain a pale yellow liquid product, 3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-aldehyde (37C) (0.4 g, yield 40%).

¹ H NMR(400MHz,CDCl ₃ ):δ10.15(d,1H),7.68–7.66(m,1H),7.21(d,1H),5.08-4.85(m,1H),4.74(t,1H),4.72(s,1H),3.87-3.84(m,1H),3.57-3.53(m,1H),1.73-1.52(m,9H)。

The third step: (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) -N- ((3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophen-2-yl) methyl) ethanamine (37D)

(R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)-N-((3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiophen-2-yl)methyl)ethanamine

3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-aldehyde 37C (0.33g, 1.5 mmol) was dissolved in dichloromethane (10 ml), to which was added in turn (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.38g, 1.5 mmol), anhydrous sodium sulfate (1.7 g). After an overnight reaction at room temperature, sodium borohydride (0.083g, 2.2mmol) was added, stirring was continued for 2H, water (20 mL) was added, extraction was performed with dichloromethane (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (dichloromethane/methanol = 30).

Ms m/z(ESI):471.3[M+H ⁺ ].

The fourth step: (R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanol (37E)

(R)-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methanol

(R) -raw material 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) -N- ((3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophen-2-yl) methyl) ethylamine (37D) (0.3g, 0.6 mmol) was added to methanol (10 mL), hydrochloric acid (1ml, 5n) was added, reacted at room temperature for 1H, water (20 mL) was added, extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and (dichloromethane/methanol = 30) to obtain (R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanol (37E) (019g, 80%) as a yellow liquid.

Ms m/z(ESI):387.2[M+H ⁺ ].

The fifth step: (R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanolic hydrochloride (Compound 37)

(R)-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methanolhydrochloride

(R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanol (37E) (0.19g, 0.49mmol) was dissolved in ethyl acetate (5 mL) and the solution was then ethyl hydrogen chloride (1mL, 4N) at 0 deg.C, followed by reaction for 0.5h and removal of the solvent under reduced pressure to give (R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanolate (Compound 37) (0.19g, 96%) as a white solid at room temperature.

Ms m/z(ESI):387.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.87(dd,1H)8.63(td,1H),8.19(d,1H),8.04(m,1H),7.46(d,1H),7.04(d,1H),4.68(s,2H),4.38(s,2H),3.77(m,2H),3.31(s,3H),3.05(td,1H),2.54(m,3H),2.34(td,1H),2.21(m,2H),1.93(m,2H),1.61(m,4H)。

Example 38

2- ((3-chlorophenyl) amine) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide hydrochloride (Compound 38)

2-((3-chlorobenzyl)amino)-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamidehydrochloride

The first step is as follows: 6-oxaspiro [4.5] decane-9-cyano (38B)

6-oxaspiro[4.5]decane-9-carbonitrile

6-oxaspiro [4.5] decan-9-one (38A) (15.7g, 102mmol) was dissolved in dimethyl glycol ether (500 mL) in a three-necked flask, p-toluenesulfonylmethylisonitrile (45.7g, 234mmol) was added, the temperature was reduced to 0 ℃ or below, ethanol (10.8g, 234mmol) was added dropwise to the reaction mixture, potassium tert-butoxide (40.0g, 356mmol) was added to the reaction mixture in portions, the exotherm was vigorous, and after the addition, the temperature was raised to 60 ℃ for 5 hours. The reaction was poured into a mixture of 100g of ice (100 mL of water). The product was extracted with methyl tert-butyl ether (100 mL. Times.3), washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/40-1/20) by column flushing and concentrated to dryness to give 6-oxaspiro [4.5] decane-9-cyano (38B) (10 g, yield 59.4%) as a pale yellow oil.

LCMS m/z＝166.1[M+H ⁺ ].

The second step: 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-cyano (38C)

9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-carbonitrile

6-Oxaspiro [4.5] decane-9-cyano (38B) (6.0g, 36mmol) was dissolved in a single-neck flask with tetrahydrofuran (60 mL), 2-fluoropyridine (3.5g, 36mmol) was added, the temperature was reduced to-70 ℃ or lower, sodium bis (trimethylsilyl) amide (25.4mL, 50.8mmol) was slowly added dropwise to the reaction mixture, and after completion of the addition, the mixture was stirred for 10 minutes, and the mixture was allowed to warm to room temperature for reaction for 3 hours. After cooling to about 0 ℃, saturated aqueous ammonium chloride solution was added dropwise, water (200 mL) was added, the mixture was extracted with ethyl acetate (100 mL × 2), the organic phases were combined, the organic phase was washed with water (200 mL), saturated sodium chloride solution (200 mL), dried, filtered and concentrated to give 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-cyano (38C) as a yellow oil (7.18 g, yield 81.6%).

LCMS m/z＝243.1[M+H ⁺ ].

The third step: 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carboxamide (38D)

9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-carboxamide

9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-cyano (38C) (0.50g, 2.06mmol), potassium carbonate (0.86g, 6.19mmol) were dissolved in dimethyl sulfoxide (10 mL) in a single-neck flask, the temperature was reduced to 0 ℃, hydrogen peroxide (1.17g, 10.32mmol) was added dropwise to the reaction mixture, and the mixture was naturally warmed to room temperature and stirred for 1 hour after completion of addition. Water (20 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate was added, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/40-1/10) using a plug column, and concentrated to dryness to give 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carboxamide (38D) (0.54 g, yield 100%) as a pale yellow oil.

LCMS m/z＝261.1[M+H ⁺ ].

The fourth step: methyl (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) carbamate (38E)

methyl(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)carbamate

9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carboxamide (38D) (0.536 g, 2.06mmol) was dissolved in methanol (10 mL), potassium hydroxide (0.231g, 4.12mmol) was added thereto and stirred well, and iodobenzene acetate (0.995g, 3.09mmol) was added to the reaction mixture and reacted at room temperature for half an hour. Water (50 mL) was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated to dryness to give methyl (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) carbamate (38E) as a yellow oil (0.6 g, 100% yield).

LCMS m/z＝291.1[M+H ⁺ ].

The fifth step: 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-amino (38F)

9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-amine

Methyl (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) carbamate (38E) (7.76g, 26.7 mmol), 3N aqueous sodium hydroxide (28.5mL, 85.5mmol), and ethanol (70 mL) were added to a microwave tube and reacted at 150 ℃ for half an hour in a microwave reactor. The solvent was dried by rotation, purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/40-1/5), and concentrated to dryness to give 9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-amino (38F) as a yellow oil (3.91 g, 63% yield).

LCMS m/z＝233.1[M+H ⁺ ].

And a sixth step: 2-chloro-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38G)

2-chloro-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamide

9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-amino (38F) (1.0g, 4.3mmol) was dissolved in methylene chloride (10 mL), triethylamine (1.3g, 12.9mmol) was added thereto, the mixture was cooled to 0 ℃ and chloroacetyl chloride (0.58g, 5.2mmol) was added dropwise to the reaction mixture, and the reaction was completed for 3 hours. The solvent was dried by rotation, purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/40-1/5), and concentrated to dryness to give 2-chloro-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38G) (0.8G, yield 60%) as a yellow solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.57-8.56(d,1H),7.71-7.67(dt,1H),7.44-7.42(d,1H),7.19-7.16(t,1H),7.06(s,1H),3.98(s,2H),3.85-3.82(m,2H),2.35-2.28(m,4H),1.83-1.39(m,8H).

The seventh step: 2-Azide-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38H)

2-azido-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamide

2-chloro-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38G) (0.8g, 2.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), and sodium azide (0.5g, 7.8mmol) was added to the solution to react at room temperature for 2 hours. Water (20 mL) was added, extraction was performed with methyl t-butyl ether (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL. Times.1), and the solvent was dried by spinning to give 2-azido-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38H) (0.62 g, 76% yield) as an orange solid.

Eighth step: 2-amino-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38I)

2-amino-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamide

After 2-azido-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38H) (0.62g, 2.0 mmol) was dissolved in tetrahydrofuran (10 mL), triphenylphosphine (0.77g, 2.9 mmol) was added thereto, and the reaction mixture was allowed to exotherm and cooled naturally to room temperature for 2 hours. The solvent was dried by rotation, purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/20-1/2), and concentrated to dryness to give 2-amino-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38I) (0.54 g, yield 95%) as a pale yellow oil.

LCMS m/z＝290.2[M+H ⁺ ].

The ninth step: 2- ((3-chlorophenyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38J)

2-((3-chlorobenzyl)amino)-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamide

2-amino-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38I) (0.30g, 1.04mmol), 3-chlorobenzaldehyde (0.22g, 1.55mmol) were dissolved in dichloromethane (10 mL), magnesium sulfate (0.62g, 5.18mmol) was added, stirring was continued overnight at room temperature, sodium borohydride (59mg, 1.55mmol) was added, stirring was continued at room temperature for 1 hour, and anhydrous methanol (3 mL) was added and stirring was continued for 2 hours. To the reaction solution was added water (20 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL), the organic phase was dried over colorless sodium sulfate, filtered and evaporated to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/10-1/1) punch column and concentrated to dryness to give 2- ((3-chlorophenyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38J) (0.3 g, yield 70%) as a pale yellow oil.

LCMS m/z＝414.2[M+H ⁺ ].

The tenth step: 2- ((3-chlorophenyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide hydrochloride (Compound 38)

N- (2- (6-oxaspiro [4.5] decan-9-yl) pyridin-3-yl) -2- ((3-chlorophenyl) amino) acetamide (38J) (0.26g, 0.63mmol) was dissolved in ethyl acetate (10 mL) in a one-neck flask, a solution of hydrogen chloride in ethyl acetate (1 mL,1.7 mol/L) was added dropwise, a solid precipitated, and the reaction was stirred for 30 minutes. The solvent was dried by evaporation to give 2- ((3-chlorophenyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide hydrochloride (compound 38) as a white solid (0.27 g, 95% yield).

LCMS m/z＝414.2[M+H ⁺ ].

¹ H NMR(400MHz,CD ₃ OD)δ8.74-8.73(dd,1H),8.55(dt,1H),8.17-8.15(d,1H),7.94-7.43(t,1H),7.53(s,1H),7.49-7.40(m,3H),4.23-4.22(d,2H),4.08-4.04(d,1H),4.01-3.99(m,1H),3.93-3.89(d,1H),3.82-3.78(m,1H),2.68-2.47(dd,2H),2.25-2.10(m,3H),176-1.57(m,7H).

Example 39

2- (((3-Methylthion-2-yl) methyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide hydrochloride (Compound 39)

2-(((3-methoxythiophen-2-yl)methyl)amino)-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamide hydrochloride

The first step is as follows: 2- (((3-methylthiophen-2-yl) methyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [ 4.5)]Decan-9-yl) acetamide (39A)

2-(((3-methoxythiophen-2-yl)methyl)amino)-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamide

2-amino-N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (38I) (0.30g, 1.04mmol), 3-methoxythiophene-2-carbaldehyde (0.22g, 1.55mmol) were dissolved in dichloromethane (10 mL), magnesium sulfate (0.62g, 5.18mmol) was added thereto, the mixture was stirred at room temperature overnight, sodium borohydride (59mg, 1.55mmol) was added thereto, the mixture was stirred at room temperature for 1 hour, and anhydrous methanol (3 mL) was added thereto and the mixture was stirred for 2 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/10-1/1) cartridge and concentrated to dryness to give 2- (((3-methylthiophen-2-yl) methyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (39A) as a pale yellow oil (0.20 g, 50% yield).

LCMS m/z＝416.3[M+H ⁺ ].

The second step is that: 2- (((3-Methylthion-2-yl) methyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide hydrochloride (Compound 39)

2- (((3-Methylthioen-2-yl) methyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide (39A) (0.20g, 0.26mmol) was dissolved in ethyl acetate (10 mL), a solution of hydrochloric acid in ethyl acetate (1 mL, 1.7mol/L) was added dropwise, a solid precipitated, stirred for half an hour, and concentrated to dryness to give 2- (((3-Methylthioen-2-yl) methyl) amino) -N- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetamide hydrochloride (Compound 39) (0.2 g, 92% yield) as a light brown solid.

LCMS m/z＝416.3[M+H ⁺ ].

¹ H NMR(400MHz,CD ₃ OD)δ8.77-8.76(d,1H),8.63(dt,1H),8.25-8.23(d,1H),8.02-7.99(t,1H),7.51-7.50(d,1H),7.05-7.04(d,1H),4.31-4.30(d,2H),4.06-4.02(m,2H),3.92(s,3H),3.88-3.84(m,2H),2.69-2.46(dd,2H),2.15-2.11(m,3H),1.76-1.59(m,6H),1.36-1.29(m,1H).

Example 40

1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -N-methyl-3- (thiophen-2-yl) propyl-2-amine hydrochloride (Compound 40)

1-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)-N-methyl-3-(thiophen-2-yl)propan-2-amine hydrochloride

The first step is as follows: 9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-ol (40B)

9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-ol

2, 6-dioxaspiro [4.5] decan-9-one (1 c) (9.24g, 60.0 mmol) was dissolved in tetrahydrofuran (20 mL) at 0 ℃ under nitrogen. Phenylmagnesium bromide (1.0M, 78.0 mL) was added dropwise to the reaction mixture. After the addition, the reaction was carried out at 0 ℃ for 4 hours. Ammonium chloride solution (40 mL) was added at 0 ℃, the product was extracted with ethyl acetate (40 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and after concentrating the filtrate, the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =10: 1-1) to give 9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-ol (40B) as an oily liquid (15.0 g, yield: 100%).

Ms m/z(ESI):273.1[M+Na ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ7.48-7.45(m,2H),7.05-7.00(m,2H),4.04-3.96(m,1H),3.73-3.72(m,1H),2.46-2.33(m,2H),1.67-1.49(m,10H).

The second step is that: 9-allyl-9- (4-fluorophenyl) -6-oxaspiro [4.5] decane (40C)

9-allyl-9-(4-fluorophenyl)-6-oxaspiro[4.5]decane

9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-ol (0.5 g,2.0 mmol) was dissolved in methylene chloride (15 mL) and cooled to 0 ℃ and boron trifluoride ether solution (0.6 g,4.0 mmol) and allyltrimethylsilane (0.5 g,4.0 mmol) were added and reacted at 0 ℃ for 2 hours after completion of the addition. Ammonium chloride solution (20 mL) was added at 0 ℃, the product was extracted with dichloromethane (20 mL × 2), the combined organic phases were washed with saturated sodium bicarbonate solution (20 mL × 1), saturated brine solution (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, after which the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =80: 1-6) to give 9-allyl-9- (4-fluorophenyl) -6-oxaspiro [4.5] decane (40C) as a yellow oily liquid (0.3 g, yield: 100%).

Ms m/z(ESI):297.1[M+Na ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ7.36-7.22(m,2H),7.02-6.98(m,2H),5.32-5.29(m,1H),5.28-5.26(t,2H),3.88-3.71(m,2H),2.07-2.06(m,1H),1.84-1.70(m,3H),1.66-1.26(m,10H).

The third step: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) acetic acid (40D)

2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)acetic acid

9-allyl-9- (4-fluorophenyl) -6-oxaspiro [4.5] decane (40C) (6.0g, 21.87mmol), sodium periodate (18.71g, 87.46mmol), ruthenium (III) trichloride hydrate (0.1g, 0.5 mmol), acetonitrile (40 mL), chloroform (40 mL) and water (40 mL) were added to a reaction flask, and after completion of the addition, the reaction was vigorous exothermic at room temperature for 4 hours. The product was extracted with ethyl acetate (40 mL × 4), the combined organic phases were washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 30.

Ms m/z(ESI):291.1[M-H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ7.28-7.26(m,2H),7.02-6.96(m,2H),3.75-3.69(m,2H),2.60-2.44(q,2H),2.43-2.40(d,1H),2.11-2.06(m,2H),1.70(m,1H),1.66(m,1H),1.52(m,1H),1.47-1.41(m,1H),1.31-1.18(m,1H).

The fourth step: 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) acetyl chloride (40E)

2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)acetyl chloride

After 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) acetic acid (40D) (0.3g, 0.99mmol) was dissolved in methylene chloride (10 mL), the temperature was lowered to 0 ℃ and N, N-dimethylformamide (0.01 mL) and oxalyl chloride (0.2g, 1.5 mmol) were added to the solution, after which the reaction was completed at 0 ℃ for 3 hours. The reaction solution was concentrated to dryness to give 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) acetyl chloride (40E) (0.3 g, yield: 100%) as a yellow oily liquid.

The fifth step: ethyl 2- (thiophen-2-yl) ethyl ester (40G)

ethyl 2-(thiophen-2-yl)acetate

After 2-thienylacetic acid (40F) (5.68g, 39.9 mmol) was dissolved in N, N-dimethylformamide (15 mL) under nitrogen, potassium carbonate (8.28g, 59.9 mmol) and iodoethane (7.48g, 47.9 mmol) were added to the reaction solution in this order, and after reaction at room temperature for 3 hours, ice water (60 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with a saturated saline solution (30 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl 2- (thien-2-yl) ethyl ester (40G) (3.6G, yield: 53%) as a brown oily liquid.

Ms m/z(ESI):171.1[M+H ⁺ ]；

And a sixth step: ethyl 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3-oxa-4- (thiophen-2-yl) butanoate (40H)

ethyl2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)-3-oxo-4-(thiophen-2-yl)butanoate

Ethyl 2- (thien-2-yl) ethyl ester (40G) (0.17g, 1.0mmol) was dissolved in tetrahydrofuran (20 mL), and the temperature was lowered to-70 ℃ to add sodium hexamethyldisilazide (1.0M, 1.3mmol) dropwise to the reaction mixture, and the reaction was carried out at-70 ℃ for 0.5 hour. After 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) acetyl chloride (40E) (0.32g, 1.0mmol) was dissolved in tetrahydrofuran (5 mL), the solution was added dropwise to the reaction mixture, and after completion of the reaction at-70 ℃ for 0.5 hour, the temperature was naturally raised to room temperature for 2 hours. The reaction solution was added with an ammonium chloride solution (10 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 6).

Ms m/z(ESI):467.1[M+Na ⁺ ]；

The seventh step: 1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-one (40I)

1-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)-3-(thiophen-2-yl)propan-2-one

Ethyl 2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3-oxa-4- (thiophen-2-yl) butyrate (40H) (0.44g, 0.99mmol) was dissolved in dimethyl sulfoxide (10 mL), and sodium chloride (0.3 g) and water (0.5 mL) were added to the reaction solution, followed by heating to 130 ℃ for 4 hours. The reaction solution was cooled to room temperature, quenched with water (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) =40: 1-6) to give 1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-one (40I) (0.2 g, yield: 50%) as a yellow oily liquid.

Ms m/z(ESI):395.1[M+Na ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ7.30-7.27(m,2H),7.16-7.14(m,1H),7.02-6.90(m,2H),6.89-6.88(m,1H),6.57-6.56(m,1H),3.73-3.70(m,2H),3.26(s,2H),2.90-2.86(d,1H),2.56-2.55(d,1H),2.34-2.33(d,1H),2.14-2.13(q,2H),1.90-1.88(m,1H),1.67-1.66(m,1H),1.51-1.50(m,1H),1.34-1.26(m,6H).

Eighth step: 1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-amine (40J)

1-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)-3-(thiophen-2-yl)propan-2-amine

1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-one (40I) (0.374g, 1.0 mmol) was dissolved in anhydrous methanol (10 mL), and ammonium acetate (1.116g, 15.1mmol) and sodium cyanoborohydride (0.189g, 3.01mmol) were added in this order, and the reaction was stirred at room temperature for 48 hours. The reaction solution was poured into ice water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (20 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-amine (40J) (0.2 g, yield: 50%) as a yellow oily liquid.

Ms m/z(ESI):374.2[M+H ⁺ ]；

The ninth step: tert-butyl (1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-yl) carboxylate (40K)

tert-butyl(1-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)-3-(thiophen-2-yl)propan-2-yl)carbamate

1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thien-2-yl) propyl-2-amine (40J) (0.374g, 1.0mmol) was added to methylene chloride (20 mL), and triethylamine (0.142g, 1.4mmol) and di-tert-butyl dicarbonate (0.284g, 1.3mmol) were further added, and the reaction was completed at 25 ℃ for 12 hours. The reaction solution was added to water (20 mL), the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with sodium chloride (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 20).

Ms m/z(ESI):496.2[M+Na ⁺ ]；

The tenth step: tert-butyl (1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-yl) (methyl) carboxylate (40L)

tert-butyl(1-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)-3-(thiophen-2-yl)propan-2-yl)(methyl)carbamate

Tert-butyl (1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-yl) carboxylate (40K) (0.15g, 0.32mmol) was added to N, N-dimethylformamide (30 mL) and the temperature was reduced to 0 ℃. Sodium hydride (10.0 mg, 0.44mmol) was added thereto, and the reaction was carried out at 0 ℃ for 0.5 hour. Methyl iodide (63.0 mg, 0.44mmol) was added dropwise to the reaction solution, and reacted at 0 ℃ for 4 hours. The reaction solution was added to water (20 mL), the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with sodium chloride (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then the crude product was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 20) to give t-butyl (1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-yl) (methyl) carboxylate (40L) (0.15 g, yield: 97%) as a yellow oily liquid.

Ms m/z(ESI):388.2[M-100]；

The eleventh step: 1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -N-methyl-3- (thiophen-2-yl) propyl-2-amine (40N)

1-(9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl)-N-methyl-3-(thiophen-2-yl)propan-2-amine

Tert-butyl (1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -3- (thiophen-2-yl) propyl-2-yl) (methyl) carboxylate (40L) (0.15g, 0.30mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 2 hours. The reaction solution was directly spin-dried to give 1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -N-methyl-3- (thiophen-2-yl) propyl-2-amine hydrochloride (40N) as a white solid (0.12 g, 98% yield).

Ms m/z(ESI):388.2[M+H ⁺ ]；

Resolution of the compound 1- (9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -N-methyl-3- (thiophen-2-yl) propyl-2-amine hydrochloride (40N):

the compound (40N) (0.15 g) was taken for resolution and after separation, four optical isomer compounds (R) -1- ((S) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -N-methyl-3- (thien-2-yl) propyl-2-amine (compound 40M-1) (11.36 mg, oily liquid,% ee = 100%), (R) -1- ((R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -N-methyl-3- (thien-2-yl) propyl-2-amine hydrochloride ((compound 40M-2) (14.66 g, oily liquid,% ee = 98.9%), (S) -1- ((R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl) -N-methyl-3- (thien-2-yl) propyl-2-amine hydrochloride compound 40M-3) (4.0 g, oily liquid,% ee = 4.5] decan-3-methyl-3- (thien-2-yl) propyl-2-amine hydrochloride compound 40M-3) (4M-3) (4.0 g, 6-oxaspiro [4.5] decan% Yl) propyl-2-amine hydrochloride ((compound 40M-4) (5.1 g, oily liquid, ee% = 96.4%).

Splitting conditions are as follows: MG II preparatory SFC (SFC-15); column ChiralPak IC,250 × 30mm i.d.,5 μm. Mobile phase a: carbon dioxide, B: methanol; gradient B30%; the flow rate is 60mL/min; back pressure is 100bar; the column temperature is 38 ℃; the wavelength is 220nm; the period is 3min; sample preparation compound 40M was dissolved in methanol to 3mg/ml; injection, 0.8 ml/needle.

The salt formation procedure of example 39 was used to synthesize the salts of the four optical isomers:

compound 40-1:

Ms m/z(ESI):389.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD)δ8.86(d,1H),8.58(d,1H),8.11(t,1H),8.00(d,1H),7.46(d,1H),7.00(d,1H),4.19(s,2H),3.97-3.67(m,7H),3.44-3.32(m,1H),3.13-2.86(m,2H),2.60-2.15(m,7H),2.12-1.87(m,2H)。

compound 40-2:

Ms m/z(ESI):389.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD)δ8.86(d,1H),8.58(d,1H),8.11(t,1H),8.00(d,1H),7.46(d,1H),7.00(d,1H),4.19(s,2H),3.97-3.67(m,7H),3.44-3.32(m,1H),3.13-2.86(m,2H),2.60-2.15(m,7H),2.12-1.87(m,2H).

compound 40-3:

Ms m/z(ESI):389.2[M+H ⁺ ]；

compound 40-4:

Ms m/z(ESI):389.2[M+H ⁺ ]；

example 42

(R) -N- ((3-Cyclobutoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 42)

(R)-N-((3-cyclobutoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: cyclobutylmethanesulfonate (42B)

cyclobutyl methanesulfonate

Cyclobutanol (42A) (2g, 27.74mmol) and triethylamine (4.21g, 33.28mmol) were dissolved in dichloromethane (30 mL), cooled to 0 deg.C, methanesulfonyl chloride (3.81g, 27.2 mmol) was added dropwise to the reaction, and the reaction was allowed to warm to room temperature for 1 hour. The reaction solution was quenched with water (30 mL), the aqueous phase of the separated liquid was extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give cyclobutylmethanesulfonate (42B) (3.8 g, yield: 91%) as a yellow oily liquid.

The second step is that: 3- (Cyclobutoxy) thiophene-2-carbaldehyde (42C)

3-cyclobutoxythiophene-2-carbaldehyde

3-Hydroxythiophene-2-carbaldehyde (0.3g, 2.3mmol) was dissolved in N, N-dimethylformamide (10 mL) at room temperature, and potassium carbonate (0.48g, 3.5 mmol) and cyclobutylmethanesulfonate (42B) (0.53g, 3.5 mmol) were added thereto, followed by reaction at 80 ℃ for 6 hours. To the reaction solution was added water (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5) to obtain 3- (cyclobutoxy) thiophene-2-carbaldehyde (42C) as an oily liquid (0.15 g, yield: 35%).

Ms m/z(ESI):183.1[M+H ⁺ ]；

The third step: (R) -N- ((3-Cyclobutoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (42D)

(R)-N-((3-cyclobutoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.214g, 0.823mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.584g, 4.11mmol) and 3- (cyclobutoxy) thiophene-2-carbaldehyde (42C) (0.15g, 0.823mmol) were added to the reaction solution, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.047g, 1.23mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and reaction with stirring for 1 hour. The reaction was quenched with water (20 mL), the aqueous phase was extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the crude product was purified by preparative HPLC (method: acetonitrile/0.1% aqueous ammonia-58% _58% _15 min) to give (R) -N- ((3-cyclobutoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (42D) (0.1 g, 28.5% yield) as a yellow oily liquid.

Ms m/z(ESI):427.2[M+H ⁺ ]。

The fourth step: (R) -N- ((3-Cyclobutoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 42)

(R) -N- ((3-Cyclobutoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (42D) (0.1g, 0.234mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((3-cyclobutoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 42) as a white solid (0.11 g, yield: 100%).

Ms m/z(ESI):427.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.84(dd,1H),8.56(td,1H),8.12(d,1H),7.99-7.96(m,1H),7.44(d,1H),6.85(d,1H),4.75-4.65(m,1H),4.20(s,2H),3.87-3.66(m,2H),2.99(td,1H),2.61-2.32(m,5H),2.29(td,1H),2.22-2.01(m,4H),1.98-1.76(m,3H),1.76-1.36(m,6H),1.20-1.17(m,1H),0.85-0.77(m,1H).

Example 43

5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 43)

5-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-1-methyl-5-(pyridin-2-yl)piperidin-2-onehydrochloride

The first step is as follows: 5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one (43A)

5-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-1-methyl-5-(pyridin-2-yl)piperidin-2-one

2- (1-methyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (36F) (0.15g, 0.65mmol) was dissolved in methylene chloride (10 ml), and (3-methoxythiophen-2-yl) methylamine (0.11g, 0.77mmol), triethylamine (0.078g, 0.77mmol), and anhydrous sodium sulfate (0.6 g) were added thereto in this order. React overnight at room temperature, add sodium borohydride (0.039g, 0.97mmol), continue stirring for 2h, add water (20 mL), extract with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated aqueous sodium chloride solution (30 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and column chromatographically (dichloromethane/methanol = 30).

Ms m/z(ESI):360.2[M+H ⁺ ]。

The second step is that: 5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 43)

5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride 43A (0.13g, 0.36mmol) was dissolved in ethyl acetate (5 mL) and the solution of ethyl hydrogen chloride acetate (2mL, 4N) was added at 0 ℃ and the reaction was continued for 0.5h after completion of addition, and the solvent was removed under reduced pressure to give 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 43) as a white solid (0.13g, 95%).

Ms m/z(ESI):360.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.80(d,1H),8.34(d,1H),7.85(d,1H),7.78(m,1H),7.46(d,1H),7.40(d,1H),4.21(s,2H),4.07(dd,1H),3.88(s,3H),3.72(m,1H),3.03(s,3H),2.89(td,1H),2.74(td,1H),2.57(td,1H),2.35(m,4H),2.08(m,1H)。

Example 44

N- (3-Cyclopropylbenzyl) -2- (9- (pyridin-2-yl) -6-oxa [4.5] decan-9-yl) ethylamine hydrochloride (Compound 44)

N-(3-cyclopropoxybenzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanaminehydrochloride

The first step is as follows: 5- ((1, 3-Dioxolan-2-yl) methyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one (44A) 5- ((1, 3-dioxolan-2-yl) methyl) -1-isoproyl-5- (pyridinyl-2-yl) piperidine-2-one

5- ((1, 3-Dioxolan-2-yl) methyl) -5- (pyridin-2-yl) piperidin-2-one (36D) (0.1g, 1mmol) was dissolved in ethylene glycol dimethyl ether (5 mL) at room temperature, potassium tert-butoxide (0.04g, 0.38mmol), isopropyl iodide (0.064g, 0.38mmol) were added at room temperature, the reaction was continued for 0.5h with warming to 60 ℃ after completion of the addition, isopropyl iodide (0.064g, 0.38mmol) and potassium tert-butoxide (0.04g, 0.38mmol) were added to the reaction solution every 1h, 8 times were repeatedly added, 20mL of water was added to the reaction solution, ethyl acetate extraction (20 mL. Times.2) was added with anhydrous sodium sulfate for drying, filtration was performed, the filtrate was concentrated under reduced pressure to remove the solvent, column chromatography (dichloromethane/methanol = 30) gave 5- ((1, 3-dioxolan-2-yl) methyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one (96A) (96A 96%

Ms m/z(ESI):305.2[M+H ⁺ ]。

The second step is that: 2- (1-isopropyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (44B)

2-(1-isopropyl-6-oxo-3-(pyridin-2-yl)piperidin-3-yl)acetaldehyde

At room temperature, 5- ((1, 3-dioxolan-2-yl) methyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one 44A (0.3g, 1mmol) was dissolved in tetrahydrofuran (10 mL) and concentrated hydrochloric acid (2 mL), stirred at room temperature overnight, and the reaction was concentrated to give the product 2- (1-isopropyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde 44B (0.3g, 100% crude) as a black oil, which was directly used in the next step.

Ms m/z(ESI):261.2[M+H ⁺ ]。

The third step: 1-isopropyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one (44C)

isopropyl-5-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-5-(pyridin-2-yl)piperidin-2-one

2- (1-isopropyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde 44B (0.15g, 0.58mmol) was dissolved in methylene chloride (10 ml), and (3-methoxythiophen-2-yl) methylamine (0.099g, 0.69mmol), triethylamine (0.070g, 0.69mmol), and anhydrous sodium sulfate (0.56 g) were added thereto in this order. React at room temperature overnight, add sodium borohydride (0.035g, 0.86mmol), continue stirring for 2h, add water (20 mL), extract with dichloromethane (30 mL × 2), combine the organic phases, wash with saturated brine solution (30 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and column chromatographe (dichloromethane/methanol = 30.

Ms m/z(ESI):388.2[M+H ⁺ ]。

The fourth step: 1-isopropyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 44)

isopropyl-5-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-5-(pyridin-2-yl)piperidin-2-onehydrochloride

1-isopropyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one 44C (0.062g, 0.16mmol) was dissolved in ethyl acetate (5 mL) and the ethyl hydrogen chloride acetate solution (2mL, 4N) was added at 0 ℃ and reacted for 0.5h further, after which the solvent was removed under reduced pressure to give 1-isopropyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 44) (0.071g, 95%) as a white solid at room temperature.

Ms m/z(ESI):358.2[M+H ⁺ ]。

¹ H NMR(400MHz,CD ₃ OD):δ8.79(d,1H),8.33(t,1H),7.89(d,1H),7.77(m,1H),7.47(d,1H),7.01(d,1H),4.21(s,2H),3.88(s,3H),3.62(d,2H),2.89(td,1H),2.73(td,1H),2.52(m,2H),2.31(m,3H),1.21(d,3H),1.10(d,3H).

Example 45

5- (2- ((3-chlorobenzyl) amino) ethyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 45)

5-(2-((3-chlorobenzyl)amino)ethyl)-1-isopropyl-5-(pyridin-2-yl)piperidin-2-onehydrochloride

The first step is as follows: 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one (45A)

5-(2-((3-chlorobenzyl)amino)ethyl)-1-isopropyl-5-(pyridin-2-yl)piperidin-2-one

2- (1-isopropyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde 44B (0.15g, 0.58mmol) was dissolved in methylene chloride (10 ml), and (3-chlorobenzyl) methylamine (0.098g, 0.69mmol), triethylamine (0.070g, 0.69mmol), and anhydrous sodium sulfate (0.56 g) were added thereto in this order. React overnight at room temperature, add sodium borohydride (0.035g, 0.86mmol), continue stirring for 2h, add water (20 mL), extract with dichloromethane (30 mL × 2), combine the organic phases, wash with saturated brine solution (30 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, column chromatographe (dichloromethane/methanol = 30.

Ms m/z(ESI):386.2[M+H ⁺ ]。

The fourth step: 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 45)

5- (2- ((3-chlorobenzyl) amino) ethyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one 45A (0.085 g, 0.22mmol) was dissolved in ethyl acetate (5 mL) at room temperature, and after completion of addition, a solution of ethyl hydrogen chloride acetate (2mL, 4N) was reacted for 0.5h, and the solvent was removed under reduced pressure to give 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride compound 45 (0.09g, 95%) as a white solid.

Ms m/z(ESI):386.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.91(dd,1H),8.60(td,1H),8.12(s,1H),8.02(dd,1H),7.55(s,1H),7.43(dd,2H),4.13(s,2H),3.88(s,3H),3.91(d,1H),3.76(d,1H),3.01(td,1H),2.84(td,1H),2.60(tt,2H),2.40(m,3H),1.24(d,3H),1.12(d,3H).

Example 46

(R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate hydrochloride (Compound 46)

(R)-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methyl acetate hydrochloride

The first step is as follows: 3- (hydroxymethyl) thiophene-2-aldehyde (46D)

3-(hydroxymethyl)thiophene-2-carbaldehyde

3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) thiophene-2-carbaldehyde (37C) (4.6 g, 22.63mmol) was dissolved in methanol (20 mL), and a hydrochloric acid solution (0.3mL, 3N) was added, and after completion of addition, the reaction was continued at room temperature for 5 hours. The reaction solution was concentrated, and column chromatography ((petroleum ether/ethyl acetate (V/V)) = 3) gave 3- (hydroxymethyl) thiophene-2-aldehyde 46D (2.3g, 90%) as a yellow oily liquid.

¹ H NMR(400MHz,CDCl ₃ ):δ9.97(s,1H),7.73(d,1H),7.21(d,1H),4.91(s,2H)

The second step is that: (R) - (2- (((2- (9-pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanol (46E)

(R)-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-y)methanol

3- (hydroxymethyl) thiophene-2-aldehyde 46D (0.33g, 1mmol) was dissolved in dichloromethane (10 ml), to which was added in turn (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.66g, 2.6 mmol), anhydrous sodium sulfate (2.31 g). After reacting overnight at room temperature, sodium borohydride (0.14g, 3.5mmol) was added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated saline aqueous solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography was performed to purify (dichloromethane/methanol =5 1) to obtain a yellow liquid (2- (((2- (9-pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanol 46E (0.5g, 80%)

Ms m/z(ESI):387.3[M+H ⁺ ]。

The third step: tert-butyl ((3- (hydroxymethyl) thiophen-2-yl) methyl) (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) carboxylate (46F)

tert-butyl((3-(hydroxymethyl)thiophen-2-yl)methyl)(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)carbamate

(R) - (2- (((2- (9-pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methanol 46E (1.1g, 2.8mmol) was dissolved in methylene chloride (20 mL), to which triethylamine (0.35g, 3.4mmol) and di-tert-butyl dicarbonate (0.68g, 3.1mmol) were added in this order, and the reaction was continued at room temperature for 5 hours. The reaction solution was concentrated and purified by column chromatography (dichloromethane/methanol =30: 1) to obtain (R) -tert-butyl ((3- (hydroxymethyl) thiophen-2-yl) methyl) (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) carboxylate 46F (1 g, yield 72%) as a yellow oily product.

Ms m/z(ESI):487.3[M+H ⁺ ]。

The fourth step: (R) - (2- ((tert-butyloxycarbonyl) (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate (46G)

(R)-(2-(((tert-butoxycarbonyl)(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methyl acetate

(R) -tert-butyl ((3- (hydroxymethyl) thiophen-2-yl) methyl) (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) carboxylate 46F (0.6G, 1.28mmol) was dissolved in dichloromethane (20 mL) at room temperature, triethylamine (0.1lg, 1.6 mmol), acetyl chloride (0.126g, 1.6 mmol) were added in this order at 0 ℃, reaction was continued for 2h, water (20 mL) was added to the reaction solution, dichloromethane (20 mL. Times.3) was extracted, the organic phases were combined, washed with a saturated saline solution (30 mL. Times.1), dried over anhydrous sodium sulfate, the filtrate was concentrated, purified by column chromatography (dichloromethane/methanol = 30) to give (R) - (2- ((tert-butoxycarbonyl) (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophene-3-methyl) acetate (250.80G)

The fifth step: (R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate (46H)

(R)-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methyl acetate

(2- ((tert-butoxycarbonyl) (2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate 46G (0.25g, 0.37mmol) was dissolved in EA (5 mL) at room temperature, an ethyl hydrogen chloride solution (2mL, 4N) was added at 0 ℃ and the reaction was continued for 2H at room temperature, the solvent was removed under reduced pressure and column chromatography (CH 2CL2/MEOH = 30) gave a yellow oily product (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate 46H (0.17g, 96%)

And a sixth step: (R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate hydrochloride (Compound 46)

(R)-(2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methyl acetatehydrochloride

(R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate 46H (0.17g, 0.37mmol) was dissolved in EA (5 mL) and the solution of ethyl hydrogen chloride (2mL, 4N) was dissolved at 0 ℃ and reacted at room temperature for 0.5H, after completion of addition, the solvent was removed under reduced pressure to give (R) - (2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl acetate (compound 46) (0.17g, 94%).

Ms m/z(ESI):429.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.50(ddd,1H),7.74(m,1H),7.47(d,1H),7.21(m,2H),6.95(d,1H),5.00(s,2H),3.79(s,2H),3.73(m,2H),2.48(dt,2H),2.40(dd,1H),2.01(m,5H),1.89(d,1H),1.61(m,10H)。

Example 47

9- (2- (((3-Methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (Compound 47)

9-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-9-(pyridin-2-yl)spiro[4.5]decan-6-onehydrochloride

The first step is as follows: dimethyl 6-oxaspiro [4.5] decane-7, 9-dicarboxylate (47B)

dimethyl 6-oxospiro[4.5]decane-7,9-dicarboxylate

Lithium diisopropylate tetrahydrofuran solution (22mL, 22mmol, 2M) was added to tetrahydrofuran (20 mL) at-70 ℃ under nitrogen. Methyl cyclopentanecarboxylate (47A) (2.56g, 20mmol) was dissolved in tetrahydrofuran (10 mL) at-70 ℃ and then added dropwise to the reaction mixture, and after the addition, the reaction was carried out at-70 ℃ for 1 hour, and methyl acrylate (3.8g, 44mmol) was dissolved in tetrahydrofuran (10 mL) and then added dropwise to the reaction mixture, and after the addition, the reaction was carried out at-70 ℃ for 4 hours. To the reaction solution was added ammonium chloride solution (20 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then the crude product was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) =100:1 to 60) to obtain dimethyl 6-oxaspiro [4.5] decane-7, 9-dicarboxylate (47B) as an oily liquid (4.2 g, yield: 41%).

Ms m/z(ESI):269.1[M+H ⁺ ]；

The second step is that: methyl 10-oxaspiro [4.5] decane-7-carboxylic ester (47C)

methyl 10-oxospiro[4.5]decane-7-carboxylate

Dimethyl 6-oxaspiro [4.5] decane-7, 9-dicarboxylate (47B) (2.1g, 7.8mmol) was dissolved in dimethyl sulfoxide (20 mL), and water (1 mL) and sodium chloride (1.2g, 9.4mmol) were added thereto, followed by completion of the reaction at 150 ℃ for 16 hours. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 100.

Ms m/z(ESI):211.3[M+H ⁺ ]；

The third step: methyl 1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-carboxylate (47D)

methyl 1,4-dioxadispiro[4.0.4 ⁶ .4 ⁵ ]tetradecane-12-carboxylate

Reacting methyl 10-oxaspiro [4.5]]Decane-7-carboxylic acid ester (47C) (0.9g, 4.0 mmol), ethylene glycol (0.3g, 5.0 mmol), p-toluenesulfonic acid (0.08g, 0.4mmol) and toluene (20 mL) were added to the reaction flask, and the reaction was heated to reflux for 4 hours. After cooling, a sodium hydrogencarbonate solution (20 mL) was added to the reaction solution, and an aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =1 to 1) to obtain methyl 1, 4-dioxaspiro [4.0.4 ⁶ .4 ⁵ ]Tetradecyl-12-carboxylate (47D) (0.9 g, yield: 80%).

Ms m/z(ESI):255.2[M+H ⁺ ]；

The fourth step: methyl 12- (pyridinyl-2-yl) -1, 4-dioxaspiro [4.0.4 ⁶ .4 ⁵ ]Tetradecyl-12-carboxylate (47E)

methyl 12-(pyridin-2-yl)-1,4-dioxadispiro[4.0.4 ⁶ .4 ⁵ ]tetradecane-12-carboxylate

Under the protection of nitrogen, methyl 1, 4-dioxaspiro [4.0.4 ] is reacted at-70 DEG C ⁶ .4 ⁵ ]Tetradecyl-12-carboxylate (47D) (0.85g, 3.3mmol) and 2-fluoropyridine (0.35g, 3.3mmol) were added to tetrahydrofuran (10 mL), and a solution of hexamethyldisilazane potassium amino tetrahydrofuran (4.0 m) was added at-70 deg.CL,4.0mmol, 1.0M) was added dropwise to the reaction mixture, and after completion of the addition, the reaction was carried out at-70 ℃ for 20 minutes, and then the temperature was naturally raised to room temperature for reaction for 3 hours. To the reaction solution at 0 ℃, ammonium chloride solution (20 mL) is added, the aqueous phase is extracted with ethyl acetate (30 mL × 3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and after the filtrate is concentrated, the crude product is purified by column chromatography (petroleum ether/ethyl acetate (v/v) =80: 1-30) to give methyl 12- (pyridin-2-yl) -1, 4-dioxaspiro [4.0.4 ⁶ .4 ⁵ ]Tetradecyl-12-carboxylate (47E) (0.7 g, yield: 60%).

Ms m/z(ESI):332.2[M+H ⁺ ]；

The fifth step: (12- (pyridinyl-2-yl) -1, 4-dioxaspiro [ 4.0.4) ⁶ .4 ⁵ ]Tetradecyl-12-yl) methanol (47F)

(12-(pyridin-2-yl)-1,4-dioxadispiro[4.0.4 ⁶ .4 ⁵ ]tetradecan-12-yl)methanol

Lithium aluminum hydride (0.152g, 4.0 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 deg.C, and the methyl 12- (pyridin-2-yl) -1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-carboxylate (47D) (0.662g, 2.0 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture, and the reaction was allowed to proceed overnight at room temperature. The reaction was cooled to 0 ℃, quenched with water (0.2 mL), sodium hydroxide solution (10%, 0.3 mL) and water (0.3 mL), dried by addition of anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give (12- (pyridin-2-yl) -1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-yl) methanol (47F) (0.55 g, yield: 91%).

Ms m/z(ESI):304.1[M+H ⁺ ]；

And a sixth step: (12- (pyridinyl-2-yl) -1, 4-dioxaspiro [ 4.0.4) ⁶ .4 ⁵ ]Tetradecyl-12-yl) methyl methanesulfonate (47G)

(12-(pyridin-2-yl)-1,4-dioxadispiro[4.0.4 ⁶ .4 ⁵ ]tetradecan-12-yl)methyl methanesulfonate

(12- (pyridyl-2-yl) -1, 4-dioxaspiro [4.0.4 ] spiro at 0 DEG C ⁶ .4 ⁵ ]Tetradecyl-12-yl) methanol (47F) (0.5g, 2.0mmol) was dissolved in methylene chloride (20 mL), and the temperature was reduced to 0 ℃ to add triethylamine (0.282g, 2.8mmol), followed by stirring for 10 minutes after completion of the addition. Methanesulfonyl chloride (0.107g, 0.94mmol) was added dropwise to the reaction solution, and after the addition, the reaction was carried out at room temperature for 3 hours. Water (10 mL) was added, and the mixture was extracted with methylene chloride (20 mL. Times.4). The organic phases were combined and washed with saturated saline solution (50 mL. Times.1). Drying over anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to give (12- (pyridyl-2-yl) -1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-yl) methyl methanesulfonate (47G) (0.35G, yield: 60%).

Ms m/z(ESI):382.3[M+H ⁺ ]；

The seventh step: 2- (12- (pyridinyl-2-yl) -1, 4-dioxaspiro [ 4.0.4) ⁶ .4 ⁵ ]Tetradecyl-12-yl) acetonitrile (47H)

2-(12-(pydin-2-yl)-1,4-dioxadispiro[4.0.4 ⁶ .4 ⁵ ]tetradecan-12-yl)acetonitrile

Reacting (12- (pyridyl-2-yl) -1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-yl) methyl methanesulfonate (47G) (0.3g, 0.8mmol) was dissolved in dimethyl sulfoxide (10 mL), and sodium cyanide (0.102g, 1.23mmol) and sodium iodide (13.8mg, 0.08mmol) were further added to complete the reaction at 150 ℃ for 8 hours. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 60) to obtain 2- (12- (pyridin-2-yl) -1, 4-dioxaspiro [4.0.4 ⁶ .4 ⁵ ]Tetradecyl-12-Yl) acetonitrile (47H) (0.3 g, yield: 100%).

Ms m/z(ESI):313.1[M+H ⁺ ]；

Eighth step: 2- (12- (pyridinyl-2-yl) -1, 4-dioxaspiro [4.0.4 ⁶ .4 ⁵ ]Tetradecyl-12-yl) ethyl-1-amine (47I)

2-(12-(pyridin-2-yl)-1,4-dioxadispiro[4.0.4 ⁶ .4 ⁵ ]tetradecan-12-yl)ethan-1-amine

Lithium aluminum hydride (0.114g, 3.0 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0 deg.C, and 2- (12- (pyridin-2-yl) -1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-yl) acetonitrile (47H) (0.312g, 1.0 mmol) in tetrahydrofuran (10 mL) was added to the reaction, and the reaction was allowed to complete at room temperature overnight. The reaction was cooled to 0 ℃, quenched with water (0.2 mL), sodium hydroxide solution (10%, 0.3 mL) and water (0.3 mL), dried with anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give 2- (12- (pyridin-2-yl) -1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-yl) ethyl-1-amine (47I) (0.316 g, yield: 100%).

Ms m/z(ESI):317.2[M+H ⁺ ]；

The ninth step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (12- (pyridinyl-2-yl) -1, 4-dioxaspiro [ 4.0.4) ⁶ .4 ⁵ ]Tetradecyl-12-yl) ethyl-1-amine (47J)

(47B)N-((3-methoxythiophen-2-yl)methyl)-2-(12-(pyridin-2-yl)-1,4-dioxadispiro[4.0.46.45]tetradecan-12-yl)ethan-1-amine

Reacting 2- (12- (pyridyl-2-yl) -1, 4-dioxaspiro [4.0.4 ] ⁶ .4 ⁵ ]Tetradecyl-12-yl) ethyl-1-amine (47I) (0.316g, 1.0mmol) was dissolved in methylene chloride (20 mL), and sodium sulfate (1.3 g,10.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.142g, 1.0 mmol) were added to the reaction, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.049 g, 1.30mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =50 ⁶ .4 ⁵ ]Tetradecyl-12-yl) ethyl-1-amine (47J) (0.15 g, 34% yield).

Ms m/z(ESI):443.2[M+H ⁺ ]；

The tenth step: 9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one (47K)

9-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-9-(pyridin-2-yl)spiro[4.5]decan-6-one

Reacting N- ((3-methoxythiophen-2-yl) methyl) -2- (12- (pyridinyl-2-yl) -1, 4-dioxaspiro [4.0.4 ⁶ .4 ⁵ ]Tetradecyl-12-yl) ethyl-1-amine (47J) (50.0 mg, 0.11mmol) was dissolved in tetrahydrofuran (4 mL), cooled to 0 ℃ and hydrochloric acid (6M, 1mL) was added to the reaction solution, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =50]Decan-6-one (47K) (30 mg, yield: 66%).

Ms m/z(ESI):399.3[M+H ⁺ ]；

The eleventh step: 9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (Compound 47)

9-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-9-(pyridin-2-yl)spiro[4.5]decan-6-one hydrochloride

9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one (47K) (30mg, 0.075 mmol) was dissolved in ethyl acetate (4 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give 9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (compound 47) as a white solid (30 mg, yield: 91.6%).

Ms m/z(ESI):399.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ9.31-9.30(d,1H),8.66-8.64(m,1H),8.16-8.11(m,2H),7.56-7.51(d,1H),7.12-7.10(d,1H),4.44(s,2H),3.98(s,3H),2.61-2.60(m,2H),2.45-2.43(m,2H),2.15(m,2H),1.94(m,2H),1.79(m,2H),1.78-1.43(m,9H).

Resolution of Compound 47

9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (compound 47) (100 mg) was taken for resolution to give, after separation, two optical isomers, compound 47-1 (retention time: 3.89min,20.53mg, white solid, ee% = 100%), compound 47-2 (retention time: 5.18min,20.47mg, white solid, ee% = 100%).

Splitting conditions are as follows: the instrument is Gilson GX-281Liquid Handler Prep HPLC BG; column Phenomenex Kinetex XB-C18 150mm 30mm,5 μm,100A, AX mobile phase A: H ₂ O (0.05% TFA), B: ACN; gradient B0-25%; the flow rate is 25mL/min; the column temperature is 25 ℃; the wavelength is 220nm; the period is 4min; sample preparation, compound 47 is dissolved in acetonitrile to prepare 3.3mg/ml; injection 2.0 ml/needle.

The twelfth step: (R) -9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (Compound 47-1)

(R)-9-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-9-(pyridin-2-yl)spiro[4.5]decan-6-one hydrochloride

(R) -9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one (compound 47) (22mg, 0.055mmol) was dissolved in ethyl acetate (4 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (compound 47-1) as a white solid (25 mg, yield: 100%).

Ms m/z(ESI):399.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ9.27-9.26(d,1H),8.62-8.60(m,1H),8.14-8.09(m,2H),7.35-7.33(d,1H),7.12-7.10(d,1H),4.41(s,2H),3.95(s,3H),2.61-2.60(m,2H),2.45-2.44(m,2H),2.17(m,2H),1.96(m,2H),1.77(m,2H),1.76-1.43(m,9H).

(S) -9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (Compound 47-2)

(S)-9-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-9-(pyridin-2-yl)spiro[4.5]decan-6-one hydrochloride

(S) -9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one (Compound 47) (20mg, 0.054mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (S) -9- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -9- (pyridin-2-yl) oxa [4.5] decan-6-one hydrochloride (compound 47-2) as a white solid (20 mg, yield 100%).

Ms m/z(ESI):399.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ9.31-9.30(d,1H),8.66-8.64(m,1H),8.16-8.11(m,2H),7.56-7.51(d,1H),7.12-7.10(d,1H),4.44(s,2H),4.14-3.98(s,3H),2.61-2.60(m,2H),2.45-2.43(m,2H),2.15(m,2H),1.94(m,2H),1.79(m,2H),1.78-1.43(m,9H).

Example 48

N- (3-chlorobenzyl) -1- ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methanamine hydrochloride (Compound 48)

N-(3-chlorobenzyl)-1-((8,9trans)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-8-yl)methanamine hydrochloride

The first step is as follows: 9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-8-ene-8-carboxylic acid methyl ester (48B)

methyl 9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-8-ene-8-carboxylate

Dissolving compound 9- (((trifluoromethyl) sulfonyl) oxy) -6-oxaspiro [4.5] dec-8-ene-carboxylic acid methyl ester (10C) (26.0g, 75.58mmol) in DMF (260 mL), adding pyridine-2-boronic acid (13.9g, 113.37mmol), 1 '-bisdiphenylphosphinoferrocene, 1' -bis (diphenylphosphino) ferrocene (4.213g, 7.558mmol), palladium acetate (0.848g, 3.77mmol), cesium carbonate (36.938g, 113.37mmol), cuprous chloride (7.482g, 75.78mmol) after addition, bubbling the reaction solution with nitrogen for 10 minutes and replacing with nitrogen 3 times, stirring and refluxing at 120 ℃ for 4 hours, cooling the reaction solution to room temperature, adding water 500 mL, extracting with ether (200 mL × 3), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, purifying with silica gel column chromatography (200-300 mesh), eluting with ethyl acetate (1.848-ene-carboxylic acid methyl ester) (1.9-8 g, colorless oil yield: 8- (9-8-5V): 32%).

Ms m/z(ESI):274.1[M+H ⁺ ]；

¹ HNMR(400MHz,CDCl ₃ )δ8.61-8.59(ddd,1H),7.69-7.64(td,1H),7.22-7.18(m,2H),4.49-4.47(t,2H),2.93(s,3H),2.60-2.58(t,2H),1.98-1.55(m,8H).

The second step is that: (9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carboxylic acid methyl ester (48C)

methyl 9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-8-carboxylate

The compound, methyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-8-ene-8-carboxylate (48B) (7.0 g, 25.64mmol), was dissolved in methanol (70 mL), and palladium on charcoal (3.0 g,10% by weight, water content 50%) was added, and the mixture was replaced with hydrogen 3 times, and stirred at room temperature under normal pressure hydrogenation overnight. Filtration was carried out, the filter cake was washed with methanol (10 mL. Times.3), and the filtrate was evaporated to dryness to give methyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carboxylate (48C) (6.3 g, yield: 90%)

Ms m/z(ESI):276.2[M+H ⁺ ].

¹ H NMR(400MHz,CD ₃ OD)δ8.44-8.42(m,1H),7.77-7.73(td,1H),7.37-7.35(dd,1H),7.23-7.20(dd,1H),4.14-4.10(dd,1H),4.03-3.99(dd,1H),3.47(s,3H),3.40-3.35(dt,1H),3.18-3.17(dd,1H),2.12-2.07(m,1H),1.88-1.54(m,9H).

The third step: (8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carboxylic acid methyl ester (48D)

(8,9trans)-methyl 9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-8-carboxylate

Methyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carboxylate (48C) (3.6 g, 13.09mmol) was dissolved in methanol (130 mL), nitrogen gas was replaced 3 times, and a methanol solution of sodium methoxide (2.91mL, 15.71mmol) was added and stirred under nitrogen for reflux for 12 hours. The reaction solution was evaporated to dryness, a saturated ammonium chloride solution (100 mL) was added and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with a saturated saline solution (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to a silica gel column chromatography (petroleum ether/ethyl acetate (V/V)) =10/1, yellow solid. Methyl (8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carboxylate (48D) was obtained as a yellow solid (2.1 g, yield: 58%).

Ms m/z(ESI):276.2[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.55-8.54(d,1H),7.67(s,1H),7.22-7.18(d,2H),4.06-4.02(dd,1H),3.76-3.70(dd,1H),3.51(s,3H),3.41(s,1H),3.21-3.14(m,1H),2.10-1.56(m,10H).

The fourth step: ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methanol (48E)

((8,9trans)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-8-yl)methanol

The compound lithium aluminum hydride (0.58g, 15.27mmol) and tetrahydrofuran (25 mL) were sequentially charged into a 250mL three-necked reaction flask, and a solution of (8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carboxylic acid methyl ester (48D) (2.10 g, 7.63mmol) in tetrahydrofuran (5 mL) was added dropwise with stirring at room temperature, and the reaction was completed at room temperature for 2 hours. The reaction solution was cooled to 0 ℃ or lower with an ice salt bath, water (0.6 mL), a 20% sodium hydroxide solution (1.2 mL), water (0.6 mL), and filtered with celite in this order with stirring, the cake was washed with tetrahydrofuran (10 mL × 3) and filtered, the filtrate was dried with anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was subjected to column chromatography with silica gel 200-300 mesh (petroleum ether/ethyl acetate (V/V) =10 1-3) to give a colorless oily product ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methanol (48E) (1.8 g, yield: 95.49%).

Ms m/z(ESI):248.2[M+Na ⁺ ]。

The fifth step: (8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carbaldehyde (48F)

(8,9trans)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-8-carbaldehyde

The compound ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methanol (48E) (0.224g, 0.91mmol) was dissolved in dichloromethane (20 mL), stirred and cooled to 0 ℃ and a solution of dess-martin oxidant (0.772g, 1.82mmol) was added and the reaction was completed at room temperature for 4 hours. To the reaction solution was added a saturated thiosulfate solution (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined and washed with a saturated sodium bicarbonate solution (50 mL. Times.1), the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a colorless oily product (8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carbaldehyde (48F) (0.20 g, yield: 91.6%).

Ms.m/z(ESI):246.1[M+Na ⁺ ]。

And a sixth step: n- (3-chlorobenzyl) -1- ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methylamine (48G)

N-(3-chlorobenzyl)-1-((8,9trans)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-8-yl)methanamine

The compound (8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-8-carbaldehyde (48F) (0.20g, 0.815mmol), 3-chlorobenzylamine (0.150g, 1.06mmol) was dissolved in dichloromethane (10 mL), and anhydrous sodium sulfate (0.579g, 4.077mmol) was added, and the mixture was stirred at room temperature overnight. Sodium borohydride (0.046 g, 1.223mmol) was added and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added and stirred for 2 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give N- (3-chlorobenzyl) -1- ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methylamine (48G) (229 mg, yield: 75.7%) as a yellow oily product.

Ms.m/z(ESI):371.1[M+H ⁺ ]；

The ninth step: n- (3-chlorobenzyl) -1- ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methanamine hydrochloride (Compound 48)

N-(3-chlorobenzyl)-1-((8,9trans)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-8-yl)methanaminehydrochloride

The compound N- (3-chlorobenzyl) -1- ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methylamine (48G) (0.228g, 0.615mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.615mL, 1.23mmol) was added and stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness to give the product N- (3-chlorobenzyl) -1- ((8, 9 trans) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-8-yl) methanamine hydrochloride (compound 48) (241 mg, yield: 97.3%) as a white solid.

Ms.m/z(ESI):371.1[M+H ⁺ -HCl]；

¹ H NMR(400MHz,CD ₃ OD)δ8.81-8.79(d,1H),8.63-8.59(t,1H),8.19-8.17(d,1H),8.02-7.99(t,1H),7.57(s,1H),7.49-7.31(m,3H),4.18-4.09(q,3H),3.61-3.55(t,1H),3.41-3.35(t,Hz,1H),3.05-2.99(t,1H),2.76-2.72(d,1H),2.63(s,1H),2.14-2.01(m,2H),1.96-1.89(m,1H),1.85-1.55(m,7H).

Example 49

9-benzyl-1- (3-chlorobenzyl) -4-oxa-1, 9-diazaspiro [5.5] undecan-2-one hydrochloride (Compound 49)

9-benzyl-1-(3-chlorobenzyl)-4-oxa-1,9-diazaspiro[5.5]undecan-2-one hydrochloride

The first step is as follows: 8-benzyl-1, 3, 8-triazaspiro [4.5] decane-2, 4-dione (49B)

8-benzyl-1,3,8-triazaspiro[4.5]decane-2,4-dione

1-Benzylpiperidin-4-one (49A) (20.0 g, 105.68mmol) was dissolved in ethanol (140 mL), added to potassium cyanide (14.3 g,219.6 mmol) and water (140 mL) with stirring, and stirred at 85 ℃ under reflux for 36 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with hot water (100 mL. Times.3) and dried to give 8-benzyl-1, 3, 8-triazaspiro [4.5] decane-2, 4-dione (49B) (24.3 g, yield: 88.68%) as a white solid.

Ms.m/z(ESI):260.1[M+H ⁺ ]。

The second step is that: 4-amino-1-benzylpiperidine-4-carboxylic acid (49C)

4-amino-1-benzylpiperidine-4-carboxylic acid

8-benzyl-1, 3, 8-triazaspiro [4.5] decane-2, 4-dione (49B) (24.0 g, 92.56mmol) and water (350 mL) were charged into a reaction flask, and lithium hydroxide monohydrate (19.42g, 462.8 mmol) was added under stirring, and the mixture was refluxed for 24 hours. A large amount of the precipitated white solid was removed by filtration, and the filtrate was cooled to 0 to 5 ℃ and pH-adjusted with 5N hydrochloric acid to precipitate a large amount of white solid, which was filtered, and the filter cake was washed with water (50 mL. Times.2) and dried to give 4-amino-1-benzylpiperidine-4-carboxylic acid (49C) (20 g, yield: 92.23%) as a white solid.

Ms.m/z(ESI):235.1[M+H ⁺ ]。

The third step: (4-amino-1-benzylpiperidin-4-yl) methanol (49D)

(4-amino-1-benzylpiperidin-4-yl)methanol

4-amino-1-benzylpiperidine-4-carboxylic acid (49C) (17.0 g, 72.56mmol) and tetrahydrofuran (500 mL) were charged into a reaction flask, and lithium aluminum hydride (11.03g, 290.2mmol) was added in small portions with stirring and stirred at room temperature overnight. Water (22 mL), a 20% NaOH solution (44L) and water (22 mL) were added dropwise to the reaction solution in this order under a salt bath with ice, the mixture was stirred for 1 hour, filtered, the filter cake was dried over anhydrous sodium sulfate with tetrahydrofuran (20 mL. Times.3) as an organic phase, filtered and evaporated to dryness to give a colorless oily product (4-amino-1-benzylpiperidin-4-yl) methanol (49D) (13 g, yield: 81.33%).

Ms.m/z(ESI):221.1[M+H ⁺ ]。

The fourth step: 9-benzyl-4-oxa-1, 9-diazaspiro [5.5] undecan-2-one (49E)

9-benzyl-4-oxa-1,9-diazaspiro[5.5]undecan-2-one

(4-amino-1-benzylpiperidin-4-yl) methanol (49D) (2.0g, 9.079mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.011g, 9.986 mmol) was added with stirring, a solution of chloroacetyl chloride (0.923g, 8.171mmol) in dichloromethane (10 mL) was added dropwise at a temperature of 0 ℃ and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness, THF (10 mL) was added thereto, the mixture was stirred and cooled to 0 ℃ and a solution of potassium tert-butoxide in tetrahydrofuran (26mL, 26.33mmol) was added thereto, followed by reaction at room temperature overnight. The reaction was evaporated to dryness and silica gel column chromatography (DCM/MeOH = 20/1) afforded the product 9-benzyl-4-oxa-1, 9-diazaspiro [5.5] undecan-2-one (49E) (1.8 g, yield: 76%) as a white solid.

Ms.m/z(ESI):261.1[M+H ⁺ ]。

The fifth step: 9-benzyl-1- (3-chlorobenzyl) -4-oxa-1,9-diazaspiro [5.5] undecan-2-one (49F) 9-benzyl-1- (3-chlorobenzyl) -4-oxa-1,9-diazaspiro [5.5]

9-benzyl-1- (3-chlorobenzyl) -4-oxa-1,9-diazaspiro [5.5] undecan-2-one (49E) (1.0 g, 3.842mmol) was dissolved in tetrahydrofuran (30 mL), tetrabutylammonium iodide (1.703g, 4.610mmol) was added with stirring, sodium hydrogen (0.307g, 7.683mmol) was added at a temperature of 0 ℃, sodium hydrogen (0.307g, 7.683mmol) was added after stirring for 20 minutes, 3-chlorobenzyl bromide (0.947g, 4.610mmol) was added, and stirring was carried out at room temperature for 2.5 hours. The reaction solution was added to 40g of an ice water mixture, stirred to melt, extracted with ethyl acetate (20 mL × 3), the organic phases were combined and washed with saturated ammonium chloride (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography with DCM/MeOH =50/1 to give the product 9-benzyl-1- (3-chlorobenzyl) -4-oxa-1,9-diazaspiro [5.5] undecan-2-one (49F) (1.2 g, yield: 81.15%) as a white solid.

Ms.m/z(ESI):385.1[M+H ⁺ ]。

And a sixth step: 9-benzyl-1- (3-chlorobenzyl) -4-oxa-1,9-diazaspiro [5.5] undecan-2-one hydrochloride (Compound 49)

The compound 9-benzyl-1- (3-chlorobenzyl) -4-oxa-1,9-diazaspiro [5.5] undecan-2-one (49F) (0.200g, 0.520mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.520mL, 0.520mmol) was added and stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness to give the product 9-benzyl-1- (3-chlorobenzyl) -4-oxa-1,9-diazaspiro [5.5] undecan-2-one hydrochloride (compound 49) as a white solid (210 mg, yield: 95.9%).

Ms.m/z(ESI):385.1[M+H ⁺ -HCl]；

¹ H NMR(400MHz,CD3OD)δ7.56-7.46(m,5H),7.31-7.17(m,4H),4.70(s,2H),4.34(s,2H),4.29(s,2H),4.10(s,2H),3.44-3.35(m,2H),3.22-3.12(m,2H),2.38(td,2H),1.95(d,2H).

Example 50

2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 50)

2-((8,9trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine hydrochloride

The first step is as follows: 9- (4-fluorophenyl) -6-oxaspiro [4.5] decane-8-carboxylic acid methyl ester (50B)

methyl 9-(4-fluorophenyl)-6-oxaspiro[4.5]decane-8-carboxylate

The compound methyl 9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-ene-8-carboxylate (10D) (22.6 g, 77.85mmol) was dissolved in methanol (100 mL) and added, palladium on charcoal (10 g,10% by weight, water content 50%) was added, and the mixture was replaced with hydrogen gas 3 times, and the mixture was hydrogenated under normal pressure and stirred at room temperature overnight. The filtrate was filtered, and the filter cake was washed with methanol (10 mL. Times.3), and the filtrate was evaporated to dryness to give methyl 9- (4-fluorophenyl) -6-oxaspiro [4.5] decane-8-carboxylate (50B) (21 g, yield: 92.3%) as a colorless oily compound.

Ms m/z(ESI):293.1[M+H ⁺ ]；

The second step is that: (8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decane-8-carboxylic acid methyl ester (50C)

(8,9trans)-methyl 9-(4-fluorophenyl)-6-oxaspiro[4.5]decane-8-carboxylate

Methyl 9- (4-fluorophenyl) -6-oxaspiro [4.5] decane-8-carboxylate (50B) (9.2 g, 31.51mmol) was dissolved in methanol (300 mL), and the mixture was replaced with nitrogen 3 times, to which a methanol solution of sodium methoxide (7.0 mL, 37.81mmol) was added, and the mixture was stirred under nitrogen for 12 hours under reflux. The reaction solution was evaporated to dryness, a saturated ammonium chloride solution (100 mL) was added, extraction was performed with ethyl acetate (50 mL × 3), the organic phases were combined, and washed with a saturated saline solution (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to silica gel column chromatography (petroleum ether/ethyl acetate (V/V)) =10/1 to obtain a yellow solid (8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decane-8-carboxylic acid methyl ester yellow solid compound (50C) (6.4 g, yield: 70%).

Ms m/z(ESI):315.3[M+Na ⁺ ]；

¹ HNMR(400MHz,CD ₃ OD)δ7.25-7.20(m,2H),7.02-6.96(m,2H),3.92-3.88(d,1H),3.74-3.69(t,1H),3.43(s,3H),3.16-3.08(td,1H),2.85-2.79(td,1H),2.15-2.08(m,1H),1.85-1.56(m,9H).

The third step: ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methanol (50D)

((8,9trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)methanol

The compound lithium aluminum hydride (1.677g, 44.14mmol) and tetrahydrofuran (70 mL) were sequentially charged into a 250mL three-necked flask, and a solution of methyl (8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decane-8-carboxylate (50C) (6.400g, 22.07mmol) in tetrahydrofuran (10 mL) was added dropwise with stirring at room temperature, after which the reaction was completed at room temperature for 2 hours. The reaction solution was cooled to 0 ℃ or lower with an ice salt bath, water (2.6 mL), a 20% sodium hydroxide solution (5.2 mL), water (2.6 mL) and celite were added dropwise to the reaction solution in this order while stirring, the cake was washed with tetrahydrofuran (10 mL. Times.3) and filtered, the filtrate was dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to silica gel 200-300 mesh column chromatography using petroleum ether/ethyl acetate (V/V) =10/1-3/1 to give a colorless oily product ((8, 9-return) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) methanol (50D) (5.7 g, yield: 98.58%).

Ms m/z(ESI):287.1[M+Na ⁺ ]；

The fourth step: (8, 9 trans) -8- (chloromethyl) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decane (50E)

(8,9trans)-8-(chloromethyl)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decane

The compound (9- (4-fluorophenyl) -6-oxaspiro [4.5] dec-8-en-8-yl) methanol (50D) (6.000g, 22.90mmol) was dissolved in methylene chloride (60 mL), triethylamine (4.626 g, 45.80mmol) was added thereto, the mixture was stirred and cooled to 0 ℃ to add dropwise a methanesulfonyl chloride (3.148g, 27.48mmol) solution, and the reaction was completed at room temperature for 4 hours. To the reaction solution was added a saturated ammonium chloride solution (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined and washed with a saturated ammonium chloride solution (50 mL. Times.1), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a yellow oily product (8, 9 trans) -8- (chloromethyl) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decane (50E) (8.00 g, crude yield: over 100%).

Ms.m/z(ESI):305.1[M+Na ⁺ ]。

The fifth step: 2- ((8, 9 trans) -9- (4-fluorobenzene) -6-oxaspiro [4.5] decan-8-yl) acetonitrile (50F)

2-((8,9trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)acetonitrile

The compound (8, 9 trans) -8- (chloromethyl) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decane (50E) (7.800g, 21.76mmol) was dissolved in DMF (80 mL), and potassium cyanide (5.657g, 87.03mmol) was added and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (200 mL) was added, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined and washed with saturated brine (200 mL. Times.3), the aqueous phase was treated with sodium hypochlorite and poured into a waste vat, the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, petroleum ether/ethyl acetate (V/V) =30/1-10/1 to give 2- ((8, 9 trans) -9- (4-fluorobenzene) -6-oxaspiro [4.5] decan-8-yl) acetonitrile (50F) (5.73 g, yield: 91%) as a white solid product.

Ms.m/z(ESI):296.1[M+Na ⁺ ]。

And a sixth step: 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine (50G)

2-((8,9trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)ethanamine

The compound 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) acetonitrile (50F) (2.73g, 9.913mmol) was dissolved in THF (65 mL), and lithium aluminum hydride (0.7534g, 19.83mmol) was added with stirring, after which stirring was carried out at room temperature overnight (12 hours). Water (0.8 mL), a 20% NaOH solution (1.6 mL), and water (0.8 mL) were added dropwise to the reaction mixture in this order under an ice salt bath, and the mixture was stirred for 1 hour, filtered, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine (50G) (1.7G, yield: 61.4%) as a yellow oily product.

Ms.m/z(ESI):278.1[M+H ⁺ ]。

The seventh step: 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (50H)

2-((8,9trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)-N-((3-methoxythiophen-2-yl)methyl)ethanamine

The compound 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine (50G) (0.500g, 1.704mmol), 3-methoxythiophene-2-carbaldehyde (0.315g, 2.215mmol) was dissolved in dichloromethane (20 mL), and anhydrous sodium sulfate (1.21g, 8.521mmol) was added and stirred at room temperature overnight. Sodium borohydride (0.097g, 2.556 mmol) was added thereto and stirred at room temperature for 1 hour, and 3ml of anhydrous methanol was added thereto and stirred for 2 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (50H) as a yellow oily product (380 mg, yield: 55.2%).

Ms.m/z(ESI):404.1[M+H ⁺ ]。

Eighth step: 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 50)

The compound 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine (50H) (0.380g, 0.943mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.943mL, 0.943mmol) was added and stirred at room temperature for 2 hours. Filtration gave the product, 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) -N- ((3-methoxythiophen-2-yl) methyl) ethylamine hydrochloride (Compound 50) as a white solid (390 mg, yield: 98.9%).

Ms.m/z(ESI):404.1[M+H ⁺ -HCl]；

¹ H NMR(400MHz,CD ₃ OD)δ7.47-7.46(d,1H),7.27-7.22(m,2H),7.06-7.00(m,3H),4.11-4.08(m,2H),3.88(s,3H),3.80-3.75(dd,1H),3.44-3.38(t,1H),2.86-2.79(td,1H),2.64-2.56(m,2H),2.10-2.05(m,1H),1.89-1.37(m,12H).

Example 51

N- (3-chlorobenzyl) -2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine hydrochloride (Compound 51)

N-(3-chlorobenzyl)-2-((8R,9S)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)ethanamine hydrochloride

The first step is as follows: n- (3-chlorobenzyl) -2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethanamine (51A)

N-(3-chlorobenzyl)-2-((8R,9S)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)ethanamine

Compound 2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine (50G) (0.500g, 1.704mmol), m-chlorobenzaldehyde (0.3114g, 2.215mmol) was dissolved in methylene chloride (20 mL), and anhydrous sodium sulfate (1.21g, 8.521mmol) was added and stirred at room temperature overnight. Sodium borohydride (0.097g, 2.556 mmol) was added thereto and stirred at room temperature for 1 hour, and 3 ml of anhydrous methanol was added thereto and stirred for 2 hours. To the reaction solution was added 20mL of water, the aqueous phase was extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give N- (3-chlorobenzyl) -2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine (51A) (415 mg, yield: 60.6%) as a yellow oily product.

Ms.m/z(ESI):402.2[M+H ⁺ ]。

The second step is that: n- (3-chlorobenzyl) -2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine hydrochloride (Compound 51)

The compound N- (3-chlorobenzyl) -2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethanamine (51A) (0.380g, 0.943mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (0.943mL, 0.943mmol) was added and the mixture was stirred at room temperature for 2 hours. Filtration gave the product N- (3-chlorobenzyl) -2- ((8, 9 trans) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-8-yl) ethylamine hydrochloride (Compound 51) as a white solid (410 mg, yield: 98.7%).

Ms.m/z(ESI):402.2[M+H ⁺ -HCl]；

¹ H NMR(400MHz,CD ₃ OD)δ7.46-7.39(m,3H),7.29-7.23(m,3H),7.06-7.01(t,2H),4.08-4.00(m,2H),3.83-3.79(dd,1H),3.46-3.39(t,1H),2.95-2.87(td,1H),2.70-2.57(m,2H),2.08-2.05(d,1H),1.89-1.45(m,12H).

Example 52

N- (3-chlorophenyl) -1- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methylamine hydrochloride (Compound 52)

N-(3-chlorobenzyl)-1-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)methanamine hydrochloride

The first step is as follows: 6-oxaspiro [4.5] decane-9-carbaldehyde (52B)

6-oxaspiro[4.5]decane-9-carbaldehyde

After 6-oxaspiro [4.5] decan-9-one (1 c) (1.00g, 6.48mmol) was dissolved in tetrahydrofuran (20 mL), methoxymethyltriphenylphosphine chloride (5.56g, 16.21mmol) was added thereto, the temperature was reduced to 0 ℃ and a tetrahydrofuran solution of potassium tert-butoxide (1M, 16.2mL) was added dropwise to the reaction mixture, followed by stirring for 3 hours after the addition. Aqueous hydrochloric acid (2M, 8.1mL) was added and the mixture was stirred at room temperature overnight. Water (50 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/100-1/10) to give 6-oxaspiro [4.5] decane-9-carbaldehyde (52B) (0.95 g, yield 87%) as a yellow oil.

LCMS m/z＝169.1[M+H ⁺ ]

The second step: 6-Oxaspiro [4.5] decane-9-carboxylic acid methyl ester (52C)

methyl 6-oxaspiro[4.5]decane-9-carboxylate

6-oxaspiro [4.5] decane-9-carbaldehyde (52B) (0.95g, 5.6 mmol), potassium hydroxide (0.82g, 15mmol) were dissolved in methanol (10 mL), the temperature was lowered to 0 ℃ and elemental iodine (1.9g, 7.3mmol) was dissolved in methanol (10 mL), and then the solution was added dropwise to the reaction mixture, and the reaction was carried out for half an hour after the addition. The reaction was quenched by dropwise addition of saturated aqueous sodium thiosulfate solution, water (20 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/100-1/10) and concentrated to dryness to give methyl 6-oxaspiro [4.5] decane-9-carboxylate (52C) (1.1 g, yield 98%)

¹ H NMR(400MHz,CDCl ₃ )3.82-3.77(m,1H),3.68(s,3H),3.59-3.53(m,1H),2.63-2.57(m,1H),1.80-1.55(m,12H).

The third step: 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carboxylic acid methyl ester (52D)

methyl 9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-carboxylate

6-Oxaspiro [4.5] decane-9-carboxylic acid methyl ester (52C) (1.0 g,5.0 mmol) was dissolved in a single-neck flask with tetrahydrofuran (10 mL), 2-fluoropyridine (0.7 g,7.6 mmol) was added thereto, the temperature was lowered to-70 ℃ or below, bis (trimethylsilyl) sodium amide (5.0 mL,10.1 mmol) was slowly added dropwise to the reaction mixture, and after completion of the addition, stirring was carried out for 10 minutes, and the mixture was allowed to warm to room temperature and reacted for 3 hours. Cooling to about 0 ℃, dropwise adding saturated aqueous ammonium chloride, adding water (20 mL), extracting with ethyl acetate (20 mL × 2), combining the organic phases, washing the organic phases with water (20 mL) and saturated sodium chloride solution (20 mL), drying, filtering, concentrating, purifying the crude product by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/100-1/10) column flushing, concentrating to dryness to obtain yellow oily 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carboxylic acid methyl ester (52D) (0.6 g, yield 40%).

LCMS m/z＝276.2[M+H ⁺ ]；

The fourth step: (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methanol (52E)

(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)methanol

Aluminum lithium hydride (0.25g, 0.65mmol) was stirred in a reaction flask with tetrahydrofuran (5 mL), cooled to 0 ℃ and methyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carboxylate (52D) (0.6 g, 2.18mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the reaction mixture, and the reaction was completed for 2 hours. Water (0.25 g), 10% aqueous sodium hydroxide (0.5 g), and water (0.25 g) were added dropwise in this order, and after stirring for 10 minutes, the mixture was filtered, rinsed with ethyl acetate, and the organic phase was concentrated to dryness to give (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methanol (52E) (0.55 g, yield 100%) as a pale yellow oil.

LCMS m/z＝248.1[M+H ⁺ ]；

The fifth step: 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carbaldehyde (52F)

9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-carbaldehyde

(9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methanol (52E) (0.55g, 2.2mmol) was dissolved in methylene chloride (10 mL), cooled to 0 ℃ and dessimutan (2.2g, 5.1mmol) was added to the reaction mixture, and then allowed to spontaneously rise to room temperature for reaction for 3 hours. Water (20 mL) was added, extraction was performed with dichloromethane (20 mL × 2), the organic phases were combined, the organic phase was washed with water (20 mL), saturated sodium chloride solution (20 mL), dried, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/100-1/10) cartridge, concentrated to dryness to give 9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carbaldehyde (52F) (0.3 g, 50% yield) as a pale yellow oil.

¹ H NMR(400MHz,CDCl ₃ )9.71(s,1H),8.62-8.61(d,1H),7.72-7.68(dt,1H),7.29-7.26(d,1H),7.22-7.19(dd,1H),3.83-3.78(m,2H),2.52-2.30(m,3H),2.06-2.04(m,1H),1.88-1.41(m,8H).

And a sixth step: n- (3-chlorophenyl) -1- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methylamine (52G)

N-(3-chlorobenzyl)-1-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)methanamine

9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carbaldehyde (52F) (0.14g, 0.57mmol), 3-chlorobenzylamine (0.12g, 0.86mmol) were dissolved in methylene chloride (10 mL), magnesium sulfate (0.34g, 2.9mmol) was added, and the mixture was stirred at room temperature overnight, sodium borohydride (33mg, 0.86mmol) was added and the mixture was stirred at room temperature for 1 hour, and anhydrous methanol (3 mL) was added and the mixture was stirred for 2 hours. Water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/10-1/1) and concentrated to dryness to give N- (3-chlorophenyl) -1- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methylamine (52G) (0.20G, 90% yield) as a pale yellow oil.

LCMS m/z＝371.2[M+H ⁺ ]；

The seventh step: n- (3-chlorophenyl) -1- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methanamine hydrochloride (Compound 52)

N- (3-chlorophenyl) -1- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methylamine (52G) (0.20g, 0.5 mmol) was dissolved in ethyl acetate (10 mL), an ethyl acetate solution of hydrochloric acid (1 mL, 1.7mol/L) was added dropwise to precipitate a solid, and the mixture was stirred for half an hour and concentrated to dryness to give N- (3-chlorophenyl) -1- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methylamine hydrochloride (Compound 52) (0.21G, yield 100%) as a white solid.

LCMS m/z＝371.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD)8.77-8.75(dd,1H),8.29-8.26(d,1H),7.94-7.92(d,1H),7.78-7.75(t,1H),7.53(s,1H),7.44-7.40(m,3H),4.26-4.16(q,2H),3.78-3.76(m,2H),3.46-3.43(d,1H),2.50-2.43(m,2H),2.08-1.94(m,3H),1.76-1.22(m,10H).

Example 53

1- (3-Methoxythiophene-2-yl) -N- ((9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methyl) methanamine hydrochloride (Compound 53)

1-(3-methoxythiophen-2-yl)-N-((9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)methyl)methanamine hydrochloride

The first step is as follows: 1- (3-Methoxythiophene-2-yl) -N- ((9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methyl) methylamine (53A)

1-(3-methoxythiophen-2-yl)-N-((9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)methyl)methanamine

9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-carbaldehyde (52F) (0.14g, 0.57mmol), 3-methoxythiophene-2-methylaminobenzenesulfonate (0.26g, 0.86mmol) were dissolved in dichloromethane (10 mL), triethylamine (87mg, 0.86mmol), magnesium sulfate (0.34g, 2.9mmol) were added, stirring was continued at room temperature overnight, sodium borohydride (33mg, 0.86mmol) was added, stirring was continued at room temperature for 1 hour, and anhydrous methanol (3 mL) was added and stirring was continued for 2 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 1/20-1/3) cartridge and concentrated to dryness to give 1- (3-methoxythiophen-2-yl) -N- ((9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methyl) methylamine (53A) (0.20 g, 94% yield) as a brown oil.

LCMS m/z＝373.2[M+H ⁺ ]；

The second step is that: 1- (3-Methoxythiophene-2-yl) -N- ((9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methyl) methanamine hydrochloride (Compound 53)

1- (3-Methoxythien-2-yl) -N- ((9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methyl) methylamine (53A) (0.18g, 0.48mmol) was dissolved in ethyl acetate (10 mL), and a solution of hydrochloric acid in ethyl acetate (1L, 1.7 mol/L) was added dropwise with solid precipitated, stirred for half an hour and concentrated to dryness to give 1- (3-Methoxythien-2-yl) -N- ((9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) methyl) methylamine hydrochloride (Compound 53) (0.12 g, 61% yield) as a brown solid.

LCMS m/z＝373.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD)8.87-8.69(dd,1H),8.14(dt,1H),7.80-7.78(d,1H),7.63-7.60(dt,1H),7.48-7.46(d,1H),7.02-7.00(d,1H),4.29-4.19(q,2H),3.90(s,3H),3.79-3.74(m,2H),2.42-2.39(d,2H),2.02-1.74(m,4H),1.66-1.17(m,8H).

Example 54

N- ((3-Methoxythien-2-yl) methyl) -2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) ethylamine hydrochloride (Compound 54)

N-((3-methoxythiophen-2-yl)methyl)-2-(5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5-yl)ethanamine hydrochloride

The first step is as follows: 1- ((trimethylsilyl) ethynyl) cyclopentanol (54B)

1-((trimethylsilyl)ethynyl)cyclopentanol

Trimethylsilylacetylene (7g, 71.3 mmol) was dissolved in tetrahydrofuran (80 mL) under nitrogen, the temperature was reduced to-78 deg.C, n-butyllithium (26.2mL, 65.4 mmol) was added dropwise to the reaction, the reaction was allowed to warm to room temperature for 1 hour, the temperature was reduced to-78 deg.C, cyclopentanone (1 a) (5g, 59.4 mmol) was added dropwise to the reaction, and the reaction was continued at room temperature for 2 hours. The reaction solution was quenched with a saturated ammonium chloride solution (80 mL), the aqueous phase was extracted with methyl t-butyl ether (50 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1- ((trimethylsilyl) ethynyl) cyclopentanol (54B) (10 g, yield: 92%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ1.96-1.88(m,4H),1.84-1.65(m,4H),0.16(s,9H).

The second step: 1-acetylenyl cyclopentanol (54C)

1-ethynylcyclopentanol

1- ((trimethylsilyl) ethynyl) cyclopentanol (54B) (10g, 54.8mmol) was dissolved in methanol (100 mL), and potassium carbonate (15g, 109.6mmol) was further added to conduct a reaction at room temperature for 2 hours. Most of the solvent was removed from the reaction solution, the reaction was quenched with water (60 mL), the aqueous phase was extracted with methyl t-butyl ether (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-ethynylcyclopentanol (54C) (5.5 g, yield: 91%) as an oily liquid.

The third step: 1- (allyloxy) -1-ethynylcyclopentane (54D)

1-(allyloxy)-1-ethynylcyclopentane

Sodium hydrogen (5.4 g, 136mmol) was dissolved in tetrahydrofuran (100 mL) under ice-bath, 1-ethynylcyclopentanol (54C) (10g, 90.8mmol) was added dropwise to the reaction, reacted at room temperature for 1 hour, and allyl bromide (22g, 181.6mmol) was added dropwise to the reaction, and stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution (300 mL), the aqueous phase was extracted with methyl tert-butyl ether (80 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 100) to give 1- (allyloxy) -1-ethynylcyclopentane (54D) as an oily liquid (12.5 g, yield: 91.7%).

¹ H NMR(400MHz,CDCl ₃ )δ6.04-5.87(m,1H),5.35-5.22(m,1H),5.14(ddd,1H),4.08(dt,2H),2.47(s,1H),2.10-1.86(m,4H),1.84-1.67(m,4H).

The fourth step: 3a, 4-dihydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5 (3H) -one (54E)

3a,4-dihydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5(3H)-one

1- (allyloxy) -1-ethynylcyclopentane (54D) (0.4 g, 2.66mmol) was dissolved in n-hexane (20 mL), octacarbonyldicobalt (1g, 2.93mmol) was added to the reaction and reacted at room temperature for 0.5 hour, silica gel (10 g) was added to the reaction and stirred for 0.5 hour. The solvent was then spun dry and the mixture was heated to 50 ℃ for 1 hour under oxygen. The reaction was extracted with methyl tert-butyl ether (20 mL × 3), and after the organic phase was concentrated, the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 50.

Ms m/z(ESI):179.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ5.95(d,1H),4.26(t,1H),3.47-3.18(m,2H),2.62(dd,1H),2.18(dd,1H),2.03-1.69(m,8H).

The fifth step: tetrahydropiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5 (3H) -one (54F)

tetrahydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5(3H)-one

3a, 4-dihydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5 (3H) -one (54E) (1.6 g, 8.97mmol) was dissolved in methanol (30 mL), palladium on carbon (0.4 g, wt= 10%) was added, the reaction system was evacuated and replaced with hydrogen gas three times, and the reaction was carried out at room temperature for 5 hours under hydrogen gas (40 psi). The pad was filtered with suction and the filter cake was washed with methanol (20 mL. Times.2) and the filtrate was concentrated to give tetrahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5 (3H) -one (54F) as a yellow oil (1.5 g, 93% yield).

Ms m/z(ESI):181.1[M+H ⁺ ]；

And a sixth step: hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5-carbonitrile (54G)

hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentane]-5-carbonitrile

Tetrahydrotiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5 (3H) -one (54F) (2.3 g, 12.8mmol) and p-toluenesulfonylmethylisonitrile (5.7 g, 29mmol) were dissolved in ethylene glycol dimethyl ether (50 mL) under a nitrogen blanket, ethanol (1.4 g, 29mmol) and potassium tert-butoxide (5g, 45mmol) were added to the reaction, and the reaction was allowed to warm to 60 ℃ for 3 hours. After cooling, a saturated ammonium chloride solution (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 5).

Ms m/z(ESI):191.6[M+H ⁺ ]；

The seventh step: 5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5-carbonitrile (54H)

5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentane]-5-carbonitrile

Hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5-carbonitrile (54G) (0.6G, 3.14mmol) and 2-fluoropyridine (0.37g, 3.76mmol) were dissolved in toluene (20 mL) under nitrogen, cooled to 0 deg.C, and bis (trimethylsilyl) potassium amide (3.8mL, 3.76mmol) was added dropwise to the reaction and allowed to react overnight at room temperature. To the reaction solution was added a saturated ammonium chloride solution (20 mL), the separated aqueous phase was extracted with ethyl acetate (20 mL × 2), the combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 5).

Ms m/z(ESI):269.2[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.62(d,1H),7.85-7.73(m,1H),7.69-7.59(m,1H),7.40-7.28(m,1H),3.87-3.80(m,1H),3.77-3.61(m,1H),3.10-2.88(m,2H),2.79-2.53(m,2H),2.42-2.19(m,2H),1.96-1.44(m,7H),1.39-1.23(m,1H).

The eighth step: 5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1,1' -cyclopentane ] -5-carboxylic acid (54I)

5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentane]-5-carboxylic acid

5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1,1' -cyclopentane ] -5-carbonitrile (54H) (0.55g, 2.0 mmol) was dissolved in sodium hydroxide solution (25% aq.,6 mL) and methanol (6 mL), and the reaction was carried out by heating to 100 ℃ for 16 hours. Cooling, regulating the pH of the reaction liquid to be approximately equal to 7 by using concentrated hydrochloric acid, decompressing and concentrating the direct reaction liquid to obtain a crude product of 5- (pyridine-2-yl) hexahydrospiro [ cyclopent [ c ] furan-1,1' -cyclopentane ] -5-carboxylic acid (54I), and directly putting the crude product into the next step for reaction.

Ms m/z(ESI):288.2[M+H ⁺ ]；

The ninth step: 5- (pyridin-2-yl) hexahydrospiro [ cyclopent [ c ] furan-1,1'-cyclopentane ] -5-carboxylic acid methyl ester (54J) methyl5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1,1' -cyclopentane ] -5-carboxylate

5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1,1' -cyclopentane ] -5-carboxylic acid (54I) (0.57g, 2.0 mmol) was dissolved in N, N-dimethylformamide (20 mL), and potassium carbonate (0.55g, 4.0 mmol) and iodomethane (0.42g, 3.0 mmol) were added to the reaction, followed by reaction at room temperature for 2 hours. To the reaction solution was added water (50 mL), the aqueous phase was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with a saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 4).

Ms m/z(ESI):302.2[M+H ⁺ ]；

The tenth step: (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) methanol (54K)

(5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5-yl)methanol

Lithium aluminum hydride (0.1g, 2.65mmol) was dissolved in tetrahydrofuran (10 mL), and cooled to 0 ℃ to add 5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentane ] -5-carboxylic acid methyl ester (54J) (0.4 g, 1.33mmol) in tetrahydrofuran (5 mL) to the reaction and allowed to react at room temperature for 2 hours. The reaction was cooled to 0 ℃, quenched with water (0.1 mL), sodium hydroxide solution (10%, 0.2 mL) and water (0.3 mL) in that order, dried by adding anhydrous sodium sulfate, stirred for 20 minutes, the solid was filtered and washed with tetrahydrofuran (10 mL × 3). The combined organic phases were concentrated to give (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) methanol (54K) (0.36 g, yield: 99%).

The eleventh step: (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) methanesulfonic acid methyl ester (54L)

(5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5-yl)methyl methanesulfonate

(5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) methanol (54K) (0.36g, 1.3mmol) and triethylamine (0.20g, 2.0mmol) were dissolved in dichloromethane (15 mL), cooled to 0 ℃ and methanesulfonyl chloride (0.18g, 1.6mmol) was added dropwise to the reaction, and the reaction was allowed to proceed at room temperature for 4 hours. The reaction solution was quenched with water (20 mL), the aqueous phase of the separated liquid was extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give methyl 5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) methanesulfonate (54L) (0.45 g, yield: 97%) as a yellow oily liquid.

The twelfth step: 2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) acetonitrile (54M)

2-(5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5-yl)acetonitrile

Methyl (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) methanesulfonate (54L) (0.45g, 1.3mmol) was dissolved in N, N-dimethylformamide (10 mL), and potassium cyanide (0.17g, 2.6 mmol) was added, after which the reaction was carried out at 140 ℃ for 4 hours. To the reaction solution was added water (30 mL), the aqueous phase was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with a saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =10: 1-3) to give 2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) acetonitrile (54M) (0.19 g, yield: 53%) as an oily liquid.

Ms m/z(ESI):283.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.62(d,1H),7.70(d,1H),7.42(d,1H),7.20(d,1H),3.75(dd,1H),3.61(dd,1H),2.97-2.77(m,3H),2.75-2.53(m,2H),2.31(dd,1H),1.88-1.53(m,9H),1.29-1.25(m,1H).

The thirteenth step: 2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) ethanamine (54N)

2-(5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5-yl)ethanamine

Lithium aluminum hydride (0.05g, 1.3 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 deg.C, and 2- ((3aR, 5R,6 aS) -5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) acetonitrile (54M) (0.19g, 0.67mmol) in tetrahydrofuran (5 mL) was added to the reaction and allowed to react overnight at room temperature. The reaction was cooled to 0 ℃, quenched with water (0.05 mL), sodium hydroxide solution (10% aq.,0.1 mL) and water (0.15 mL) in that order, dried by adding anhydrous sodium sulfate, stirred for 20 minutes, and the solid was filtered and washed with tetrahydrofuran (10 mL × 3). The combined organic phases were concentrated to give 2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) ethanamine (54N) (0.19 g, yield: 99%).

Ms m/z(ESI):287.2[M+H ⁺ ]；

A fourteenth step of: n- ((3-Methoxythiophen-2-yl) methyl) -2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan ] -5-yl) ethanamine (54O)

N-((3-methoxythiophen-2-yl)methyl)-2-(5-(pyridin-2-yl)hexahydrospiro[cyclopenta[c]furan-1,1'-cyclopentan]-5-yl)ethanamine

2- ((3aR, 5R, 6aS) -5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) ethylamine (54N) (0.19g, 0.66mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.47g, 3.3mmol) and 3-methoxythiophene-2-carbaldehyde (0.14g, 1.0mmol) were added to the reaction and reacted at room temperature overnight. Sodium borohydride (0.038g, 1.0mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):413.2[M+H ⁺ ]；

The fifteenth step: n- ((3-Methoxythien-2-yl) methyl) -2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan ] -5-yl) ethylamine hydrochloride (Compound 54)

N- ((3-Methoxythiophen-2-yl) methyl) -2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan ] -5-yl) ethylamine (54N) (0.12g, 0.291mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added, and the reaction was stirred at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give N- ((3-methoxythiophen-2-yl) methyl) -2- (5- (pyridin-2-yl) hexahydrospiro [ cyclopenta [ c ] furan-1, 1' -cyclopentan-5-yl) ethylamine hydrochloride (compound 54) as a white solid (0.13 g, yield: 100%).

Ms m/z(ESI):413.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.85(dd,1H),8.59(td,1H),8.15(d,1H),8.03-7.97(m,1H),7.47(d,1H),7.01(d,1H),4.20(s,2H),3.90(d,3H),3.76(dd,1H),3.60(dd,1H),2.96-2.88(m,1H),2.81-2.62(m,4H),2.42-2.27(m,3H),1.79-1.58(m,9H),1.36-1.27(m,1H).

Resolution of Compound 54

Compound 54 (0.12 g) was isolated to give two optical isomers, compound 54O-1 (retention time: 4.56min,43.23mg, oily liquid, ee% =100%, configuration), compound 54O-2 (retention time: 4.89min,44.64mg, oily liquid, ee% = 97.2%).

SFC preparation conditions:

the apparatus is a THar80 preparatory SFC (SFC-16);

a column, chiralPak AD,250 × 30mm I.D.,5 μm;

mobile phase A: carbon dioxide, B: isopropyl alcohol;

gradient B30%;

the flow rate is 60mL/min;

back pressure is 100bar;

the column temperature is 38 ℃; the wavelength is 220nm;

the period is about 8min;

sample preparation, compound is dissolved in methanol to 6mg/ml; injection 2 ml/needle.

The two compounds 54O-1 and 54O-2 are salified according to the method for 54 to obtain 54-1 and 54-2:

Compound 54-1:

Ms m/z(ESI):413.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.85(dd,1H),8.58(td,1H),8.14(d,1H),8.04-7.91(m,1H),7.47(d,1H),7.01(d,1H),4.20(s,2H),3.89(s,3H),3.77(dd,1H),3.59(dd,1H),2.94-2.88(m,1H),2.84-2.58(m,4H),2.39-2.28(m,3H),1.88-1.51(m,9H),1.34-1.26(m,1H).

compound 54-2:

Ms m/z(ESI):413.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.84(dd,1H),8.54(t,1H),8.11(d,1H),7.99-7.92(m,1H),7.47(d,1H),7.01(d,1H),4.20(s,2H),3.89(s,3H),3.76(dd,1H),3.64-3.56(m,1H),2.95-2.88(m,1H),2.81-2.61(m,4H),2.40-2.26(m,3H),1.85-1.51(m,9H),1.35-1.28(m,1H).

example 55

N- ((3-Methylthioen-2-yl) methyl) -2- ((1r, 1aR,1a1r, 5aS) -1- (pyridin-2-yloctahydro 1H-cyclobutyl [ cd ] pent-1-yl) ethylamine hydrochloride (Compound 55)

N-((3-methoxythiophen-2-yl)methyl)-2-((1r,1aR,1a1r,5aS)-1-(pyridin-2-yl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)ethanamine hydrochloride

The first step is as follows: (E/Z) -methyl 2-cyano-2- ((1aR, 1a1S, 5aS) -octahydro-1H-cyclobutyl [ cd ] pentan-1-ylidene) carboxylate (55B)

(E/Z)-methyl2-cyano-2-((1aR,1a1S,5aS)-octahydro-1H-cyclobuta[cd]pentalen-1-ylidene)acetate

(1aR, 1a1r, 5aS) -octahydro-1H-cyclobutylpentan-1-one (55A) (0.6 g,4.0 mmol), methyl cyanoacetate (0.4 g,4.0 mmol), ammonium acetate (0.3 g,4.0 mmol), acetic acid (0.3 g, 5.1mmol) and toluene (50 mL) were added to a reaction flask, and the reaction was warmed to reflux for 16 hours. After cooling, a sodium hydrogencarbonate solution (50 mL) was added to the reaction solution, aqueous ethyl acetate (30 mL × 3) was extracted, the organic phases were combined, washed with a saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 100.

Ms m/z(ESI):218.2[M+H ⁺ ]；

The second step is that: (2R) -methyl 2-cyano-2- ((1r, 1aR,1a1R, 5aS) -1- (pyridin-2-yl) octahydro-1H-cyclobutyl [ cd ] pentanyl-1-yl) carboxylate (55C)

(2R)-methyl2-cyano-2-((1r,1aR,1a1R,5aS)-1-(pyridin-2-yl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate

Isopropyl magnesium chloride (3.0mL, 6.0mmol) was added into a reaction flask under the protection of nitrogen, the temperature was reduced to 0 ℃, a tetrahydrofuran (10 mL) solution of 2-bromopyridine (0.71g, 6.0mmol) was added dropwise to the reaction, after reaction at room temperature for 3 hours, cuprous iodide (0.05g, 0.05mmol) was added to the reaction, and the reaction was stirred for 0.5 hours, and then a tetrahydrofuran (10 mL) solution of (E/Z) -methyl 2-cyano-2- ((1aR, 1a1S, 5aS) -octahydro-1H-cyclobutyl [ cd ] pentylene-1-ylidene) carboxylate (55B) (0.65g, 3.0mmol) was added to the reaction solution, and reacted at 50 ℃ to 55 ℃ for 8 hours. The reaction mixture was added with ice water (20 mL) and 1N hydrochloric acid (10 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated aqueous solution of brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 80.

Ms m/z(ESI):297.1[M+H ⁺ ]；

The third step: 2- ((1r, 1aR,1a1r, 5aS) -1- (pyridin-2-yloctahydro-1H-cyclobutyl [ cd ] pentanyl-1-yl) acetonitrile (55D)

2-((1r,1aR,1a1r,5aS)-1-(pyridin-2-yl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetonitrile

Ethylene glycol (10 mL) was added to (2R) -methyl 2-cyano-2- ((1r, 1aR,1a1R, 5aS) -1- (pyridin-2-yl) octahydro-1H-cyclobutyl [ cd ] pentanyl-1-yl) carboxylic acid ester (55C) (0.4g, 1.35mmol), potassium hydroxide (0.2g, 0.27mmol) was further added thereto, and the mixture was heated to 120 ℃ for reaction at 3 hours. The reaction solution was cooled, water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL × 4), the organic phases were combined, washed with sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 1) to give 2- ((1r, 1ar,1a1r, 5as) -1- (pyridin-2-yl octahydro 1H-cyclobutyl [ cd ] pentyl-1-yl) acetonitrile (55D) as a yellow oily liquid (0.2 g, yield: 62.2%).

Ms m/z(ESI):239.1[M+H ⁺ ]；

The fourth step: 2- ((1r, 1aR,1a1r, 5aS) -1- (pyridin-2-yloctahydro-1H-cyclobutyl [ cd ] pentanyl-1-yl) ethylamine (55E)

2-((1r,1aR,1a1r,5aS)-1-(pyridin-2-yl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)ethanamine

Lithium aluminum hydride (0.1g, 3.0mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 ℃ and 2- ((1r, 1aR,1a1r, 5aS) -1- (pyridin-2-yloctahydro 1H-cyclobutyl [ cd ] pentyl-1-yl) acetonitrile (55D) (0.2 g, 0.8mmol) in tetrahydrofuran (5 mL) was added to the reaction, and the reaction was allowed to complete overnight at room temperature, cooled to 0 ℃, quenched with water (0.2 mL), sodium hydroxide solution (10%, 0.6 mL) and water (0.4 mL), dried by adding anhydrous sodium sulfate, stirred for 20 minutes, the solid was filtered and washed with tetrahydrofuran (20 mL. Times.3). The combined organic phases were concentrated to give 2- ((1r, 1aR, 1a1a1aR, 5aS) -1- (pyridin-2-yloctahydro 1H-cyclobutyl [ cd ] pentyl-1-yl) ethylamine (55 g, 100: 242%) as an oil.

Ms m/z(ESI):243.2[M+H ⁺ ]；

The fifth step: n- ((3-Methylthioen-2-yl) methyl) -2- ((1r, 1aR,1a1r, 5aS) -1- (pyridin-2-yloctahydro-1H-cyclobutyl [ cd ] pent-anyl-1-yl) ethanamine (55F)

N-((3-methoxythiophen-2-yl)methyl)-2-((1r,1aR,1a1r,5aS)-1-(pyridin-2-yl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)ethanamine

2- (9- (pyridin-2-yl) -2, 6-dioxaspiro [4.5] decan-9-yl) ethylamine (55E) (0.22g, 0.91mmol) was dissolved in methylene chloride (15 mL), and sodium sulfate 0.5 g) and 3-methoxythiophene-2-carboxaldehyde (0.13g, 0.91mmol) were added to the reaction, and reacted at room temperature overnight. Sodium borohydride (0.045g, 1.3 mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (5 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after column chromatography of the crude product with column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):369.2[M+H ⁺ ]；

And a sixth step: n- ((3-Methylthioen-2-yl) methyl) -2- ((1r, 1aR,1a1r, 5aS) -1- (pyridin-2-yloctahydro 1H-cyclobutyl [ cd ] pent-1-yl) ethylamine hydrochloride (Compound 55)

N- ((3-Methylthioen-2-yl) methyl) -2- ((1r, 1aR,1a1r, 5aS) -1- (pyridin-2-yloctahydro 1H-cyclobutyl [ cd ] pent-1-yl) ethylamine (55F) (0.10g, 0.3mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir at room temperature for 0.5 hour, and the reaction mixture was directly spin-dried to obtain N- ((3-Methylthion-2-yl) methyl) -2- ((1r, 1a1r, 5aS) -1- (pyridin-2-yloctahydro 1H-cyclobutyl [ cd ] pent-1-yl) ethylamine hydrochloride (compound 55) (0.10 g, yield 90%).

Ms m/z(ESI):369.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.83-8.82(d,1H),8.59(m,1H),8.21-8.19(d,1H),7.98-7.96(m,1H),7.47-7.46(d,1H),7.09-6.96(d,1H),4.18(s,2H),3.88(s,3H),3.12(m,2H),2.98-2.96(m,1H),2.60-2.55(m,1H),2.54-2.53(m,2H),2.20-1.96(m,2H),1.92-1.87(m,6H),1.69-1.66(m,2H).

Example 57

(R) -N- ((2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl) acetamide hydrochloride (Compound 57)

(R)-N-((2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methyl)acetamide hydrochloride

The first step is as follows: 3- (bromomethyl) thiophene (57B)

3-(bromomethyl)thiophene

Thiophen-3-ylcarbinol (28A) (3g, 43mmol) was dissolved in hydrobromic acid (40ml, 48%), reacted for 3h, cooled, added with water (50 mL), extracted with dichloromethane (50 mL × 4), washed with saturated saline solution (150 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography for purification (n-hexane/ethyl acetate =10: 1) to give 3- (bromomethyl) thiophene 57B (3 g, yield 70%

¹ H NMR(400MHz,CDCl ₃ ):δ7.32–7.28(m,2H),7.12–7.11(m,1H),4.61(s,2H).

The second step is that: 3- (Azidomethyl) thiophene (57C)

3-(azidomethyl)thiophene

3- (bromomethyl) thiophene 57B (3 g, 22.63mmol) was dissolved in DMF (20 mL), sodium azide (2.2 g,33.9 mmol) was added, and the reaction was continued at 60 ℃ for 5h after the addition was complete. Water (100 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with a saturated saline solution (30 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3- (azidomethyl) thiophene 57C (3 g, 96% yield) as a yellow oil, which was directly charged to the next step.

¹ H NMR(400MHz,CDCl ₃ ):δ7.32–7.28(m,2H),7.12–7.11(m,1H),4.34(s,2H)

The third step: thiophene-3-ylmethylamines (57D)

thiophen-3-ylmethanamine

3- (azidomethyl) thiophene 57C (3g, 21.55mmol) was dissolved in methanol (40 ml), pd/C (10%) was added, reacted for 2h under an atmosphere of hydrogen balloon, filtered, the filtrate was concentrated, and purified by column chromatography (CH 2Cl2/MeOH = 10).

¹ H NMR(400MHz,CDCl ₃ ):δ7.32–7.25(m,2H),7.12–7.10(m,1H),3.89(s,2H)

The fourth step: n- (thien-3-ylmethyl) acetamide (57E)

N-(thiophen-3-ylmethyl)acetamide

Thiophene-3-ylmethylamine 57D (1.3 g, 11mmol) was dissolved in dichloromethane (20 mL) at room temperature, triethylamine (2.3 g, 23mmol) and acetyl chloride (1.4g, 17mmol) were sequentially added at 0 ℃, the reaction was continued for 2h, 20mL of water was added to the reaction solution, dichloromethane (20 mL × 3) was extracted, the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, the filtrate was concentrated, and purified by column chromatography (CH 2Cl2/MeOH = 10) to give N- (thiophene-3-ylmethyl) acetamide 57E (1.4g, 80%

¹ H NMR(400MHz,CDCl ₃ ):δ7.30–7.28(m,1H),7.15(s,1H),7.02(d,1H),5.96(br,1H),4.44(d,2H),2.01(s,3H)

The fifth step: n- ((2-Formylthiophen-3-yl) methyl) acetamide (57F)

N-((2-formylthiophen-3-yl)methyl)acetamide

N- (thien-3-ylmethyl) acetamide 57E (0.4g, 2.2mmol) was dissolved in tetrahydrofuran (10 mL), the reaction was cooled to-78 ℃ and N-butyllithium (1.3mL, 3.1mmol) was added, after completion of addition, the reaction was raised to zero for 0.5h, and DMF (0.21g, 3mmol) was added and the reaction was continued for 2h. Ammonium chloride water (20 mL) was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography for purification (N-hexane/ethyl acetate =5: 1) to obtain N- ((2-formylthiophen-3-yl) methyl) acetamide 57F as a yellow oil (0.2 g, yield 73%).

¹ H NMR(400MHz,CDCl ₃ ):δ9.97(s,1H),7.70–7.69(d,1H),7.21-7.20(d,1H),6.43(br,1H),4.67(d,2H),2.01(s,3H)

And a sixth step: (R) -N- ((2- (((2- (9- (pyridin-2-yl) -6-Oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl) acetamide (57G)

(R)-N-((2-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)amino)methyl)thiophen-3-yl)methyl)acetamide

N- ((2-formylthiophen-3-yl) methyl) acetamide 57F (0.2g, 1mmol) was dissolved in methylene chloride (10 ml), and (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine intermediate 1 (0.39g, 1.5 mmol), anhydrous sodium sulfate (1.31 g) were successively added thereto. After an overnight reaction at room temperature, sodium borohydride (0.065g, 1.73mmol) was added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography purification (dichloromethane/methanol =5 1) was performed to obtain (R) -N- ((2- (((2- (9- (pyridin-2-yl) -6-oxospiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl) acetamide 57G (0.2g, 40%) as a yellow oil.

Ms m/z(ESI):428.2[M+H ⁺ ]。

The seventh step: (R) -N- ((2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl) acetamide hydrochloride (Compound 57)

(R) -N- ((2- (((2- (9- (pyridin-2-yl) -6-Oxospiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl) acetamide 57G (0.16g, 0.37mmol) was dissolved in ethyl acetate (5 mL) at room temperature, ethyl hydrogen chloride in ethyl acetate (2mL, 4N) at 0 deg.C, after completion of the addition, the reaction was continued for 0.5h, and the solvent was removed under reduced pressure to give N- ((2- (((2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) amino) methyl) thiophen-3-yl) methyl) acetamide hydrochloride (Compound 57) (0.16g, 96%)

Ms m/z(ESI):428.2[M+H ⁺ ]

¹ H NMR(400MHz,CD ₃ OD):δ8.88(dd,1H),8.66(s,1H),8.22(d,1H),8.06(s,1H),7.49(d,1H),7.03(d,1H),4.41(s,2H),4.24(s,2H),3.85(m,1H),3.74(m,1H),3.09(td,1H),2.64(td,1H),2.47(d,2H),2.23(m,2H),2.20(d,1H),1.91(s,3H),1.61(m,5H),1.24(t,2H)。

Example 58

(R) -N- ((3- (Cyclopropyloxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 58)

(R)-N-((3-(cyclopropoxymethyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 3- (bromomethyl) thiophene (58B)

3-(bromomethyl)thiophene

Thiophen-3-ylcarbinol (3g, 43mmol) was dissolved in hydrobromic acid (40ml, 48%) and reacted for 3h, cooled, water (50 mL) was added, extracted with dichloromethane (50 mL × 4), washed with saturated aqueous sodium chloride solution (150 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and purified by column chromatography (n-hexane/ethyl acetate =10: 1) to give 3- (bromomethyl) thiophene (58B) as a colorless liquid (3 g, yield 70%).

¹ H NMR(400MHz,CDCl ₃ ):δ7.32–7.28(m,2H),7.12–7.11(m,1H),4.61(s,2H).

The second step is that: 2- (Thien-3-ylmethoxy) ethanol (58C)

2-(thiophen-3-ylmethoxy)ethanol

3- (bromomethyl) thiophene 58B (3g, 22.63mmol) was dissolved in DMF (20 mL), and sodium hydride (0.6 g, 25mmol), ethylene glycol (1.58g, 25mmol), tetrabutylammonium bromide (0.06g, 0.17mmol) were added in that order, and after the addition, the reaction was continued at room temperature for 15 hours. Water (100 mL) was added, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (petroleum ether/ethyl acetate (V/V) = 3) was performed to obtain 2- (thiophen-3-ylmethoxy) ethanol 58C (2 g, yield 40%) as a colorless liquid.

¹ H NMR(400MHz,CDCl ₃ ):δ7.32–7.26(m,1H),7.23–7.22(m,1H),7.09–7.07(m,1H),4.57(s,2H)，3.76–3.74(q,2H),3.60–3.58(q,2H).

The third step: 3- ((2-Bromoethoxy) methyl) thiophene (58D)

3-((2-bromoethoxy)methyl)thiophene

Dissolving 2- (thiophen-3-ylmethoxy) ethanol 58C (3.4g, 21mmol) in tetrahydrofuran (40 mL), adding carbon tetrabromide (14g, 43mmol), adding triphenylphosphine (11g, 43mmol) dropwise at zero degrees, reacting at room temperature for 2h, filtering, washing the filter cake with petroleum ether (20 mL), concentrating the organic solvent, and performing column chromatography petroleum ether/ethyl acetate (V/V) =50: 1) Yellow liquid 3- ((2-bromoethoxy) methyl) thiophene 58D (4.7 g, 100% yield) was obtained.

¹ H NMR(400MHz,CDCl ₃ ):δ7.32–7.26(m,1H),7.24–7.23(m,1H),7.10–7.08(m,1H),4.60(s,2H)，3.79–3.76(t,2H),3.49–3.46(t,2H).

The fourth step: 3- ((vinyloxy) methyl) thiophene (58E)

3-((vinyloxy)methyl)thiophene

Dissolving 3- ((2-bromoethoxy) methyl) thiophene 58D (4.7g, 21mmol) in tetrahydrofuran (20 mL) at room temperature, adding potassium tert-butoxide (4.8g, 43mmol) at 0 ℃, continuing to react for 2h at room temperature after the addition is finished, adding water (40 mL) into the reaction liquid, extracting with ethyl acetate (20 mL x 3), combining organic phases, washing with saturated saline solution (30 mL x 1), drying with anhydrous sodium sulfate, concentrating the filtrate, and separating and purifying by column chromatography (100% petroleum ether) to obtain a light yellow liquid product, namely 3- ((vinyloxy) methyl) thiophene (58E) (2.2g, 60%).

¹ H NMR(400MHz,CDCl ₃ ):δ7.33–7.31(m,1H),7.09(t,1H),6.55(q,1H),4.77(s,2H)，4.31–4.28(t,1H),4.09–4.07(q,1H).

The fifth step: 3- (Cyclopropyloxymethyl) thiophene (58F)

3-(cyclopropoxymethyl)thiophene

3- ((vinyloxy) methyl) thiophene (58E) (1.6 g, 13mmol) was dissolved in dichloromethane (30 mL), diiodomethane (7g, 26mmol) was added, diethyl zinc (3.2g, 26mmol) was added dropwise at zero degrees, and after completion of addition, the reaction was carried out at room temperature for 5 hours. Ammonium chloride solution (15 mL) was added, and extraction was performed with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography for purification (n-hexane/ethyl acetate =20 = 1) to obtain 3- (cyclopropyloxymethyl) thiophene (58F) (0.9 g, yield 73%) as a pale yellow liquid product.

¹ H NMR(400MHz,CDCl ₃ ):δ9.97(s,1H),7.30–7.26(m,1H),7.22(q,1H),7.08-7.07(m,1H),4.65(s,2H),3.36–3.32(m,1H),0.65–0.61(m,2H),0.50–0.45(m,2H).

And a sixth step: 3- (Cyclopropyloxymethyl) thiophene-2-aldehyde (58G)

3-(cyclopropoxymethyl)thiophene-2-carbaldehyde

3- (Cyclopropyloxymethyl) thiophene (58F) (0.4g, 3mmol) was dissolved in tetrahydrofuran (15 mL), added and the reaction was cooled to-78 deg.C, n-butyllithium (1.2mL, 3mmol) was added, the reaction was raised to zero for 0.5h, dimethylformamide (0.3g, 4mmol) was added and the reaction was continued for 2h. Ammonium chloride water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to column chromatography separation and purification (n-hexane/ethyl acetate =30: 1) to obtain a pale yellow liquid product, 3- (cyclopropyloxymethyl) thiophene-2-aldehyde (58G) (0.2G, 50% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ10.10(d,1H),7.67(d,1H),7.26(t,1H),4.87(s,2H),3.41-3.38(m,1H),0.66-0.55(m,1H),0.54-0.52(m,1H).

The seventh step: (R) -N- ((3- (Cyclopropyloxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (58H)

(R)-N-((3-(cyclopropoxymethyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

3- (Cyclopropoxymethyl) thiophene-2-aldehyde 58G (0.2g, 1mmol) was dissolved in dichloromethane (10 ml), and (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.3g, 1mmol), anhydrous sodium sulfate (1.31G) was added thereto in this order. After reacting overnight at room temperature, sodium borohydride (0.060g, 2mmol) was added, stirring was continued for 2H, water (20 mL) was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (dichloromethane/methanol =15: 1) to obtain (R) -N- ((3- (cyclopropyloxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine (58H) (0.18g, 46%)

Ms m/z(ESI):427.2[M+H ⁺ ]

The eighth step: (R) -N- ((3- (Cyclopropyloxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine hydrochloride (Compound 58)

(R) -N- ((3- (Cyclopropoxymethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine (58H) (0.18g, 0.42mmol) was dissolved in ethyl acetate (5 mL) and after addition of ethyl hydrogen chloride solution (2mL, 4N) at 0 ℃ for 0.5H, the solvent was removed under reduced pressure to give (R) -N- ((3- (cyclopropylmethyl) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] sunflower-9-yl) ethylamine hydrochloride (compound 58) (0.1g, 96%) as a white solid.

Ms m/z(ESI):427.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.86(d,1H),8.57(m,2H),8.14(d,1H),7.49(d,1H),7.04(d,1H),4.63(s,2H),4.36(s,2H),3.84(m,1H),3.73(ddd,1H),3.43(m,1H),3.07(m,1H),2.53(m,2H),2.31(m,1H),2.18(m,2H),1.60(m,5H),1.23(m,1H),0.60(m,2H),0.53(m,2H).

Example 59

N- ((3-Methoxythien-2-yl) methyl) -2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentan-6-yl) ethylamine hydrochloride (Compound 59)

N-((3-methoxythiophen-2-yl)methyl)-2-(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentan]-6-yl)ethanamine hydrochloride

The first step is as follows: 1- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) cyclopentanol (59B)

1-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)cyclopentanol

Under the protection of nitrogen, 2- (2-propargyloxy) tetrahydropyran (1 a) (30g, 214mmol) is dissolved in tetrahydrofuran (150 mL), the temperature is reduced to-78 ℃, n-butyl lithium (103mL, 257mmol) is added into the reaction dropwise, after the addition is finished, the reaction is carried out for 0.5 hour, cyclopentanone (19g, 225mmol) is added into the reaction dropwise, and the reaction is continued for 2 hours after the temperature is raised to room temperature. The reaction solution was quenched with a saturated ammonium chloride solution (80 mL), separated, the aqueous phase was extracted with ethyl acetate (80 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) cyclopentanol (59B) (50 g, yield: 95%) as an oily liquid.

The second step is that: 1- (3-hydroxypropan-1-yn-1-yl) cyclopentanol (59C)

1-(3-hydroxyprop-1-yn-1-yl)cyclopentanol

1- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) cyclopentanol (59B) (50g, 223mmol) was dissolved in methanol (150 mL), cooled to 0 deg.C, and concentrated hydrochloric acid (1.9 mL, 23mmol) was added dropwise and reacted at room temperature for 2 hours. To the reaction was added saturated sodium bicarbonate solution to adjust PH ≈ 7, most of methanol was removed, water (80 mL) was added, the aqueous phase was extracted with ethyl acetate (80 mL × 4), the organic phases were combined, washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10) to obtain 1- (3-hydroxypropan-1-yn-1-yl) cyclopentanol (59C) as an oily liquid (30 g, yield: 96%).

¹ H NMR(400MHz,CDCl ₃ )δ4.31(s,2H),2.18(s,2H),2.03-1.87(m,4H),1.88-1.66(m,4H).

The third step: 1- (3-hydroxypropan-1-en-1-yl) cyclopentanol (59D)

1-(3-hydroxyprop-1-en-1-yl)cyclopentanol

1- (3-hydroxyprop-1-yn-1-yl) cyclopentanol (59C) (30g, 214mmol) was dissolved in ethyl acetate (120 mL) and quinoline (120 mL), and lindlar palladium (3g, 5% by weight) was added, and the mixture was replaced with hydrogen three times, and stirred under a hydrogen balloon at room temperature overnight for reaction. Suction filtering the reaction pad with diatomite, washing the filter cake with ethyl acetate (30 mL multiplied by 2), concentrating the filtrate to remove the ethyl acetate, and dissolving the product 1- (3-hydroxypropane-1-en-1-yl) cyclopentanol (59D) in quinoline to directly carry out the next reaction.

¹ H NMR(400MHz,CDCl ₃ )δ5.73-5.61(m,2H),4.34(d,2H),1.97-1.79(m,6H),1.77-1.63(m,4H).

The fourth step: 1-oxaspiro [4.4] non-3-ene (59E)

1-oxaspiro[4.4]non-3-ene

1- (3-hydroxyprop-1-en-1-yl) cyclopentanol (59D) (20g, 140.6 mmol) was dissolved in quinoline (160 mL), and cooled to 0 ℃ to add p-toluenesulfonyl chloride (35g, 183mmol) to the reaction in portions, and reacted at room temperature overnight. The reaction solution was directly distilled under reduced pressure, heated to 100-110 ℃ in an oil bath, and the collected fraction was subjected to oil-bath heating to give 1-oxaspiro [4.4] non-3-ene (59E) (10.0 g, yield: 57%) as a colorless liquid product.

¹ H NMR(400MHz,CDCl ₃ )δ5.86-5.76(m,1H),5.73(dt,1H),4.59(dd,2H),1.84-1.74(m,4H),1.69-1.60(m,4H).

The fifth step: ethyl 3-oxaspiro [ bicyclo [3.1.0] hexane-2, 1' -cyclopentane ] -6-carboxylic acid ethyl ester (59F)

ethyl 3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentane]-6-carboxylate

1-oxaspiro [4.4] non-3-ene (59E) (5g, 40.3 mmol) was dissolved in toluene (40 mL) under nitrogen protection, copper sulfate (0.64g, 4.03mmol) was added thereto, the temperature was raised to 100 ℃ and ethyl diazoacetate (9.2g, 80.6 mmol) was dissolved in toluene (20 mL) and slowly dropped (about 7 hours) into the reaction with a syringe pump, and the reaction was continued at 100 ℃ for 1 hour. After cooling, the reaction solution was filtered and the organic phase was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 30.

Ms m/z(ESI):211.1[M+H ⁺ ]；

And a sixth step: 3-oxaspiro [ bicyclo [3.1.0] hexane-2, 1' -cyclopentane ] -6-carboxamide (59G)

3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentane]-6-carboxamide

Ethyl 3-oxaspiro [ bicyclo [3.1.0] hexane-2, 1' -cyclopentane ] -6-carboxylate (59F) (3.6 g, 17.1mmol) was dissolved in formamide (40 mL), and sodium methoxide (2.3 g,42.8 mmol) was added to the reaction, and the temperature was raised to 60 ℃ for reaction for 3 hours. After cooling, a saturated ammonium chloride solution (80 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (40 mL. Times.5), the organic phases were combined, washed with a saturated sodium chloride solution (40 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give yellow 3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carboxamide (59G) (2.0G, yield: 64.5%).

Ms m/z(ESI):182.1[M+H ⁺ ]；

The seventh step: 3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carbonitrile (59H)

3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentane]-6-carbonitrile

3-Oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carboxamide (59G) (2.0G, 11.0 mmol) was dissolved in dichloromethane (40 mL), triethylamine (2.8g, 27.6 mmol) was added to the reaction, it was cooled to 0 ℃ and the compound trifluoroacetic anhydride (3.0G, 14.3 mmol) was added dropwise to the reaction and reacted at room temperature for 3 hours. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 10).

Ms m/z(ESI):164.1[M+H ⁺ ]；

Eighth step: 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2,1' -cyclopentane ] -6-carbonitrile (59I)

6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentane]-6-carbonitrile

Under nitrogen protection, 3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carbonitrile (59H) (1.50g, 9.19mmol) and 2-fluoropyridine (1.07g, 11.0mmol) were dissolved in toluene (20 mL), cooled to 0 ℃ and bis (trimethylsilyl) amino potassium (11.0mL, 11.0mmol) was added dropwise to the reaction, and the reaction was allowed to proceed overnight at room temperature. To the reaction solution was added a saturated ammonium chloride solution (30 mL), the separated aqueous phase was extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with a saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 5).

Ms m/z(ESI):241.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.47(ddd,1H),7.80(dt,1H),7.71(td,1H),7.18(ddd,1H),4.26(d,1H),4.13-4.01(m,1H),2.67(d,2H),2.30-2.20(m,1H),2.04-1.95(m,1H),1.89-1.57(m,6H).

The ninth step: 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2,1'-cyclopentane ] -6-carboxamide (59J) 6- (pyridin-2-yl) -3-oxapiro [ bicyclo [3.1.0] hexane-2,1' -cyclopentane ] -6-carboxamide

6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carbonitrile (59I) (0.50g, 2.08mmol) was dissolved in sodium hydroxide solution (25% aq.,10 mL) and ethylene glycol (10 mL), and reacted for 12 hours with warming to 150 ℃. Cooling, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with a saturated saline solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 1 to 20) to give 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carboxamide (59J) (0.45 g, yield: 84%) as a white solid.

Ms m/z(ESI):259.1[M+H ⁺ ]；

The tenth step: 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2,1'-cyclopentane ] -6-carboxylic acid (59K) 6- (pyridin-2-yl) -3-oxapiro [ bicyclo [3.1.0] hexane-2,1' -cyclopentane ] -6-carboxylic acid

6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carboxamide (59J) (0.35g, 1.36mmol) was dissolved in acetic acid (3 mL) and acetic anhydride (6 mL) under nitrogen protection, and sodium nitrite (0.94g, 13.6 mmol) was added to the reaction, followed by stirring at room temperature overnight. Water (20 mL) and a 1M hydrochloric acid solution (10 mL) were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2,1' -cyclopentane ] -6-carboxylic acid (59K) (0.30 g, yield: 85.4%) as an oily liquid.

Ms m/z(ESI):260.1[M+H ⁺ ]；

The eleventh step: 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2,1' -cyclopentane ] -6-carboxylic acid methyl ester (59L)

Methyl6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentane]-6-carboxylate

6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentane ] -6-carboxylic acid (59K) (0.30g, 1.16mmol) was dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (0.32g, 2.31mmol) and iodomethane (0.25g, 1.74mmol) were added to the reaction solution and reacted at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated saline solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5) to give methyl 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carboxylate (59L) (0.30 g, yield: 95%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ8.49(ddd,1H),7.59(td,1H),7.19(d,1H),7.11(ddd,1H),4.23(d,1H),3.87-3.69(m,4H),2.39(d,1H),2.26(dd,1H),2.19-2.12(m,1H),1.91-1.69(m,3H),1.70-1.54(m,4H).

The twelfth step: (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2, 1' -cyclopentan-6-yl) methanol (59M)

(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentan]-6-yl)methanol

Lithium aluminum hydride (0.11g, 2.93mmol) was dissolved in tetrahydrofuran (10 mL), and cooled to 0 ℃ to add 6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentane ] -6-carboxylic acid methyl ester (59L) (0.4g, 1.46mmol) in tetrahydrofuran (5 mL) for reaction overnight at room temperature. The reaction solution was quenched with water (0.11 mL), sodium hydroxide solution (10% aq.,0.22 mL) and water (0.33 mL) in this order, dried by adding anhydrous sodium sulfate, stirred for 20 minutes, filtered, and the filter cake was washed with tetrahydrofuran (10 mL × 3). The organic phase was concentrated to give (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentan-6-yl) methanol (59M) (0.30 g, yield: 83.6%).

Ms m/z(ESI):246.2[M+H ⁺ ]；

The thirteenth step: (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentan-6-yl) methanesulfonic acid methyl ester (59N)

(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentan]-6-yl)methylmethanesulfonate

(6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentan-6-yl) methanol (59M) (0.30g, 1.22mmol) and triethylamine (0.18g, 1.83mmol) were dissolved in dichloromethane (15 mL), cooled to 0 ℃ and methanesulfonyl chloride (0.17g, 1.47mmol) was added dropwise to the reaction and reacted at room temperature for 4 hours. The reaction solution was quenched with water (20 mL), separated, the aqueous phase was extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give methyl (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentan-6-yl) methanesulfonate (59N) (0.39 g, yield: 99%) as a yellow oily liquid.

The fourteenth step is that: 2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentan-6-yl) acetonitrile (59O)

2-(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentan]-6-yl)acetonitrile

Methyl (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentan-6-yl) methanesulfonate (59N) (0.39g, 1.2mmol) was dissolved in N, N-dimethylformamide (10 mL), and potassium cyanide (0.16g, 2.4mmol) was added thereto, followed by reaction at 140 ℃ for 6 hours. To the reaction solution was added water (50 mL), the aqueous phase was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with a saturated saline solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =1 to 3) to obtain 2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentan-6-yl) acetonitrile (59O) (0.07 g, yield: 20%) as an oily liquid.

Ms m/z(ESI):255.1[M+H ⁺ ]；

The fifteenth step: 2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2, 1' -cyclopentan-6-yl) ethylamine (59P)

2-(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentan]-6-yl)ethanamine

Lithium aluminum hydride (0.021g, 0.55mmol) was dissolved in tetrahydrofuran (6 mL), and the temperature was lowered to 0 ℃ to add 2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentan-6-yl) acetonitrile (59O) (0.07g, 0.28mmol) in tetrahydrofuran (2 mL) to react overnight at room temperature. The reaction solution was cooled to 0 ℃, quenched with water (0.02 mL), sodium hydroxide solution (10% aq.,0.04 mL) and water (0.06 mL) in this order, dried by adding anhydrous sodium sulfate, stirred for 20 minutes, filtered, and the filter cake was washed with tetrahydrofuran (10 mL × 2). The combined organic phases were concentrated to give 2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentan-6-yl) ethylamine (59P) (0.07 g, yield: 100%).

Ms m/z(ESI):259.1[M+H ⁺ ]；

Sixteenth, step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2, 1' -cyclopentan-6-yl) ethylamine (59R)

N-((3-methoxythiophen-2-yl)methyl)-2-(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]hexane-2,1'-cyclopentan]-6-yl)ethanamine

2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] n-hexane-2, 1' -cyclopentan-6-yl) ethanamine (59P) (0.07g, 0.27mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.19g, 1.4mmol) and 3-methoxythiophene-2-carbaldehyde (0.077g, 0.54mmol) were added to the reaction and allowed to react at room temperature overnight. Sodium borohydride (0.015g, 0.41mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (5 mL) and stirring for 1 hour. The reaction was quenched with water (20 mL), the aqueous phase was extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude N- ((3-methoxythiophen-2-yl) methyl) -2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentan-6-yl) ethylamine (59R) (0.023 g, yield: 22%) as a yellow oily liquid by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):385.2[M+H ⁺ ]；

Seventeenth step: n- ((3-Methoxythien-2-yl) methyl) -2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] hexane-2, 1' -cyclopentan-6-yl) ethylamine hydrochloride (Compound 59)

N- ((3-Methoxythien-2-yl) methyl) -2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentan-6-yl) ethylamine (59R) (0.023g, 0.06mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to obtain N- ((3-methoxythiophen-2-yl) methyl) -2- (6- (pyridin-2-yl) -3-oxaspiro [ bicyclo [3.1.0] N-hexane-2, 1' -cyclopentan-6-yl) ethylamine hydrochloride (compound 59) (0.025 g, yield: 99%) as a gray solid.

Ms m/z(ESI):385.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.79(dd,1H),8.57(td,1H),8.05-7.97(m,2H),7.47(d,1H),7.01(d,1H),4.23(s,2H),4.11(d,1H),4.05(dd,1H),3.88(s,3H),3.04-2.86(m,2H),2.66-2.40(m,3H),2.23-2.10(m,2H),1.93-1.72(m,4H),1.71-1.60(m,3H).

Example 60

(R) -N- ((4-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (Compound 60)

(R)-N-((4-ethynyl-3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine 4-methylbenzenesulfonate

The first step is as follows: 4-bromo-3-hydroxythiophene-2-carboxylic acid methyl ester (60B)

methyl 4-bromo-3-hydroxythiophene-2-carboxylate

Methyl 3-hydroxythiophene-2-carboxylate (60A) (5 g,31.6 mmol) was dissolved in acetic acid (30 mL) under nitrogen, and bromine (10.1g, 63.2mmol) was added dropwise to the reaction, after which the reaction was allowed to proceed overnight at room temperature. To the reaction solution was added a saturated sodium hydrogen sulfite solution (50 mL), the aqueous phase was extracted with methyl t-butyl ether (30 mL. Times.3), the combined organic phases were washed with a saturated sodium hydrogen carbonate solution (30 mL. Times.2) and a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and after the crude product was recrystallized from methanol, a white solid methyl 4-bromo-3-hydroxythiophene-2-carboxylate (60B) (3.0 g, yield: 40%) was obtained.

¹ H NMR(400MHz,CDCl ₃ )δ9.73(s,1H),7.37(s,1H),3.92(s,3H).

The second step is that: 4-bromo-3-methoxythiophene-2-carboxylic acid methyl ester (60C)

methyl 4-bromo-3-methoxythiophene-2-carboxylate

Methyl 4-bromo-3-hydroxythiophene-2-carboxylate (60B) (3.0g, 12.7mmol) was dissolved in N, N-dimethylformamide (30 mL), and potassium carbonate (3.55g, 25.3mmol) and iodomethane (2.69g, 19.0mmol) were added thereto, and the reaction was completed at 60 ℃ for 2 hours. After cooling, water (60 mL) was added to the reaction mixture, and the solid product was washed out, filtered, and the filter cake was washed with water (20 mL. Times.3) to obtain methyl 4-bromo-3-methoxythiophene-2-carboxylate (60C) (2.85 g, yield: 89.7%) as a white solid after drying.

¹ H NMR(400MHz,CDCl ₃ )δ7.38(s,1H),4.02(s,3H),3.88(s,3H).

The third step: 3-methoxy-4- ((trimethylsilyl) ethynyl) thiophene-2-carboxylic acid methyl ester (60D)

methyl 3-methoxy-4-((trimethylsilyl)ethynyl)thiophene-2-carboxylate

Methyl 4-bromo-3-methoxythiophene-2-carboxylate (60℃) (2.85g, 11.4 mmol) and trimethylsilyne (2.23g, 22.7 mmol) were dissolved in tetrahydrofuran (15 mL) and triethylamine (15 mL), and bis (triphenylphosphine) palladium (II) dichloride (0.398g, 0.57mmol) and cuprous iodide (0.216g, 1.14mmol) were added to the reaction under nitrogen and the temperature was raised to 60 ℃ for 12 hours. The reaction solution was filtered, and the organic phase was directly concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 50.

Ms m/z(ESI):269.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ7.50(s,1H),4.13(s,3H),3.85(s,3H),0.24(m,9H).

The fourth step: (3-methoxy-4- ((trimethylsilyl) ethynyl) thiophen-2-yl) methanol (60E) (3-methoxy-4- ((trimethylsilyl) ethyl) thiophen-2-yl) methanol

Lithium aluminum hydride (0.66g, 17.47mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0 deg.C, and a solution of methyl 3-methoxy-4- ((trimethylsilyl) ethynyl) thiophene-2-carboxylate (60D) (2.8g, 11.65mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction and allowed to react at room temperature for 2 hours. The reaction was cooled to 0 ℃, and the reaction was quenched with water (0.66 mL), sodium hydroxide solution (10% aq.,1.3 mL) and water (1.3 mL) in this order, and then dried over anhydrous sodium sulfate, filtered, the solid was washed with tetrahydrofuran (20 mL × 2), and the combined organic phases were concentrated to give (3-methoxy-4- ((trimethylsilyl) ethynyl) thiophen-2-yl) methanol (60E) (2.4 g, yield: 85.7%) as an oily liquid.

Ms m/z(ESI):263.1[M+Na ⁺ ]；

The fifth step: 3-methoxy-4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (60F) 3-methoxy-4- ((trimethylsilyl) ethyl) thiophene-2-carbaldehyde

(3-methoxy-4- ((trimethylsilyl) ethynyl) thiophen-2-yl) methanol (60E) (2.4 g, 9.98mmol) was dissolved in dichloromethane (50 mL), cooled to 0 ℃ and manganese dioxide (8.68g, 99.8mmol) was added to the reaction and reacted at room temperature for 12 hours. The reaction was filtered, the filter cake was washed with dichloromethane (20 mL × 2), and the combined organic phases were concentrated to give 3-methoxy-4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (60F) as an oily liquid (1.8 g, yield: 75.6%).

And a sixth step: 4-ethynyl-3-methoxythiophene-2-carbaldehyde (60G)

4-ethynyl-3-methoxythiophene-2-carbaldehyde

3-methoxy-4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (60F) (1.8g, 7.55mmol) was dissolved in methanol (20 mL), and potassium carbonate (1.6 g, 11.3mmol) was added to the reaction, followed by reaction at room temperature for 1 hour. The reaction solution was quenched with water (50 mL), the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10) to obtain 4-ethynyl-3-methoxythiophene-2-carbaldehyde (60G) as a yellow solid (1.0G, yield: 79.7%).

¹ H NMR(400MHz,CDCl ₃ )δ10.01(d,1H),7.76(d,1H),4.26(s,3H),3.26(s,1H).

The seventh step: (R) -N- ((4-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (60H)

(R)-N-((4-ethynyl-3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.3g, 1.15mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.818g, 5.76mmol) and 4-ethynylthiophene-2-carbaldehyde (60G) (0.287g, 1.73mmol) were added to the reaction at room temperature overnight. Sodium borohydride (0.07g, 1.73mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):411.2[M+H ⁺ ]；

The eighth step: (R) -N- ((4-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (Compound 60) (R) -N- ((4-ethyl-3-methoxythiopen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxapiro [4.5] can-9-yl) ethanamine 4-methylbenezene sulfonate

(R) -N- ((4-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (60H) (0.08g, 0.2mmol) was dissolved in ethyl acetate (4 mL), and p-toluenesulfonic acid monohydrate (0.04g, 0.2mmol) was dissolved in ethyl acetate (2 mL) and added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction solution was directly spin-dried and dried to give (R) -N- ((4-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (compound 60) as a white solid (0.12 g, yield: 100%).

Ms m/z(ESI):411.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.58(d,1H),7.86(t,1H),7.70(d,2H),7.66(s,1H),7.55(d,1H),7.33(t,1H),7.23(d,2H),4.16(s,2H),4.00(s,3H),3.77-3.73(m,3H),2.94(td,1H),2.50-2.38(m,3H),2.37(s,3H),2.11(td,1H),1.92-1.83(m,2H),1.76-1.64(m,3H),1.58-1.41(m,4H),1.14-1.07(m,1H),0.75-0.67(m,1H).

Example 61

3- (3-Isopropoxyphenyl) -N- ((3-methoxythiophen-2-yl) methyl) -3- (pyridin-2-yl) propyl-1-amine hydrochloride (Compound 61)

3-(3-isopropoxyphenyl)-N-((3-methoxythiophen-2-yl)methyl)-3-(pyridin-2-yl)propan-1-amine hydrochloride

The first step is as follows: 3-Isopropoxybenzaldehyde (61B)

3-isopropoxybenzaldehyde

3-hydroxybenzaldehyde (61A) (3.05g, 25.0 mmol) was dissolved in N, N-dimethylformamide (30 mL), and potassium carbonate (6.9g, 50.0 mmol) and iodoisopropane (5.09g, 30.0 mmol) were added to the reaction, followed by reaction at 50 ℃ for 6 hours. The reaction was cooled to 0 ℃ and water (90 mL) was added, the aqueous phase was extracted with methyl t-butyl ether (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3-isopropoxybenzaldehyde (61B) (3.9 g, yield: 95%).

¹ H NMR(400MHz,CDCl ₃ )δ9.96(s,1H),7.43-7.41(m,2H),7.38-7.37(m,1H),7.15-7.13(m,1H),4.66–4.60(m,1H),1.37-1.35(d,2H).

The second step: (3-Isopropoxyphenyl) (pyridin-2-yl) methanol (61C)

(3-isopropoxyphenyl)(pyridin-2-yl)methanol

A solution of 2-bromopyridine (1.74g, 11mmol) in tetrahydrofuran (15 mL) was added dropwise to a solution of isopropyl magnesium chloride (5.5 mL, 2M in tetrahydrofuran) at 0 deg.C under nitrogen, then the mixture was stirred at room temperature for 3 hours, then a solution of 3-isopropoxybenzaldehyde (61B) (1.64g, 10mmol) in tetrahydrofuran (20 mL) was added over 30 minutes. The mixture was then stirred at room temperature for 12 hours. The reaction mixture was poured into a mixture of 50g ice/1N HCl (20 mL). The product was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (3-isopropoxyphenyl) (pyridin-2-yl) methanol (61C) (1.5 g, yield: 62%) as a yellow oily liquid

Ms m/z(ESI):244.1[M+H ⁺ ]；

The third step: (3-Isopropoxyphenyl) (pyridin-2-yl) methanone (61D)

(3-isopropoxyphenyl)(pyridin-2-yl)methanone

(3-Isopropoxyphenyl) (pyridin-2-yl) methanol (61C) (1.2 g,4.9 mmol) was dissolved in dichloromethane (20 mL) at room temperature, pyridinium chlorochromate (2.1g, 9.9 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was filtered, and the filtrate was concentrated and directly spin-dried to give (3-isopropoxyphenyl) (pyridin-2-yl) methanone (61D) (0.8 g, 70% yield) as a brown liquid.

Ms m/z(ESI):242.1[M+H ⁺ ].

The fourth step: (Z/E) -3- (3-Isopropoxyphenyl) -3- (pyridin-2-yl) acrylonitrile (61E)

(Z/E)-3-(3-isopropoxyphenyl)-3-(pyridin-2-yl)acrylonitrile

Sodium hydride (0.09g, 4 mmol) was added to tetrahydrofuran (20 mL), the temperature was reduced to 0 ℃ and diethyl cyanomethylphosphonate (0.6g, 3 mmol) was added and, after the addition, the reaction was carried out at 0 ℃ for 1 hour. (pyridin-2-yl) methanone (61D) (0.8g, 3 mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the reaction mixture, and then the mixture was allowed to naturally warm to room temperature for 4 hours. The reaction was cooled to 0 ℃, ammonium chloride solution (30 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (Z/E) -3- (3-isopropoxyphenyl) -3- (pyridin-2-yl) acrylonitrile (61E) (0.75 g, 90% yield).

Ms m/z(ESI):265.1[M+H ⁺ ]；

The fifth step: 3- (3-Isopropoxyphenyl) -3- (pyridin-2-yl) propyl-1-amine (61F)

3-(3-isopropoxyphenyl)-3-(pyridin-2-yl)propan-1-amine

(Z/E) -3- (3-isopropoxyphenyl) -3- (pyridin-2-yl) acrylonitrile (61E) (0.88g, 3.31mmol) was dissolved in anhydrous methanol (30 mL), cobalt dichloride hexahydrate (0.86g, 6.6 mmol) was added, and sodium borohydride (1.26g, 33.1mmol) was added in portions. The reaction was stirred at room temperature for 12 hours. Water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3- (3-isopropoxyphenyl) -3- (pyridin-2-yl) propyl-1-amine (61F) (0.42 g, 47% yield).

Ms m/z(ESI):271.2[M+H ⁺ ].

And a sixth step: 3- (3-Isopropoxyphenyl) -N- ((3-methoxythiophen-2-yl) methyl) -3- (pyridin-2-yl) propyl-1-amine (61G)

3-(3-isopropoxyphenyl)-N-((3-methoxythiophen-2-yl)methyl)-3-(pyridin-2-yl)propan-1-amine

3- (3-Isopropoxyphenyl) -3- (pyridin-2-yl) propyl-1-amine (61F) (0.41g, 1.5 mmol) was dissolved in methylene chloride (20 mL), and sodium sulfate (1.3 g,7.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.23g, 1.6 mmol) were added to the reaction, followed by reaction overnight at room temperature. Sodium borohydride (0.09g, 2.0 mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =50

Ms m/z(ESI):397.1[M+H ⁺ ]；

The seventh step: 3- (3-Isopropoxyphenyl) -N- ((3-methoxythiophen-2-yl) methyl) -3- (pyridin-2-yl) propyl-1-amine hydrochloride (Compound 61)

3- (3-Isopropoxyphenyl) -N- ((3-methoxythiophen-2-yl) methyl) -3- (pyridin-2-yl) propyl-1-amine (61G) (50mg, 0.12mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction was directly spun dry to give 3- (3-isopropoxyphenyl) -N- ((3-methoxythiophen-2-yl) methyl) -3- (pyridin-2-yl) propyl-1-amine hydrochloride (compound 61) as a brown solid (50 mg, 100% yield).

Ms m/z(ESI):397.1[M+H ⁺ ]；

Example 62

1-cyclopentyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 62)

1-cyclopentyl-5-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-5(pyridin-2-yl)piperidin-2-onehydrochloride

The first step is as follows: 5- ((1, 3-Dioxolan-2-yl) methyl) -1-cyclopentyl-5- (pyridin-2-yl) piperidin-2-one (62A)

5-((1,3-dioxolan-2-yl)methyl)-1-cyclopentyl-5-(pyridin-2-yl)piperidin-2-one

At room temperature, 5- ((1, 3-dioxolan-2-yl) methyl) -5- (pyridin-2-yl) piperidin-2-one (36D) (0.3 g, 1mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), and potassium tert-butoxide (0.12g, 1.14mmol), bromocyclopentane (0.21g, 1.14mmol) and added thereto, the reaction was continued for 0.5h while warming to 60 ℃, bromocyclopentane (0.12g, 1.14mmol) was added to the reaction solution every 1h, potassium tert-butoxide (0.12g, 1.14mmol) was added repeatedly for 8 times, water (20 mL) was added to the reaction solution, ethyl acetate was extracted (20 mL × 2) and anhydrous sodium sulfate was added thereto and dried, the filtrate was filtered, the solvent was removed by concentration under reduced pressure, column chromatography (dichloromethane/methanol = 30) gave 5- ((3-dioxolan-2-yl) methyl) -1-cyclopentyl-5- (pyridin-2-yl) piperidin-2-one (62 g,92 g) piperidine-2-one (a) as a yellow oily product.

Ms m/z(ESI):263.1[M+H ⁺ ]。

The second step is that: 2- (1-cyclopentyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (62B)

2-(1-cyclopentyl-6-oxo-3-(pyridin-2-yl)piperidin-3-yl)acetaldehyde

5- ((1, 3-Dioxolan-2-yl) methyl) -1-methyl-5- (pyridin-2-yl) piperidin-2-one 62A (0.5g, 1mmol) was dissolved in tetrahydrofuran (15 mL) and concentrated hydrochloric acid (1 mL) at room temperature, stirred overnight at room temperature, and the reaction was concentrated to give 2- (1-cyclopentyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (62B) (0.4g, 100% crude) as a black oily product, which was directly used in the next step.

Ms m/z(ESI):287.2[M+H ⁺ ]。

The third step: 1-cyclopentyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one (62C)

1-cyclopentyl-5-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-5-(pyridin-2-yl)piperidin-2-one

2- (1-cyclopentyl-6-oxo-3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (62B) (0.50g, 1.7 mmol) was dissolved in methylene chloride (15 mL), and (3-methoxythiophen-2-yl) methylamine (0.3g, 2.1mmol), triethylamine (0.23g, 1.3mmol), and anhydrous sodium sulfate (1.7 g) were added thereto in this order. The reaction was allowed to react overnight at room temperature, sodium borohydride (0.1g, 2.6 mmol) was added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated brine solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (dichloromethane/methanol = 30).

Ms m/z(ESI):414.2[M+H ⁺ ]。

The fourth step: 1-cyclopentyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 62)

1-cyclopentyl-5- (2- (((3-methoxythiophen-2-yl) methyl) amino) ethyl) -5- (pyridin-2-yl) piperidin-2-one (62C) (0.15g, 0.36mmol) was dissolved in ethyl acetate (5 mL) and the solution of ethyl hydrogen chloride acetate (2mL, 4N) was added at 0 ℃ and the reaction was continued for 0.5h after completion of addition and the solvent was removed under reduced pressure to give 5- (2- ((3-chlorobenzyl) amino) ethyl) -1-isopropyl-5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 62) (0.16g, 95%) as a white solid at room temperature.

Ms m/z(ESI):414.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.84(d,1H),8.44(s,1H),7.94(m,2H),7.47(d,1H),7.01(d,1H),4.21(s,2H),3.88(s,3H),3.70(d,2H),2.90(td,1H),2.74(td,1H),2.59-2.24(m,6H),1.80-1.61(m,7H)。

Example 63

5- (2- (((3-methoxythiophen-2-yl) amino) ethyl) -1- (pent-3-yl) -5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 63)

5-(2-(((3-methoxythiophen-2-yl)methyl)amino)ethyl)-1-(pentan-3-yl)-5-(pyridin-2-yl)piperidin-2-one

The first step is as follows: 5- ((1, 3-Dioxolan-2-yl) methyl) -1- (pentane-3-yl) -5- (pyridin-2-yl) piperidin-2-one (63A)

5-((1,3-dioxolan-2-yl)methyl)-1-(pentan-3-yl)-5-(pyridin-2-yl)piperidin-2-one

At room temperature, 5- ((1, 3-dioxolan-2-yl) methyl) -5- (pyridin-2-yl) piperidin-2-one (36D) (0.7g, 2.7mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), potassium tert-butoxide (0.3g, 2.7mmol), bromocyclopentane (0.4g, 2.7mmol) were added at room temperature, the reaction was continued for 0.5h by heating to 60 ℃, 3-bromopentane (0.4g, 2.7mmol) and potassium tert-butoxide (0.3g, 2.7mmol) were added to the reaction solution every 1h, 8 times were repeated, 20mL of water was added to the reaction solution, ethyl acetate was extracted (20 mL × 2), anhydrous sodium sulfate was added and dried, the filtrate was filtered, the solvent was removed by concentration under reduced pressure, and column chromatography (dichloromethane/methanol = 30) gave 5- ((1, 3-dioxolan-2-yl) methyl) -1- (piperidin-2-yl) piperidin-2-one (a) as a yellow oily product (63 g,86 g, b).

Ms m/z(ESI):333.2[M+H ⁺ ]。

The second step is that: 2- (6-oxo-1- (pent-3-yl) -3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (63B)

2-(6-oxo-1-(pentan-3-yl)-3-(pyridin-2-yl)piperidin-3-yl)acetaldehyde

5- ((1, 3-Dioxolan-2-yl) methyl) -1- (pentan-3-yl) -5- (pyridin-2-yl) piperidin-2-one 63A (0.5g, 2mmol) was dissolved in tetrahydrofuran (15 mL) and concentrated hydrochloric acid (1 mL) at room temperature, stirred overnight at room temperature, and the reaction was concentrated to give 2- (6-oxo-1- (pentan-3-yl) -3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde 63B (0.4g, 100% crude) as a black oil, which was directly used in the next step.

Ms m/z(ESI):289.2[M+H ⁺ ]。

The third step: 5- (2- (((3-methoxythiophen-2-yl) amino) ethyl) -1- (pent-3-yl) -5- (pyridin-2-yl) piperidin-2-one (63C)

2- (6-oxo-1- (pent-3-yl) -3- (pyridin-2-yl) piperidin-3-yl) acetaldehyde (63B) (0.50g, 1.7mmol) was dissolved in methylene chloride (15 ml), and (3-methoxythiophen-2-yl) methylamine (0.3g, 2.1mmol), triethylamine (0.23g, 1.3mmol), anhydrous sodium sulfate (1.7 g) were added thereto in this order. The reaction was allowed to react overnight at room temperature, sodium borohydride (0.1g, 2.6 mmol) was added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated brine solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (dichloromethane/methanol = 30).

Ms m/z(ESI):416.2[M+H ⁺ ]。

The fourth step: 5- (2- (((3-methoxythiophen-2-yl) amino) ethyl) -1- (pent-3-yl) -5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 63)

5- (2- (((3-methoxythiophen-2-yl) amino) ethyl) -1- (pent-3-yl) -5- (pyridin-2-yl) piperidin-2-one 63C (0.15g, 0.36mmol) was dissolved in ethyl acetate (5 mL) at room temperature, and an ethyl hydrogen chloride solution (2mL, 4N) was added thereto at 0 ℃ and the reaction was continued for 0.5h, and the solvent was removed under reduced pressure to give 5- (2- (((3-methoxythiophen-2-yl) amino) ethyl) -1- (pent-3-yl) -5- (pyridin-2-yl) piperidin-2-one hydrochloride (Compound 63) (0.16g, 95%) as a white solid.

Ms m/z(ESI):416.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.89(dd,1H),8.54(td,1H),8.11(d,1H),7.98(m,1H),7.47(d,1H),7.01(d,1H),4.38(td,1H),4.21(s,2H),3.88(s,3H),3.83(d,1H),3.64(d,1H),2.99(td,1H),2.61(m,3H),2.4(m,3H),1.52(m,3H),0.90(t,3H),0.58(t,3H)。

Example 64

(R) -N- ((5-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (Compound 64)

(R)-N-((5-ethynyl-3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine 4-methylbenzenesulfonate

The first step is as follows: 2, 5-bromo-3-methoxythiophene (64B)

2,5-dibromo-3-methoxythiophene

3-Methoxythiophene (64A) (11.4g, 99.851mmol) was dissolved in dichloromethane (200 mL) and N-bromosuccinimide (39.63g, 222.67mmol) was added in small portions with stirring and stirring was completed at room temperature for 2 hours. To the reaction mixture was added saturated brine (180 mL), and liquid separation was performed, and the organic phase was washed with a saturated sodium thiosulfate solution (180 mL × 1), and the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 10/1) to give 2, 5-bromo-3-methoxythiophene (64B) as a brown oil (11 g, yield: 40.5%).

¹ H NMR(400MHz,CDCl ₃ )δ6.79(s,1H),3.86(s,3H).

The second step: 5-bromo-3-methoxythiophene-2-carbaldehyde (64C)

5-bromo-3-methoxythiophene-2-carbaldehyde

The compound 2, 5-bromo-3-methoxythiophene (64B) (5.0g, 18.39mmol) was dissolved in tetrahydrofuran (50 mL) and n-butyllithium (7.4mL, 18.39mmol) was added dropwise at-78 ℃ and stirred at-78 ℃ for 0.5 hour, and then a solution of DMF (2.016g, 27.58mmol) in tetrahydrofuran (5 mL) was added dropwise and the reaction was completed at-78 ℃ for 1 hour. To the reaction solution was added a saturated ammonium chloride solution (80 mL), liquid separation was performed, the organic phase was washed with a saturated sodium chloride solution (80 mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 10/1) was performed to obtain 5-bromo-3-methoxythiophene-2-carbaldehyde (64C) as a yellow solid (1.5 g, yield: 37%).

¹ H NMR(400MHz,CDCl ₃ )δ9.99(d,J＝1.3Hz,1H),6.73(d,J＝1.2Hz,1H),3.92(s,3H).

The third step: 3-methoxy-5- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (64D)

3-methoxy-5-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde

The compound 5-bromo-3-methoxythiophene-2-carbaldehyde (64C) (1.3g, 5.88mmol) was dissolved in tetrahydrofuran (15 mL), trimethylsilylacetylene (1.155g, 11.76mmol), cuprous iodide (0.112g, 0.588mmol), palladium (0.206g, 0.294mmol) ditriphenylphosphine dichloride triethylamine (15 mL) were added, and the reaction was completed at 60 ℃ for 6 hours. Filtration and evaporation to dryness gave a yellow solid as crude 3-methoxy-5- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (64D) (0.9 g, yield: 60%) which was used directly in the next step.

The fourth step: 5-ethynyl-3-methoxythiophene-2-carbaldehyde (64E)

5-ethynyl-3-methoxythiophene-2-carbaldehyde

Crude compound 3-methoxy-5- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (64D) (0.90g, 3.78mmol) was dissolved in methanol (10 mL), potassium carbonate (1.04g, 7.55mmol) was added, and the mixture was stirred at room temperature for 1 hour. Filtration, washing of the cake with ether (50 mL × 1) and the organic phase with saturated brine (50 mL × 1), drying over anhydrous sodium sulfate, filtration, and evaporation of the silica gel column chromatography petroleum ether/ethyl acetate (V/V) =30/1 gave 5-ethynyl-3-methoxythiophene-2-carbaldehyde (64E) as a yellow solid product (500 mg, yield: 79.7%).

The fifth step (R) -N- ((5-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (64F)

(R)-N-((5-ethynyl-3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

The compound 5-ethynyl-3-methoxythiophene-2-carbaldehyde (64E) (0.300g, 1.81mmol), (R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.423g, 1.62mmol) was dissolved in dichloromethane (20 mL), and anhydrous sodium sulfate (1.36g, 9.60mmol) was added and stirred at room temperature overnight. Sodium borohydride (0.039g, 2.44mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour, and then 3 ml of anhydrous methanol was added thereto, and the mixture was stirred for 2 hours. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 1), the organic phase was dried over colorless sodium sulfate, filtered, evaporated to dryness, and subjected to silica gel column chromatography, EA/PE =2/1-3/1 to give (R) -N- ((5-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (64F) as a yellow solid product (300 mg, yield: 45%).

Ms.m/z(ESI):411.2[M+H ⁺ ]。

Sixth step (R) -N- ((5-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (Compound 64)

(R)-N-((5-ethynyl-3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine4-methylbenzenesulfonate

The compound (R) -N- ((5-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (64F) (0.165g, 0.402mmol) was dissolved in methylene chloride (20 mL), and p-toluenesulfonic acid (0.069g, 0.402mmol) was added and stirred at room temperature for 1 hour. The reaction solution was evaporated to dryness to give a yellow solid product, N- ((5-ethynyl-3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine p-toluenesulfonate (compound 64) (220 mg, yield: 93.9%). (Note: nuclear magnetism is 1.5 p-toluene sulfonate)

Ms.m/z(ESI):411.2[M+H ⁺ -172]；

¹ H NMR(400MHz,CD3OD)δ8.83(dd,1H),8.52(td,1H),8.09(d,1H),7.96–7.89(m,1H),7.70(d,3H),7.24(d,3H),6.61(s,1H),4.32(s,2H),3.94(s,1H),3.83(s,3H),3.81–3.76(m,1H),3.73–3.64(m,1H),3.04(td,1H),2.55(td,1H),2.43(d,2H),2.37(s,4.5H),2.28(td,1H),2.18–2.08(m,2H),1.94–1.40(m,9H).

Example 65

N- ((3-Methoxythien-2-yl) methyl) -2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine hydrochloride (Compound 65)

N-((3-methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)bicyclo[2.2.2]octan-2-yl)ethanaminehydrochloride

The first step is as follows: bicyclo [2.2.2] octane-2-carbonitrile (65B)

bicyclo[2.2.2]octane-2-carbonitrile

At room temperature, bicyclo [2.2.2] octan-2-one 65A (0.5g, 4.0mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), p-toluenesulfonylmethylisonitrile (1.8g, 9.3mmol), ethanol (0.42g, 9.1mmol), potassium tert-butoxide (1.6 g, 14mmol) were added in this order under zero-temperature conditions, the reaction was continued for 18 hours while heating to 60 ℃,50 mL of water was added to the reaction solution, ethyl acetate was extracted (30 mL × 2), anhydrous sodium sulfate was added for drying, filtration was performed, the filtrate was concentrated under reduced pressure to remove the solvent, and column chromatography (petroleum ether/ethyl acetate = 5) was performed to obtain a yellow oily product bicyclo [2.2.2] octane-2-carbonitrile 65B (0.3g, 50%).

¹ H NMR(400MHz,CD ₃ OD):δ2.71(m,1H)，1.79-1.68(m,2H)，1.62(m,1H),1.58(m,8H)。

The second step is that: 2- (pyridin-2-yl) bicyclo [2.2.2] octan-2-carbonitrile (65C)

2-(pyridin-2-yl)bicyclo[2.2.2]octane-2-carbonitrile

At room temperature, (65B) (0.5g, 2.59mmol) and 2-fluoropyridine (0.3g, 3.1mmol) were dissolved in toluene (5 mL), the system temperature was controlled to 20 ℃ below zero, potassium hexamethyldisilazane (0.5g, 2.59mmol) was added dropwise, after completion of addition, reaction was carried out at room temperature for 5 hours, 50mL of water was added to the reaction solution, ethyl acetate was extracted (30 mL × 2), anhydrous sodium sulfate was added thereto, drying was carried out, filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, and column chromatography (petroleum ether/ethyl acetate = 10.

Ms m/z(ESI):213.1[M+H ⁺ ]。

The third step: methyl 2- (pyridin-2-yl) bicyclo [2.2.2] octan-2-carboxylate (65D)

methyl 2-(pyridin-2-yl)bicyclo[2.2.2]octane-2-carboxylate

2- (pyridin-2-yl) bicyclo [2.2.2] octan-2-carbonitrile (65C) (1.9g, 8.9mmol) was dissolved in methanol (20 mL), sulfuric acid (13g, 132mmol) was added thereto at zero degrees, after addition, the reaction was heated to 130 degrees and reacted for 12 hours, the reaction solution was slowly added to 250mL of a sodium hydrogencarbonate solution (cooled), stirred for 15 minutes, extracted with ethyl acetate (40 mL. Times.3), washed with a saturated aqueous salt solution (50 mL. Times.1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (petroleum ether/ethyl acetate (V/V) = 1) was performed to obtain methyl 2- (pyridin-2-yl) bicyclo [2.2.2] octan-2-carboxylate (65D) (1g, 50%) as a yellow oily product.

Ms m/z(ESI):246.1[M+H ⁺ ]。

The fourth step: (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) methanol (65E)

(2-(pyridin-2-yl)bicyclo[2.2.2]octan-2-yl)methanol

Methyl 2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-carboxylate 65D (0.9g, 3.7mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, lithium aluminum hydride (0.21g, 5.5mmol) was added at 0 deg.C, and after completion, the reaction was continued at room temperature for 2 hours, and water (0.21 mL), a sodium hydroxide solution (0.42mL, 10 wt), water (0.21 mL) and stirring were added to the system in this order, followed by stirring for ten minutes, sodium sulfate (0.5 g) and stirring for 10 minutes, followed by filtration, and removal of the solvent under reduced pressure to give 2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) methanol 65E (0.45g, 57%) as a white solid.

Ms m/z(ESI):218.2[M+H ⁺ ]。

The fifth step: (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) methyl methanesulfonate (65F) (2- (pyridin-2-yl) bicyclo [2.2.2] ]octan-2-yl) methyl methansulfonate

2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) methanol 65E (0.45g, 2.1mmol) was dissolved in dichloromethane (10 mL) at room temperature, triethylamine (0.31g, 3.1mmol) and methanesulfonyl chloride (0.28g, 2.5 mmol) were added in this order at 0 ℃, and after completion of addition, reaction was continued at room temperature for 1 hour, water (20 mL) was added to the system, ethyl acetate was extracted (40 mL. Times.3), the mixture was washed with a saturated aqueous salt solution (50 mL. Times.1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the solvent was removed under reduced pressure to give a yellow oily substance (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) methylmethanesulfonate 65F (0.59 g), which was directly used in the next step.

Ms m/z(ESI):296.2[M+H ⁺ ]。

And a sixth step: 2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) acetonitrile (65G)

2-(2-(pyridin-2-yl)bicyclo[2.2.2]octan-2-yl)acetonitrile

At room temperature, (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) methyl methanesulfonate 65F (0.59g, 2.0mmol) was dissolved in N, N-dimethylformamide (6 mL), potassium cyanide (0.33g, 5.0mmol) was added, and after completion, the reaction was continued at 140 degrees for 3 hours, and water (10 mL) was added to the system, followed by extraction with ethyl acetate (20 mL × 2), washing with a saturated aqueous salt solution (20 mL × 1), drying over anhydrous sodium sulfate, concentration under reduced pressure, column chromatography (petroleum ether/ethyl acetate (V/V) = 1), to obtain 2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) acetonitrile 65G (0.35g, 70%) as a yellow oily substance.

Ms m/z(ESI):226.2[M+H ⁺ ]。

The seventh step: 2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine (65H)

2-(2-(pyridin-2-yl)bicyclo[2.2.2]octan-2-yl)ethanamine

2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) acetonitrile 65G (0.35g, 1.55mmol) was dissolved in tetrahydrofuran (8 mL) at room temperature, lithium aluminum hydride (0.12g, 3.09mmol) was added at zero degrees, and after completion of the addition, the reaction was carried out at room temperature for 10 hours, and water (0.12 mL), a sodium hydroxide solution (0.24mL, 10 wt), water (0.12 mL) and the like were added to the system in this order, followed by stirring for ten minutes, addition of sodium sulfate 0.5G and the like, followed by stirring for 10 minutes, filtration, and removal of the solvent under reduced pressure to obtain 2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine 65H (0.30g, 85%) as a yellow oily substance.

Ms m/z(ESI):231.2[M+H ⁺ ]。

The eighth step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine (65I)

N-((3-methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)bicyclo[2.2.2]octan-2-yl)ethanamine

2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine 65H (0.20g, 0.90mmol) was dissolved in methylene chloride (10 mL), and 3-methoxythiophene-2-aldehyde (0.15g, 1mmol) and anhydrous sodium sulfate (0.5 g) were added thereto in this order. After an overnight reaction at room temperature, 3mL of methanol and sodium borohydride (0.05g, 1.35mmol) were added, stirring was continued for 2h, water (20 mL) was added, extraction was performed with dichloromethane (20 mL × 2), the organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (dichloromethane/methanol = 30) was performed to give the product N- ((3-methoxythiophen-2-yl) methyl) -2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine 65I (0.14g, 50%) as a yellow oil.

Ms m/z(ESI):357.2[M+H ⁺ ]。

The ninth step: n- ((3-Methoxythien-2-yl) methyl) -2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine hydrochloride (Compound 65)

N- ((3-Methoxythien-2-yl) methyl) -2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine 65I (0.14g, 0.39mmol) was dissolved in ethyl acetate (5 mL) and the ethyl hydrogen chloride acetate solution (2mL, 4N) was added at 0 ℃ and the reaction was continued for 0.5h, and the solvent was removed under reduced pressure to give N- ((3-Methoxythien-2-yl) methyl) -2- (2- (pyridin-2-yl) bicyclo [2.2.2] oct-2-yl) ethylamine hydrochloride (Compound 65) (0.16g, 97%) as a white solid.

Ms m/z(ESI):357.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD):δ8.85(q,1H),8.63(d,1H),8.19(d,1H),8.02(t,1H),7.47(d,1H),7.00(d,1H),4.19(s,2H),3.88(s,3H),2.65(m,2H),2.39(m,1H),2.18(m,3H),2.02(m,4H),1.75-1.38(m,7H).

Example 66

N- ((3-Methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-2-en-9-yl) ethylamine hydrochloride (Compound 66)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)ethanamine hydrochloride

The first step is as follows: 1, 4-dioxaspiro [4.4] cyclo-7-ene (66B)

1,4-dioxaspiro[4.4]non-7-ene

Trimethylsilyltriflate (2.21g, 12.2mmol) was added to dichloromethane (100 mL) at-70 ℃ under nitrogen. 1, 2-bis (trimethylsiloxy) ethane (25.1g, 122mmol) and 3-cyclopenten-1-one (66A) (10g, 122mmol) were added dropwise to the reaction mixture at-70 ℃ to complete the reaction at-70 ℃ for 5 hours. Triethylamine (20 mL) and a sodium hydrogencarbonate solution (20 mL) were added dropwise to the reaction solution successively at-70 ℃ and the aqueous phase was extracted with methylene chloride (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1, 4-dioxaspiro [4.4] cyclo-7-ene (66B) (10 g, yield: 65%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ5.64(s,2H),3.88(s,4H),2.51(s,1H)。

The second step is that: 1- (2-hydroxyethoxy) cyclopentyl-3-enemethyl cyanide (66C)

1-(2-hydroxyethoxy)cyclopent-3-enecarbonitrile

1, 4-dioxaspiro [4.4] cyclo-7-ene (66B) (6.4g, 51mmol) and cyanotrimethylsilane (5g, 51mmol) were charged into a reaction flask, and cooled to 0 ℃ and zinc diiodide (0.065g, 0.2mmol) was added to the reaction solution, after which the reaction was allowed to proceed overnight at room temperature. Methanol (30 mL) and 1N hydrochloric acid (30 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The aqueous phase was extracted with dichloromethane (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1- (2-hydroxyethoxy) cyclopentyl-3-enemethyl cyanide (66C) as a yellow oily liquid (7 g, yield: 90%).

¹ H NMR(400MHz,CDCl ₃ )δ5.70(s,2H),3.79-3.74(m,4H),2.97-2.96(m,2H),2.88-2.83(m,2H)。

The third step: 1- (2-hydroxyethoxy) cyclopentyl-3-enecarboxylic acid (66D)

1-(2-hydroxyethoxy)cyclopent-3-enecarboxylic acid

After 1- (2-hydroxyethoxy) cyclopentyl-3-enecarbonitrile (66C) (3g, 20mmol) was dissolved in ethanol (50 mL), sodium hydroxide (3.9g, 9.8mmol) and water (50 mL) were sequentially added, and the mixture was heated to reflux for 4 hours. After cooling and concentration to remove ethanol, the reaction mixture was adjusted to PH =3-4 by adding 3N hydrochloric acid (50 mL), aqueous phase was extracted with ethyl acetate (30 mL × 5), organic phases were combined, washed with saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1- (2-hydroxyethoxy) cyclopentyl-3-enecarboxylic acid (66D) (2.4 g, yield: 71%).

Ms m/z(ESI):171.1[M-H ⁺ ]；

The fourth step: 2- ((1- (hydroxymethyl) cyclopentyl-3-en-1-yl) oxy) ethanol (66E) 2- ((1- (hydroxymethyl) cyclic-3-en-1-yl) oxy) ethanol

Lithium aluminum hydride (1.5 g, 39mmol) was dissolved in tetrahydrofuran (40 mL), the temperature was reduced to 0 ℃ and 1- (2-hydroxyethoxy) cyclopentyl-3-enecarboxylic acid (66D) (3.4 g, 20mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, and the reaction was carried out overnight at room temperature. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (1.2 mL), dried with anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give 2- ((1- (hydroxymethyl) cyclopentyl-3-en-1-yl) oxy) ethanol (66E) (2.2 g, yield: 70%).

Ms m/z(ESI):159.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ5.68(s,2H),3.72-3.70(m,2H),3.62(s,2H),3.46-3.45(m,2H),3.13(s,2H),2.47-2.37(q,4H).

The fifth step: (1- (2- ((methylsulfonyl) oxy) ethoxy) cyclopentyl-3-en-1-yl) methyl methanesulfonate (66F)

(1-(2-((methylsulfonyl)oxy)ethoxy)cyclopent-3-en-1-yl)methyl methanesulfonate

2- ((1- (hydroxymethyl) cyclopentyl-3-en-1-yl) oxy) ethanol (66E) (2.2g, 14mmol) was dissolved in dichloromethane (50 mL) and then cooled to-20 ℃. Triethylamine (4.5g, 45mmol) and methanesulfonyl chloride (3.8g, 33mmol) were added dropwise to the reaction mixture at-20 ℃ in this order, and the reaction was carried out at-20 ℃ for 2 hours. Water (80 mL) was added, the aqueous phase was extracted with dichloromethane (50 mL. Times.2), the organic phases were combined, washed with sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (1- (2- ((methylsulfonyl) oxy) ethoxy) cyclopentyl-3-en-1-yl) methyl methanesulfonate (66F) as a yellow oily liquid (4.2 g, yield: 96%).

¹ H NMR(400MHz,CDCl ₃ )δ5.69(s,2H),4.35-4.34(m,2H),4.32(s,2H),3.65-3.64(m,2H),3.11-3.04(d,6H),2.53-2.50(m,4H).

And a sixth step: ethyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-ene-9-carboxylate (66G)

ethyl 9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-ene-9-carboxylate

Sodium hydride (0.83g, 20.0 mmol) was dissolved in toluene (20 mL), the temperature was lowered to 0 ℃ and pyridine-2-acetic acid ethyl ester (1.4g, 8.3 mmol) was added to the reaction, after which the reaction was carried out at room temperature for 1 hour. A toluene solution (20 mL) of (1- (2- ((methylsulfonyl) oxy) ethoxy) cyclopentyl-3-en-1-yl) methyl methanesulfonate (66F) (2.6 g,8.3 mmol) was added dropwise to the reaction mixture at 0 ℃ and the mixture was heated under reflux for 3 hours. The reaction was cooled to 0 ℃, the reaction was quenched with ammonium chloride solution (30 mL), the aqueous phase was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with sodium chloride (30 mL × 1), dried by adding anhydrous sodium sulfate, filtered, concentrated the crude product and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1-2) to give ethyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-ene-9-carboxylate (66G) (0.92G, yield: 39%).

Ms m/z(ESI):288.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.62-8.60(d,1H),7.72-7.68(m,1H),7.52-7.38(d,1H),7.2-7.19(m,1H),5.67(s,2H),4.26-4.14(m,2H),3.98-3.88(m,1H),3.86-3.84(m,1H),2.49-2.31(m,8H),1.37-1.26-(t,3H).

The seventh step: (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) methanol (66H)

(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)methanol

Lithium aluminum hydride (0.5g, 7 mmol) was dissolved in tetrahydrofuran (20 mL), the temperature was reduced to 0 ℃ and then tetrahydrofuran (10 mL) of ethyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-ene-9-carboxylate (66G) (1g, 3.5 mmol) was added dropwise to the reaction mixture, and after completion of addition, the reaction was allowed to proceed overnight at room temperature. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (0.6 mL), dried with anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) methanol (66H) (0.72 g, yield: 84%).

Ms m/z(ESI):246.2[M+H ⁺ ]。

Eighth step: (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) methyl methanesulfonate (66I)

(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)methyl methanesulfonate

(9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) methanol (66H) (0.72g, 2.9 mmol) was dissolved in dichloromethane (30 mL) and then cooled to 0 ℃. Triethylamine (0.45g, 4.4 mmol) and methylsulfonyl chloride (0.4 g,3.5 mmol) were added dropwise to the reaction mixture in this order at 0 ℃ and reacted at 0 ℃ for 2 hours. Water (20 mL) was added, the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with sodium chloride (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5.

Ms m/z(ESI):324.1[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.63-8.60(d,1H),7.71-7.69(m,1H),7.39-7.38(d,1H),7.22-7.19(m,1H),5.63(s,1H),5.46(s,1H),4.41-4.39(d,1H),4.27-4.25(d,1H),3.90-3.87(m,2H),2.84(s,3H),2.49-2.38(m,4H),1.96-1.81(m,4H).

The ninth step: 2-9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) acetonitrile (66J)

2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)acetonitrile

(9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) methyl methanesulfonate (66I) (0.97g, 3 mmol) was dissolved in dimethyl sulfoxide (40 mL), and sodium cyanide (0.6 g,9 mmol) and sodium iodide (50mg, 0.08mmol) were added thereto, and the reaction was completed at 150 ℃ for 8 hours. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 6-1 to 3) to give 2-9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) acetonitrile (66J) as a yellow solid (0.65 g, yield: 85%).

Ms m/z(ESI):255.1[M+H ⁺ ]。

The tenth step: 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-2-en-9-yl) ethylamine (66K)

2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)ethanamine

Lithium aluminum hydride (0.19g, 5.1mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 deg.C, and then 2-9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) acetonitrile (66J) (0.65g, 2.6 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture, and the reaction was allowed to proceed overnight at room temperature. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (0.8 mL), dried by addition of anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethylamine (66K) (0.6 g, yield: 98%).

Ms m/z(ESI):259.2[M+H ⁺ ]。

The eleventh step: n- ((3-Methoxythien-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethanamine (66L)

N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)ethanamine

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethylamine (66K) (0.34g, 1.3 mmol) was dissolved in methylene chloride (15 mL), and sodium sulfate (1.3 g,10.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.22g, 1.6 mmol) were added to the reaction solution, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.074g, 2.0 mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =50

Ms m/z(ESI):385.2[M+H ⁺ ]。

A twelfth step: n- ((3-Methoxythien-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethylamine hydrochloride (Compound 66)

N- ((3-Methylthioen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethanamine (66L) (0.05g, 0.13mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give N- ((3-methoxythiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethylamine hydrochloride (Compound 66) (0.05 g, yield 92.6%) as a yellow solid.

Ms m/z(ESI):385.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.78-8.77(d,1H),8.36-8.35(m,1H),7.96-7.81(d,1H),7.78(m,1H),7.46(d,1H),7.04-7.01(d,1H),5.61(s,1H),5.46(s,1H),4.07(s,2H),3.88-3.84(m,5H),2.99-2.95(m,1H),2.45-2.31(m,2H),2.31-2.25(m,3H),2.04(m,1H),2.03-1.95(m,3H),1.88-1.64(m,2H).

Example 67

N- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-2-en-9-yl) ethanamine (Compound 67)

N-((3-(difluoromethoxy)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)ethanamine hydrochloride

The first step is as follows: n- ((3- (difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-2-en-9-yl) ethanamine (67A)

N-((3-(difluoromethoxy)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)ethanamine

2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethylamine (66K) (0.34g, 1.3 mmol) was dissolved in methylene chloride (15 mL), and sodium sulfate (1.3 g,10.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.22g, 1.6 mmol) were added to the reaction solution, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.074g, 2.0 mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude N- ((3-methylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethylamine (67A) (0.05 g, yield: 10%) as a yellow oily liquid by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):421.2[M+H ⁺ ]。

The second step: n- ((3- (Difluoromethoxy) thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethanamine (Compound 67)

N- ((3-Methylthioen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethanamine (67A) (0.05g, 0.13mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction was directly spin-dried to give N- ((3-methylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-en-9-yl) ethylamine hydrochloride (compound 67) as a yellow solid (0.05 g, yield 92.6%).

Ms m/z(ESI):421.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.81-8.80(d,1H),8.65-8.63(m,1H),7.97(d,1H),7.82-7.79(m,1H),7.63-7.60(m,1H),7.05-7.04(d,1H),6.90-6.88(m,1H),6.72-6.69(m,1H),5.61(s,1H),5.46(s,1H),4.31-4.27(d,2H),3.86-3.84(m,2H),3.13-2.99(m,2H),2.58-2.32(m,4H),2.19-2.04(m,2H),2.03-1.95(m,2H),1.94-1.64(m,2H).

Example 68

N- ((3-Methoxythiophen-2-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (Compound 68)

The first step is as follows: ethyl 4' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -carboxylate (68A)

ethyl 4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-carboxylate

Ethyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-2-ene-9-carboxylate (66G) (0.86g, 3.0mmol) was dissolved in methylene chloride (40 mL), and the solution was cooled to 0 ℃ to add diethyl zinc n-hexane solution (1.0M, 15mL) and diiodomethane (30.0mmol, 3.5mL) to the reaction solution in this order, and reacted at room temperature for 12 hours. The reaction was cooled to 0 ℃, the reaction was quenched with ammonium chloride solution (30 mL), the aqueous phase was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with sodium chloride (30 mL × 1), dried by adding anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1-2).

Ms m/z(ESI):302.2[M+H ⁺ ]；

The second step is that: (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) methanol (68B)

(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)methanol

Lithium aluminum hydride (0.2g, 5.32mmol) was dissolved in tetrahydrofuran (20 mL), the temperature was reduced to 0 ℃ and then tetrahydrofuran (10 mL) of 4' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -carboxylate (68A) (0.8g, 2.66mmol) was added dropwise to the reaction mixture, and the reaction was carried out at room temperature for 4 hours. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (0.6 mL), dried by addition of anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) methanol (68B) (0.6 g, yield: 87.1%).

Ms m/z(ESI):260.2[M+H ⁺ ]。

The third step: (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) methyl methanesulfonate (68C)

(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)methyl methanesulfonate

(4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) methanol (68B) (0.6 g, 2.9.31mmol) was dissolved in dichloromethane (30 mL) and then cooled to 0 ℃. Triethylamine (0.35g, 3.47mmol) and methanesulfonyl chloride (0.34g, 3.0mmol) were added dropwise to the reaction mixture in this order at 0 ℃ and reacted at 0 ℃ for 2 hours. Water (20 mL) was added, the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with sodium chloride (20 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5.

Ms m/z(ESI):338.2[M+H ⁺ ]。

The fourth step: 2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) acetonitrile (68D)

2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)acetonitrile

(4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) methyl methanesulfonate (68C) (0.5 g,1.5 mmol) was dissolved in dimethyl sulfoxide (20 mL), and sodium cyanide (0.44g, 6.0 mmol) and sodium iodide (50mg, 0.08mmol) were added thereto, and the reaction was completed at 150 ℃ for 8 hours. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 6.

Ms m/z(ESI):269.2[M+H ⁺ ]。

The fifth step: 2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (68E)

2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine

Lithium aluminum hydride (0.1g, 2.6 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 deg.C, and 2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) acetonitrile (68D) (0.35g, 1.3 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture, and the reaction was allowed to proceed overnight at room temperature. The reaction was cooled to 0 ℃, quenched with water (0.6 mL), sodium hydroxide solution (10%, 1.2 mL) and water (0.8 mL), dried by addition of anhydrous sodium sulfate, stirred for 20 minutes, the solid filtered and washed with tetrahydrofuran (20 mL × 3). The combined organic phases were concentrated to give 2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (68E) (0.3 g, yield: 84.8%).

Ms m/z(ESI):273.3[M+H ⁺ ]。

And a sixth step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (68F)

N-((3-methoxythiophen-2-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine

2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (68E) (0.30g, 1.3 mmol) was dissolved in dichloromethane (15 mL), and sodium sulfate (1.3g, 10.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.22g, 1.6 mmol) were added to the reaction solution, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.074g, 2.0 mmol) was added to the reaction, and the reaction was stirred for 20 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (30 mL × 4), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):399.1[M+H ⁺ ]。

The seventh step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (Compound 68)

N- ((3-Methoxythien-2-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (68F) (0.15g, 0.37mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction was directly spin dried to give N- ((3-methoxythiophen-2-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrooxaspiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (compound 68) as a yellow solid (0.15 g, 93.4% yield).

Ms m/z(ESI):399.1[M+H ⁺ ]；

¹ H NMR(400MHz,CD ₃ OD)δ8.79(s,1H),8.40(s,1H),7.97-7.84(d,2H),7.51-7.49(m,1H),7.01-6.99(d,1H),4.17(s,2H),3.88(s,3H),3.61-3.48(m,2H),2.94-2.91(m,2H),2.35-1.84(m,10H),1.22-1.16(m,4H).

Resolution of the compound N- ((3-methoxythiophen-2-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) ethylamine hydrochloride (compound 68)

(compound 68) (420 mg) was taken for resolution, and after separation, two optical isomers, compound 68-1 (retention time: 5.107min,191.76mg, oily liquid, ee% = 99.3%), compound 68-2 (retention time: 6.236min,187.59mg, oily liquid, ee% = 99.7%) were obtained.

Splitting conditions are as follows: apparatus is THar 80 preparatory SFC (SFC-16); a column, chiralPak AD,220 × 80mm i.d.,10 μm; mobile phase A: carbon dioxide, B: ethanol (0.1% ammonia); gradient B40%; the flow rate is 80mL/min; back pressure is 100bar; the column temperature is 38 ℃; the wavelength is 220nm; the period is 5min; sample preparation, compound is dissolved in methanol to make 42mg/ml; injection 2 ml/needle.

The salifying method of the compound 68 is adopted to obtain a compound 68-1 and a compound 68-2:

compound 68-1:

Ms m/z(ESI):399.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.85(dd,1H),8.58(td,1H),8.10(d,1H),8.00(t,1H),7.47(d,1H),7.00(d,1H),4.18(s,2H),3.88(s,3H),3.84-3.75(m,2H),2.93(dd,1H),2.47-2.41(m,1H),2.36-2.26(m,3H),2.18(dd,1H),2.03(dd,2H),1.94-1.84(m,2H),1.43(d,1H),1.26-1.21(m,2H),1.15-1.11(m,1H),0.56(q,1H),0.34-0.23(m,1H).

compound 68-2:

Ms m/z(ESI):399.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.84(dd,1H),8.57(td,1H),8.09(d,1H),7.99(t,1H),7.47(d,1H),7.00(d,1H),4.18(s,2H),3.85(d,3H),3.81-3.72(m,2H),2.95(td,1H),2.44(td,1H),2.36-2.25(m,3H),2.16(td,1H),2.11-1.99(m,2H),1.96-1.84(m,2H),1.43(d,1H),1.29-1.21(m,2H),1.15-1.10(m,1H),0.56(q,1H),0.29(td,1H).

example 69

(R) -N- ((2, 3-dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 69)

(R)-N-((2,3-dihydrothieno[3,4-b]furan-6-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 4-bromo-3- (2-bromoethoxy) thiophene-2-carboxylic acid methyl ester (69A)

methyl 4-bromo-3-(2-bromoethoxy)thiophene-2-carboxylate

Methyl 4-bromo-3-hydroxythiophene-2-carboxylate (60B) (5 g, 21.1mmol) was dissolved in N, N-dimethylformamide (50 mL) at room temperature, and potassium carbonate (11.6 g,84.4 mmol) and dibromoethane (31.7 g,168.7 mmol) were added thereto, and the reaction was completed at 80 ℃ for 2 hours. To the reaction solution was added water (100 mL), the aqueous phase was extracted with methyl tert-butyl ether (50 mL × 3), the combined organic phases were washed with a saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 20.

¹ H NMR(400MHz,CDCl ₃ )δ7.40(s,1H),4.48(t,2H),3.88(s,3H),3.69(t,2H).

The second step: 2, 3-Dihydrothieno [3,4-B ] furan-6-carboxylic acid methyl ester (69B)

methyl 2,3-dihydrothieno[3,4-b]furan-6-carboxylate

Methyl 4-bromo-3- (2-bromoethoxy) thiophene-2-carboxylate (69A) (5.0g, 14.5 mmol) was dissolved in tetrahydrofuran (50 mL), and the temperature was reduced to-78 ℃ to add n-butyllithium (6.4mL, 16.0mmol) dropwise to the reaction, and the reaction was completed at-78 ℃ for 1.5 hours. The reaction solution was quenched with a saturated ammonium chloride solution (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) = 20.

¹ H NMR(400MHz,CDCl ₃ )δ6.94(t,1H),5.08(t,2H),3.85(s,3H),3.03(td,2H).

The third step: (2, 3-Dihydrothieno [3,4-b ] furan-6-yl) methanol (69C) (2, 3-dihydrothieno [3,4-b ] furan-6-yl) methanol

Lithium aluminum hydride (0.155g, 4.07mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 deg.C, and a solution of methyl 2,3-dihydrothieno [3,4-B ] furan-6-carboxylate (69B) (0.5g, 2.71mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction, followed by reaction at room temperature for 2 hours. The reaction was cooled to 0 ℃, and the reaction was quenched with water (0.16 mL), sodium hydroxide solution (10%, 0.32 mL) and water (0.32 mL) in this order, followed by addition of anhydrous sodium sulfate, drying, filtering the solid and washing with tetrahydrofuran (20 mL. Times.2), and concentrating the combined organic phases to give an oily liquid (2, 3-dihydrothieno [3,4-b ] furan-6-yl) methanol (69C) (0.41 g, yield: 96.7%).

The fourth step: 2,3-Dihydrothieno [3,4-b ] furan-6-carbaldehyde (69D)

2,3-dihydrothieno[3,4-b]furan-6-carbaldehyde

(2, 3-Dihydrothieno [3,4-b ] furan-6-yl) methanol (69C) (0.40g, 2.56mmol) was dissolved in dichloromethane (10 mL), manganese dioxide (2.23g, 2.56mmol) was added to the reaction, and the reaction was completed at room temperature for 12 hours. The reaction solution was filtered to remove a solid and washed with dichloromethane (10 mL. Times.2), and the combined organic phases were concentrated to give 2,3-dihydrothieno [3,4-b ] furan-6-carbaldehyde (69D) as a yellow solid (0.38 g, yield: 96%).

Ms m/z(ESI):155.0[M+H ⁺ ]。

The fifth step: (R) -N- ((2, 3-dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (69E)

(R)-N-((2,3-dihydrothieno[3,4-b]furan-6-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.30g, 1.15mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.82g, 5.76mmol) and 2, 3-dihydrothieno [3,4-b ] furan-6-carbaldehyde (69D) (0.266g, 1.73mmol) were added to the reaction mixture at room temperature overnight. Sodium borohydride (0.065g, 1.73mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):399.2[M+H ⁺ ]。

And a sixth step: (R) -N- ((2, 3-dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 69)

(R) -N- ((2, 3-dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (69E) (0.15g, 0.376 mmol) was dissolved in ethyl acetate (4 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((2, 3-dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (compound 69) (0.16 g, yield: 98%) as a white solid.

Ms m/z(ESI):399.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.87(d,1H),8.61(t,1H),8.18(t,1H),8.03(dd,1H),6.96(t,1H),4.92(t,2H),4.11(s,2H),3.89-3.69(m,2H),3.03-2.96(m,3H),2.53-2.46(m,3H),2.37-2.25(m,1H),2.24-2.11(m,2H),1.99-1.83(m,2H),1.74-1.46(m,5H),1.24-1.17(m,1H),0.88-0.81(m,1H).

Example 70

N- ((3-Methoxythiophen-2-yl) methyl) -2- (2- (pyridin-2-yl) -11-oxadispiro [ 3.1.4) ⁶ .3 ⁴ ]Tridecan-2-yl) ethan-1-amine hydrochloride (Compound 70)

N-((3-methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)-11-oxadispiro[3.1.4 ⁶ .3 ⁴ ]tridecan-2-yl)ethan-1-amine hydrochloride

The first step is as follows: 9-Methenyl6-oxaspiro [4.5] decane (70B)

9-methylene-6-oxaspiro[4.5]decane

Potassium tert-butoxide (10.92g, 97.27mmol) and methyltriphenylphosphonium bromide (34.74g, 97.27mmol) were dissolved in diethyl ether (100 mL), added to a reaction flask, heated to reflux for 1 hour, and 6-oxaspiro [4.5] decan-9-one (70A) (10.00g, 64.85mmol) was dissolved in diethyl ether (10 mL) and added dropwise to the reaction and refluxed for 1.5 hours. After cooling, water (100 mL) was added to the reaction solution, and aqueous phase ether (50 mL × 3) was extracted, the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 20) to give 9-methylalnyl-6-oxaspiro [4.5] decane (70B) as an oily liquid (8.0 g, yield: 80%).

The second step is that: 11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-one (70C)

11-oxadispiro[3.1.4 ⁶ .3 ⁴ ]tridecan-2-one

Reacting 9-methyl alkenyl-6-oxaspiro [4.5 ]]Decane (70B) (7g, 46.05mmol), dissolved in diethyl ether (100 mL), zn-Cu (40.4g, 621.68mmol) added, stirred and cooled to 0 ℃ and a solution of trichloroacetyl chloride (45.2g, 248.68mmol) in ethylene glycol dimethyl ether (50 mL) added dropwise, after reaction at room temperature for 3 hours, filtered, the filter cake washed with diethyl ether (50 mL. Times.1), the filtrate evaporated to dryness and dissolved in glacial acetic acid (150 mL), zinc dust (31.31g, 478.7 mmol) added in small portions and reacted at 60 ℃ for 3 hours. Cooling, filtration, washing of the filter cake with ether (50 mL × 1), addition of water (300 mL × 3) to the reaction solution, extraction with aqueous ether (100 mL × 3), combination of the organic phases, washing with water (300 mL × 1), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification of the crude product by column chromatography (petroleum ether/ethyl acetate (v/v) =10 ⁶ .3 ⁴ ]Tridecan-2-one (70C) (6.0 g, yield: 67.8%).

¹ H NMR(400MHz,CDCl ₃ )δ3.70-3.63(m,2H),2.87(q,2H),2.84-2.74(m,2H),1.90-1.81(m,4H),1.72(ddd,4H),1.59(tdd,2H),1.46-1.36(m,2H).

The third step: 2-cyano-2- (11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-ylidene) acetic acid methyl ester (70D)

methyl 2-cyano-2-(2,6-dioxaspiro[4.5]decan-9-ylidene)acetate

Reacting 11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-one (70C) (1.8g, 9.26mmol), methyl cyanoacetate (1.84g, 18.53mmol), ammonium acetate (0.72g, 9.26mmol), acetic acid (0.56g, 9.26mmol) and toluene (25 mL) were charged to a reaction flask and the temperature was raised to reflux for 12 hours. After cooling, a sodium hydrogencarbonate solution (50 mL) was added to the reaction mixture, and aqueous ethyl acetate (30 mL × 3) was extracted, the organic phases were combined, washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =1 to 5) ⁶ .3 ⁴ ]Tridecan-2-ylidene) acetic acid methyl ester (70D) (2.0 g, yield: 78.4%).

Ms m/z(ESI):276.2[M+H ⁺ ]。

The fourth step: 2-cyano-2- [2- (2-pyridyl) -11-oxadispiro [3.1.4 ⁶ .3 ⁴ ]Tridecan-2-yl radical]Acetic acid methyl ester (70E)

methyl 2-cyano-2-[2-(2-pyridyl)-11-oxadispiro[3.1.4 ⁶ .3 ⁴ ]tridecan-2-yl]acetate

Adding isopropyl magnesium chloride (5.7mL, 11.4mmol) into a reaction flask under the protection of nitrogen, cooling to 0 ℃, adding a tetrahydrofuran (15 mL) solution of 2-bromopyridine (1.8g, 11.4mmol) dropwise into the reaction, reacting at room temperature for 2 hours, adding cuprous iodide (0.14g, 0.76mmol) into the reaction, stirring the reaction for 0.5 hours, and adding 2-cyano-2- (11-oxadispiro [3.1.4 ] spiro [3.1.4 ] ⁶ .3 ⁴ ]A solution of methyl tridecan-2-ylidene) acetate (70D) (2.1g, 7.6 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, and the temperature was raised to 50 ℃ for 5 hours. The reaction was quenched by adding ice water (20 mL) and 1N hydrochloric acid (20 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =10Oily liquid 2-cyano-2- [2- (2-pyridyl) -11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-yl radical]Methyl acetate (70E) (1 g, yield: 37%).

Ms m/z(ESI):355.2[M+H ⁺ ]。

The fifth step: 2- [2- (2-pyridinyl) -11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-yl radical]Acetonitrile (70F)

2-[2-(2-pyridyl)-11-oxadispiro[3.1.4 ⁶ .3 ⁴ ]tridecan-2-yl]acetonitrile

Ethylene glycol (20 mL) was added to 2-cyano-2- [2- (2-pyridyl) -11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-yl radical]To methyl acetate (70E) (1.0 g, 2.82mmol) was added potassium hydroxide (0.32g, 5.64mmol), and the mixture was heated at 120 ℃ for reaction for 3 hours. The reaction solution was cooled, water (80 mL) was added, the aqueous phase was extracted with methyl t-butyl ether (30 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) =1 to 2) ⁶ .3 ⁴ ]Tridecan-2-yl radical]Acetonitrile (70F) (0.48 g, yield: 57.4%).

Ms m/z(ESI):297.2[M+H ⁺ ]；

¹ H NMR(400MHz,CDCl ₃ )δ8.60(d,1H),7.73(d,1H),7.40(d,1H),7.21(dd,1H),3.64(t,2H),2.87(s,2H),2.61(d,2H),2.32(d,2H),1.82-1.63(m,6H),1.57-1.50(m,3H),1.37-1.26(m,3H).

And a sixth step: 2- [2- (2-pyridinyl) -11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-yl radical]Ethylamine (70G)

2-[2-(2-pyridyl)-11-oxadispiro[3.1.4 ⁶ .3 ⁴ ]tridecan-2-yl]ethanamine

Lithium aluminum hydride (0.123g, 3.24mmol) was dissolved in tetrahydrofuran (10 mL), and 2- [2- (2-pyridyl) -11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-yl]Acetonitrile (70F) (0.48g, 1.62mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was quenched with water (0.12 mL), sodium hydroxide solution (10%, 0.24 mL) and water (0.24 mL) in this order, dried by adding anhydrous sodium sulfate, stirred for 20 minutes, filtered, and the solid was washed with tetrahydrofuran (20 mL. Times.2). The combined organic phases were concentrated to give 2- [2- (2-pyridyl) -11-oxadispiro [3.1.4 ] as an oily liquid ⁶ .3 ⁴ ]Tridecan-2-yl radical]Ethylamine (70G) (0.48G, yield: 98.7%).

Ms m/z(ESI):301.2[M+H ⁺ ]。

The seventh step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (2- (pyridin-2-yl) -11-oxadispiro [ 3.1.4) ⁶ .3 ⁴ ]Tridecan-2-yl) ethan-1-amine (70H)

N-((3-methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)-11-oxadispiro[3.1.4 ⁶ .3 ⁴ ]tridecan-2-yl)ethan-1-amine

2- [2- (2-pyridyl) -11-oxadispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-yl radical]Ethylamine (70G) (0.30g, 0.99mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.71g, 4.9mmol) and 3-methoxythiophene-2-carboxaldehyde (0.21g, 1.5mmol) were added to react at room temperature overnight. Sodium borohydride (0.056 g,1.5 mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water (30 mL), the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) =50Dispiro [3.1.4 ] ⁶ .3 ⁴ ]Tridecan-2-yl) ethan-1-amine (70H) (0.15 g, yield: 35.2%).

Ms m/z(ESI):427.2[M+H ⁺ ]。

Eighth step: n- ((3-Methoxythiophen-2-yl) methyl) -2- (2- (pyridin-2-yl) -11-oxadispiro [ 3.1.4) ⁶ .3 ⁴ ]Tridecan-2-yl) ethan-1-amine hydrochloride (Compound 70)

Reacting N- ((3-methoxythiophen-2-yl) methyl) -2- (2- (pyridin-2-yl) -11-oxadispiro [ 3.1.4) ⁶ .3 ⁴ ]Tridecan-2-yl) ethan-1-amine (70H) (0.15g, 0.35mmol) was dissolved in ethyl acetate (5 mL), and an ethyl acetate solution of hydrogen chloride (1 mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. Directly spin-drying the reaction solution to obtain white solid N- ((3-methoxythiophene-2-yl) methyl) -2- (2- (pyridine-2-yl) -11-oxadispiro [ 3.1.4) ⁶ .3 ⁴ ]Tridecan-2-yl) ethan-1-amine hydrochloride (Compound 70) (0.16 g, 98.3% yield).

Ms m/z(ESI):427.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.81(dd,1H),8.61(td,1H),8.05-7.94(m,2H),7.47(d,1H),7.00(d,1H),4.22(s,2H),3.88(s,3H),3.68-3.64(m,2H),2.81-2.70(m,2H),2.61-2.35(m,6H),1.82-1.78(m,4H),1.72-1.51(m,6H),1.41-1.36(m,2H).

Example 71

(R) -N- ((3- (difluoromethoxy) -4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (Compound 71)

(R)-N-((3-(difluoromethoxy)-4-ethynylthiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine 4-methylbenzenesulfonate

The first step is as follows: 4-bromo-3- (difluoromethoxy) thiophene-2-carboxylic acid methyl ester (71A)

methyl 4-bromo-3-(difluoromethoxy)thiophene-2-carboxylate

Methyl 4-bromo-3-hydroxythiophene-2-carboxylate (60B) (2.0 g, 8.44mmol) was dissolved in acetonitrile (20 mL) at room temperature, the temperature was reduced to-10 deg.C, a solution of potassium hydroxide (9.5 g, 1699 mmol) in water (20 mL) was added to the reaction, diethyl bromofluoromethylphosphonate (4.5 g,16.9 mmol) was added dropwise to the reaction, and the reaction was stirred at-10 deg.C for 1 hour. The reaction solution was extracted with methyl tert-butyl ether (20 mL × 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 20.

Ms m/z(ESI):310.9[M+Na ⁺ ]；

The second step: (4-bromo-3- (difluoromethoxy) thiophen-2-yl) methanol (71B)

(4-bromo-3-(difluoromethoxy)thiophen-2-yl)methanol

Lithium aluminum hydride (0.18g, 4.7mmol) was dissolved in tetrahydrofuran (10 mL), the temperature was lowered to 0 ℃ and a solution of methyl 4-bromo-3- (difluoromethoxy) thiophene-2-carboxylate (71A) (0.90g, 3.14mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction and the reaction was carried out at room temperature for 2 hours. The reaction solution was cooled to 0 ℃, and the reaction was quenched with water (0.18 mL), sodium hydroxide solution (10% aq.,0.36 mL) and water (0.36 mL) in this order, and then anhydrous sodium sulfate was added to dry, filter, wash the solid with tetrahydrofuran (20 mL × 2), and concentrate the combined organic phases to give (4-bromo-3- (difluoromethoxy) thiophen-2-yl) methanol (71B) (0.70 g, yield: 86.2%) as an oily liquid.

The third step: 4-bromo-3- (difluoromethoxy) thiophene-2-carbaldehyde (71C)

4-bromo-3-(difluoromethoxy)thiophene-2-carbaldehyde

(4-bromo-3- (difluoromethoxy) thiophen-2-yl) methanol (71B) (0.70g, 2.70mmol) was dissolved in dichloromethane (10 mL), and manganese dioxide (2.35g, 27.0 mmol) was added to the reaction, and the reaction was allowed to proceed at room temperature for 12 hours. The reaction was filtered, the filter cake was washed with dichloromethane (20 mL. Times.2), and the combined organic phases were concentrated to give 4-bromo-3- (difluoromethoxy) thiophene-2-carbaldehyde (71C) (0.30 g, yield: 43.2%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ9.96(d,1H),7.68(d,1H),6.68(t,1H).

The fourth step: 3- (Difluoromethoxy) -4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (71D)

3-(difluoromethoxy)-4-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde

4-bromo-3- (difluoromethoxy) thiophene-2-carbaldehyde (71C) (0.30g, 1.17mmol) and trimethylsilyne (0.46g, 4.67mmol) were dissolved in tetrahydrofuran (5 mL) and triethylamine (5 mL), and trans-bis (triphenylphosphine) palladium (II) dichloride (0.164g, 0.233mmol) and cuprous iodide (0.045g, 0.233mmol) were added to the reaction under nitrogen protection, and the temperature was raised to 100 ℃ for 12 hours. The reaction solution was filtered, and the organic phase was directly concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 50.

¹ H NMR(400MHz,CDCl ₃ )δ9.98(d,1H),7.77(d,1H),6.90(t,2H),0.26(s,9H).

The fifth step: 3- (Difluoromethoxy) -4-ethynylthiophene-2-carbaldehyde (71E)

3-(difluoromethoxy)-4-ethynylthiophene-2-carbaldehyde

3- (difluoromethoxy) -4- ((trimethylsilyl) ethynyl) thiophene-2-carbaldehyde (71D) (0.08g, 0.29mmol) was dissolved in methanol (5 mL), and potassium carbonate (0.06g, 0.43mmol) was added to the reaction, after which the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was quenched with water (20 mL), the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10) to give 3- (difluoromethoxy) -4-ethynylthiophene-2-carbaldehyde (71E) as a yellow solid (0.045 g, yield: 68%).

¹ H NMR(400MHz,CDCl ₃ )δ9.98(s,1H),7.84(d,1H),6.85(t,2H),3.28(s,1H).

And a sixth step: (R) -N- ((3- (difluoromethoxy) -4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (71F)

(R)-N-((3-(difluoromethoxy)-4-ethynylthiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.058g, 0.223mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.116g, 1.11mmol) and 3- (difluoromethoxy) -4-ethynylthiophene-2-carbaldehyde (71E) (0.045g, 0.223mmol) were added to the reaction at room temperature overnight. Sodium borohydride (0.013g, 0.334mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (2 mL) and stirring for 1 hour. The reaction was quenched with water (20 mL), the aqueous phase was extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the crude product was purified with preparative plate (dichloromethane/methanol (v/v) = 10.

Ms m/z(ESI):447.2[M+H ⁺ ]；

Eighth step: (R) -N- ((3- (difluoromethoxy) -4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (Compound 71)

(R) -N- ((3- (difluoromethoxy) -4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (71F) (0.035g, 0.078mmol) was dissolved in ethyl acetate (4 mL), and p-toluenesulfonic acid monohydrate (0.015g, 0.078mmol) was dissolved in ethyl acetate (2 mL) and added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction solution was directly spin-dried and dried to obtain (R) -N- ((3- (difluoromethoxy) -4-ethynylthiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine 4-methylbenzenesulfonate (compound 71) as a white solid (0.050 g, yield: 100%).

Ms m/z(ESI):447.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.76(d,1H),8.32(t,1H),7.93(d,1H),7.82(s,1H),7.75(t,1H),7.70(d,2H),7.24(d,2H),6.89(t,1H),4.27(s,2H),3.80-3.68(m,3H),3.07-2.99(m,1H),2.57-2.40(m,3H),2.37(s,3H),2.28-2.18(m,1H),2.11-2.01(m,2H),1.88-1.78(m,2H),1.69-1.62(m,1H),1.59-1.47(m,4H),1.20-1.15(s,1H),0.81-0.73(m,1H).

Example 72

(R) -N- ((3-methoxybenzo [ b ] thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 72)

(R)-N-((3-methoxybenzo[b]thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 3-methoxybenzo [ B ] thiophene (72B)

3-methoxybenzo[b]thiophene

3-bromobenzo [ b ] thiophene (72A) (4.45g, 20.8 mmol) was dissolved in N, N-dimethylformamide (40 mL) and sodium methoxide solution (30 wt%,40 mL) under nitrogen, and cuprous iodide (0.08g, 0.42mmol), cupric oxide (0.84g, 10.5 mmol) and potassium iodide (0.05g, 0.3 mmol) were added to the reaction, and the reaction was allowed to warm to 120 ℃ for 6 hours. The reaction solution was cooled to 0 ℃, the reaction was quenched with water (50 mL), filtered with celite, the filtrate was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated ammonium chloride (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and after the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 100) to give 3-methoxybenzo [ B ] thiophene (72B) (2.6 g, yield: 75.8%) as an oily liquid.

¹ H NMR(400MHz,CDCl ₃ )δ7.79-7.73(m,2H),7.38-7.32(m,2H),6.29(s,1H),3.97(s,3H).

The second step: 3-Methoxybenzo [ b ] thiophene-2-carbaldehyde (72C)

3-methoxybenzo[b]thiophene-2-carbaldehyde

3-methoxybenzo [ B ] thiophene (72B) (1.64g, 10.0 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen, the temperature was reduced to-78 deg.C, N-butyllithium (4.4 mL,11.0 mmol) was added dropwise to the reaction, the reaction was stirred for 0.5 hour, N-dimethylformamide (0.88g, 12.0 mmol) was added dropwise to the reaction, and the reaction was continued for 1 hour. The reaction solution was quenched with a saturated ammonium chloride solution (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1 to 10) to obtain 3-methoxybenzo [ b ] thiophene-2-carbaldehyde (72C) as an oily liquid (1.6 g, yield: 83.3%).

¹ H NMR(400MHz,CDCl ₃ )δ10.37(s,1H),7.90(d,1H),7.75(d,1H),7.52-7.48(m,1H),7.45-7.37(m,1H),4.33(s,3H).

The third step: (R) -N- ((3-methoxybenzo [ b ] thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (72D)

(R)-N-((3-methoxybenzo[b]thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.30g, 1.15mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.818g, 5.76mmol) and 3-methoxybenzo [ b ] thiophene-2-carbaldehyde (72C) (0.276 g, 1.38mmol) were added to the reaction and reacted overnight at room temperature. Sodium borohydride (0.065g, 1.73mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):437.2[M+H ⁺ ]；

The fourth step: (R) -N- ((3-methoxybenzo [ b ] thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 72)

(R) -N- ((3-methoxybenzo [ b ] thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (72D) (0.19g, 0.44mmol) was dissolved in ethyl acetate (4 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((3-methoxybenzo [ b ] thiophen-2-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (compound 72) as a white solid (0.32 g, yield: 100%).

Ms m/z(ESI):437.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.83(dd,1H),8.57-8.48(m,1H),8.14(dd,1H),7.96(dd,1H),7.86-7.82(m,2H),7.51-7.39(m,2H),4.40(s,2H),4.03(s,3H),3.84-3.79(m,1H),3.75-3.65(m,1H),3.08-3.01(m,1H),2.60-2.40(m,3H),2.40-2.12(m,3H),1.98-1.90(m,1H),1.87-1.83(m,1H),1.68-1.43(m,5H),1.25-1.15(m,1H),0.87-0.82(m,1H).

Example 74

(R) -N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 74)

(R)-N-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride

The first step is as follows: 2, 3-dihydrobenzofuran-7-carbaldehyde (74B)

2,3-dihydrobenzofuran-7-carbaldehyde

Under the protection of nitrogen, 7-bromo-2, 3-dihydrobenzofuran (74A) (2.0g, 10.05mmol) is dissolved in tetrahydrofuran (20 mL), the temperature is reduced to-78 ℃, N-butyllithium (4.5mL, 11.05mmol) is dropwise added into the reaction, the reaction is stirred for 0.5 hour, then N, N-dimethylformamide (1.1g, 15.07mmol) is dropwise added into the reaction, and the reaction is continued for 1 hour. The reaction solution was quenched with a saturated ammonium chloride solution (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and after the crude product was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) =10: 1-4) to give 2, 3-dihydrobenzofuran-7-carbaldehyde (74B) as an oily liquid (1.4 g, yield: 94%).

¹ H NMR(400MHz,CDCl ₃ )δ10.20(s,1H),7.58(d,1H),7.40(dd,1H),6.93(t,1H),4.74(t,2H),3.24(t,2H).

The second step is that: (R) -N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethanamine (74C)

(R)-N-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

(R) -2- (9- (pyridin-2-yl) -6-dioxaspiro [4.5] decan-9-yl) ethylamine (intermediate 1) (0.260g, 1.0 mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.71g, 5.0 mmol) and 2, 3-dihydrobenzofuran-7-carbaldehyde (74B) (0.8g, 1.2mmol) were added to the reaction mixture, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.06g, 1.2mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):393.3[M+H ⁺ ]；

The third step: (R) -N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (Compound 74)

(R) -N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine (74C) (0.18g, 0.46mmol) was dissolved in ethyl acetate (4 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give (R) -N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethylamine hydrochloride (compound 74) as a white solid (0.195 g, yield: 99.1%).

Ms m/z(ESI):393.4[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.82(d,1H),8.53(d,1H),8.14-7.90(dd,2H),7.27(d,1H),7.10(d,1H),6.87(t,1H),4.61(t,2H),4.07(s,2H),3.83-3.64(m,2H),3.24(t,2H),3.04-2.98(m,1H),2.50-2.44(m,3H),2.31-2.28(m,1H),2.18-2.10(m,2H),1.95-1.83(m,2H),1.70-1.54(m,5H),1.23-1.17(m,1H),0.85-0.83(m,1H).

Example 75

N- ((2, 3-Dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (4 '- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] pyran ] -4' -yl) ethylamine hydrochloride (Compound 75)

N-((2,3-dihydrothieno[3,4-b]furan-6-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine hydrochloride

The first step is as follows: n- ((2, 3-dihydrothieno [3,4-B ] furan-6-yl) methyl) -2- (4 '- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] pyran ] -4' -yl) ethylamine (75B)

N-((2,3-dihydrothieno[3,4-b]furan-6-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine

(4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) ethylamine (68E) (0.20g, 0.734mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.52g, 3.67mmol) and 2, 3-dihydrothieno [3,4-b ] furan-6-carbaldehyde (0.14g, 0.88mmol) were added to the reaction solution, and the reaction was allowed to proceed overnight at room temperature. Sodium borohydride (0.04g, 1.10 mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):411.2[M+H ⁺ ]。

The second step is that: n- ((2, 3-Dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (4 '- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] pyran ] -4' -yl) ethylamine hydrochloride (Compound 75)

N- ((2, 3-dihydrothieno [3,4-B ] furan-6-yl) methyl) -2- (4 '- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] pyran ] -4' -yl) ethylamine (75B) (0.10g, 0.24mmol) was dissolved in ethyl acetate (4 mL), and an ethyl acetate solution of hydrogen chloride (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give N- ((2, 3-dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (4 '- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] pyran-4' -yl) ethylamine hydrochloride (compound 75) as a white solid (0.11 g, yield: 100%).

Ms m/z(ESI):411.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.87(dd,1H),8.62(td,1H),8.15(d,1H),8.06-8.12(m,1H),6.96(t,1H),4.92(td,2H),4.10(s,2H),3.84-3.72(m,2H),3.02-2.92(m,3H),2.46(td,1H),2.38-2.31(m,3H),2.24-2.15(m,1H),2.13-2.03(m,1H),1.99(s,2H),1.95-1.85(m,2H),1.31-1.21(m,2H),1.17-1.09(m,1H),0.56(q,1H),0.32-0.26(td,1H).

Resolution of the compound N- ((2, 3-dihydrothieno [3,4-b ] furan-6-yl) methyl) -2- (4 '- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] pyran ] -4' -yl) ethylamine hydrochloride (Compound 75)

N- ((2, 3-dihydrothieno [3,4-B ] furan-6-yl) methyl) -2- (4 '- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] pyran ] -4' -yl) ethylamine hydrochloride (100 mg) was taken for resolution, and after separation, two free base compound optical isomers were obtained, compound 75B-1 (retention time: 3.27min,24.46mg, oily liquid, ee% = 100%), compound 75B-2 (retention time: 5.55min,37.3mg, oily liquid, ee% = 100%).

Splitting conditions are as follows: the instrument is Waters 80 preparatory SFC (SFC-6); column ChiralPak AD,300 × 50mm i.d.,10 μm mobile phase a: carbon dioxide, B: ethanol (0.1% ammonia); gradient B40%; the flow rate is 80mL/min; back pressure is 100bar; the column temperature is 38 ℃; the wavelength is 220nm; the period is 8min; sample preparation, compound is dissolved in methanol to prepare 5mg/mL; injection of 4 mL/needle.

Compound 75B-1 and Compound 75B-2 following the salt formation procedure for Compound 75, two optical isomers Compound 75-1 and Compound 75-2, can be obtained:

compound 75-1:

Ms m/z(ESI):411.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.83(dd,1H),8.53(td,1H),8.12-7.87(m,2H),6.96(t,1H),4.92(td,2H),4.09(s,2H),3.81-3.73(m,2H),3.02-2.91(m,3H),2.45(td,1H),2.36-2.24(m,3H),2.19-1.99(m,3H),1.94-1.84(m,2H),1.43(d,1H),1.26-1.09(m,3H),0.56(q,1H),0.29(td,1H).

compound 75-2:

Ms m/z(ESI):411.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.85(dd,1H),8.57(td,1H),8.14-7.97(m,2H),6.96(d,1H),4.92(t,2H),4.09(s,2H),3.82-3.75(m,2H),3.02-2.92(m,3H),2.45(td,1H),2.36-2.26(m,3H),2.16(td,1H),2.11-1.97(m,2H),1.94-1.85(m,2H),1.43(d,1H),1.24(dt,2H),1.18-1.12(m,1H),0.56(q,1H),0.29(td,1H).

example 76

N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (compound 76)

N-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine hydrochloride

The first step is as follows: n- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (76B)

N-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine

(4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (68E) (0.22g, 0.8mmol) was dissolved in methylene chloride (10 mL), and sodium sulfate (0.57g, 4.04mmol) and 2, 3-dihydrobenzofuran-7-carbaldehyde (0.144g, 0.97mmol) were added to the reaction mixture to react at room temperature overnight. Sodium borohydride (0.046 g, 1.10mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):405.3[M+H ⁺ ]。

The second step is that: n- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) ethylamine hydrochloride (compound 76)

N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) ethylamine (76B) (0.22g, 0.54mmol) was dissolved in ethyl acetate (4 mL), and an ethyl acetate solution of hydrogen chloride (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction was directly spin-dried to give N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (compound 76) as a white solid (0.24 g, yield: 100%).

Ms m/z(ESI):405.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.84(d,1H),8.56(t,1H),8.10-7.96(m,2H),7.27(dd,1H),7.11(d,1H),6.87(t,1H),4.61(t,2H),4.07(s,2H),3.81-3.72(m,2H),3.24(t,2H),2.98(td,1H),2.47(td,1H),2.31(dd,3H),2.22-2.16(m,1H),2.03(dd,2H),1.94-1.85(m,2H),1.43(d,1H),1.27-1.19(m,2H),1.15-1.10(m,1H),0.56(q,1H),0.29(td,1H).

Resolution of the compound N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) ethylamine hydrochloride (compound 76)

N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (compound 76) (240 mg) was taken for resolution, and after separation, two optical isomers, compound 76B-1 (retention time: 5.566min,126.78mg, oily liquid, ee% = 100%), compound 76B-2 (retention time: 7.202min,95.87mg, oily liquid, ee% = 100%) were obtained.

Splitting conditions are as follows: apparatus is THar 80 preparatory SFC (SFC-16); column Phenomenex Lux Cellulose-2,250 × 30mm i.d.,5 μm. Mobile phase a: carbon dioxide, B: ethanol (0.1% ammonia); gradient B40%; the flow rate is 50mL/min; back pressure is 100bar; the column temperature is 38 ℃; the wavelength is 220nm; the period is 15min; sample preparation, compound is dissolved in methanol to make 8mg/ml; injection 2 ml/needle.

By the salt-forming method of the compound 76, N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- ((4S) -4'- (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4 '-yl) ethylamine (the compound 76-1) and N- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- ((4' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2 '-pyran ] -4' -yl) ethylamine (the compound 76-2) can be obtained:

compound 76-1:

Ms m/z(ESI):405.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.84(dd,1H),8.58(t,1H),8.11(d,1H),8.00(t,1H),7.27(dd,1H),7.11(d,1H),6.87(t,1H),4.61(t,2H),4.07(s,2H),3.82-3.72(m,2H),3.24(t,2H),2.98(td,1H),2.47(td,1H),2.36-2.29(m,3H),2.19(td,1H),2.03(dd,2H),1.94-1.86(m,2H),1.43(d,1H),1.26-1.21(m,2H),1.17-1.10(m,1H),0.56(q,1H),0.29(td,1H).

compound 76-2:

Ms m/z(ESI):405.3[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.84(dd,1H),8.58(t,1H),8.11(d,1H),8.00(t,1H),7.27(dd,1H),7.12(d,1H),6.87(t,1H),4.61(t,2H),4.07(s,2H),3.82-3.75(m,2H),3.24(t,2H),2.98(td,1H),2.47(td,1H),2.32(dd,3H),2.21(dd,1H),2.10–1.99(m,2H),1.94-1.86(m,2H),1.43(d,1H),1.26-1.21(m,2H),1.16-1.07(m,1H),0.56(q,1H),0.29(td,1H).

example 77

N- ((5-Fluoropyridin-3-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (Compound 77)

N-((5-fluoropyridin-3-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine hydrochloride

The first step is as follows: n- ((5-Fluoropyridin-3-yl) methyl) -2- (4 ' - (pyridin-2-yl) Tetrahydropiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (77B)

N-((5-fluoropyridin-3-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine

(4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran-4 ' -yl) ethylamine (68E) (0.25g, 0.918mmol) was dissolved in dichloromethane (10 mL), and sodium sulfate (0.65g, 4.59mmol) and 5-fluoropyridine-3-carbaldehyde (0.14g, 1.10mmol) were added to the reaction and reacted at room temperature overnight. Sodium borohydride (0.052g, 1.38mmol) was added to the reaction, and the reaction was stirred for 10 minutes, followed by addition of methanol (10 mL) and stirring for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50.

Ms m/z(ESI):382.2[M+H ⁺ ].

The second step is that: n- ((5-Fluoropyridin-3-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (Compound 77)

N- ((5-Fluoropyridin-3-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine (77B) (0.25g, 0.655 mmol) was dissolved in ethyl acetate (4 mL), and a solution of hydrogen chloride in ethyl acetate (1mL, 2.0M) was added to stir the reaction at room temperature for 0.5 hour. The reaction solution was directly spin-dried to give N- ((5-fluoropyridin-3-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (compound 77) as a white solid (0.27 g, yield: 98.6%).

Ms m/z(ESI):382.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.80-8.66(m,4H),8.24(dd,2H),8.11-8.07(m,1H),4.33-4.27(m,2H),3.88-3.73(m,2H),3.13(td,1H),2.64(td,1H),2.44-2.30(m,4H),2.12(dd,2H),2.01-1.91(m,2H),1.48(d,1H),1.26-1.22(m,2H),1.20-1.11(m,1H),0.58(q,1H),0.30(td,1H).

Resolution of the Compound N- ((5-Fluoropyridin-3-yl) methyl) -2- (4 ' - (pyridin-2-yl) Tetrahydropiro [ bicyclo [3.1.0] Hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (Compound 77)

N- ((5-fluoropyridin-3-yl) methyl) -2- (4 ' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2' -pyran ] -4' -yl) ethylamine hydrochloride (compound 77) (265 mg) was taken for resolution to give, after separation, two optical isomers compound 77B-1) (retention time: 5.46min,115.09mg, oily liquid, ee% = 99.1%), compound 77B-2 retention time: 5.97min,84.81mg, oily liquid, ee% = 99.4%).

Splitting conditions are as follows: the apparatus is a THar 80 preparatory SFC (SFC-16); column Phenomenex Lux Cellulose-2,250 × 30mm i.d.,5 μm. Mobile phase a: carbon dioxide, B: ethanol (0.1% ammonia); gradient B35%; the flow rate is 60mL/min; back pressure is 100bar; the column temperature is 38 ℃; the wavelength is 220nm; the period is 8min; sample preparation, compound is dissolved in methanol to 8.8mg/ml; injection 2 ml/needle.

By the salt-forming method using the compound 77, N- ((5-fluoropyridin-3-yl) methyl) -2- ((4's) -4' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2 '-pyran ] -4' -yl) ethylamine (the compound 77-1) and N- ((5-fluoropyridin-3-yl) methyl) -2- ((4 'r) -4' - (pyridin-2-yl) tetrahydrospiro [ bicyclo [3.1.0] hexane-3, 2 '-pyran ] -4' -yl) ethylamine (the compound 77-2) can be obtained:

compound 77-1:

Ms m/z(ESI):382.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.88(dd,1H),8.73(dt,3H),8.21(d,2H),8.08(t,1H),4.31(s,2H),3.87-3.73(m,2H),3.15-3.10(m,1H),2.67-2.61(m,1H),2.41-2.30(m,4H),2.12(dd,J＝20.3,14.0Hz,2H),2.00-1.92(m,2H),1.47(d,1H),1.30-1.22(m,2H),1.17-1.11(m,1H),0.57(q,1H),0.30(td,1H).

compound 77-2:

Ms m/z(ESI):382.2[M+H ⁺ ]；

¹ H NMR(400MHz,CD3OD)δ8.88(dd,1H),8.77-8.66(m,3H),8.21(d,2H),8.08(t,1H),4.29(s,2H),3.87-3.73(m,2H),3.12(td,1H),2.63(td,1H),2.42-2.30(m,4H),2.11(dd,2H),2.00-1.91(m,2H),1.47(d,1H),1.29-1.22(m,2H),1.17-1.11(m,1H),0.58(q,1H),0.30(td,1H).

biological testing

1. In vitro mu receptor Activity assay

Forskolin stimulates cAMP release from OPRM1 cells (available from DiscoveviRx) which are a cell line with high expression of human mu-opioid receptor, and mu-opioid receptor agonist inhibits Forskolin-stimulated cAMP release. The agonistic activity of a compound at the human mu-opioid receptor can be determined by assaying the inhibitory effect of the compound on forskolin stimulated cAMP release. Firstly, forskolin with a certain concentration and a test compound with different concentrations are incubated with a human mu-opioid receptor high-expression cell strain. Then, use

The Ultra cAMP kit (purchased from PerkinElmer's cat # TRF 0263) detects cAMP levels in cells based on the principle of time-resolved fluorescence resonance energy transfer (TR-FRET). The specific method comprises the following steps:

CHO-K1OPRM1 cells were cultured in DMEM-F12 medium containing diabody (100U/ml penicillin, 100g/ml streptomycin) and 10% FBS. On the day of the experiment, cells were detached with PBS/5mM EDTA and harvested by centrifugation. Then, the cells were resuspended with a StULATION Buffer (14.5 ml 1X HBSS, 75. Mu.l 1M HEPES, 30. Mu.l 250mM IBMX, 200. Mu.l 7.5% BSAstabilizer, PH7.4) and the cell concentration was adjusted to 1X 105cells/ml. Forskolin (final concentration of 1.5. Mu.M) and various concentrations of compounds (final concentration of 1000,200,40,8,1.6,0.32,0.064,0 nM) were added to the Ststimulation Buffer and 5. Mu.l per well were added to 384 well plates. A further 5. Mu.l of cell suspension (cell mass 500 cells/well) was added to each well and incubated at room temperature for 30min. Then, 5. Mu.l of 4X Eu-cAMP tracer working solution (Eu-cAMP stock solution diluted 50-fold with cAMP Detection Buffer) was added to each well. Then 5. Mu.l of 4 × Ulight-anti-cAMP working solution (dilution of the ULight-anti-cAMP stock solution 150 times with cAMP Detection Buffer) was added to each well. And incubated at room temperature for 1h. The 384 well plates were tested for cAMP levels using a microplate reader (Perkin Elmer, envision) TR-FRET method. The data obtained were processed and fitted with origin7.5 software to EC50 and the maximum pharmacodynamic activity (Efficacy (%)) of the compound was calculated. Efficacy (%) = maximum pharmacodynamic activity of compound/maximum pharmacodynamic activity of positive compound 100%, positive compound is TRV-130. The test results are shown in Table 1.

TABLE 1 in vitro assay of mu receptor Activity

The TRV-130 structure is as follows:

and (4) conclusion: the compound can activate opioid mu receptor and has obvious activity in vitro.

2. In vitro detection of beta-arrestin activity

OPRM1 cells (purchased from Discovex Rx company) are cell lines with high expression of human mu-opioid receptor, meanwhile, the cell lines also highly express beta-arrestin 2 fused with beta galactosidase fragments, and the highly expressed human mu-opioid receptor genes are fused with complementary fragments of the beta-galactosidase. If the compound is capable of acting on the beta-arrestin pathway, it will promote the binding of the mu-receptor to beta-arrestin 2, when the two fragments of beta galactosidase are fused together, exhibiting intact beta-galactosidase activity. Thus, by using a beta galactosidase activity detection kit (purchased from Applied Biosystems) to detect beta galactosidase activity, it is possible to detect whether a compound acts on the beta-arrestin pathway. The specific method comprises the following steps:

CHO-K1OPRM1 cells were cultured in DMEM-F12 medium containing diabody (100U/ml penicillin, 100g/ml streptomycin) and 10% FBS. The day before the experiment, cells were digested with trypsin, collected by centrifugation, counted, and plated in 96-well cell culture plates (20000) cells/well), and cultured for 24h. On the day of the experiment, the medium was aspirated and 90. Mu.l of fresh medium was added. Dilution of the Positive or test Compounds with medium gradient (final concentration 1X 10- ³ ,10- ⁴ ,10- ⁵ ,10- ⁶ ,10- ⁷ ,10- ⁸ ,10- ⁹ M), add 10. Mu.l to 96-well plates and incubate for 90min in an incubator. Then, the cells were washed once with PBS, PBS was removed, and 20. Mu.l of lysine Solution (containing 0.5mM DTT) was added to each well and incubated for 10min. Add 4 μ l of lysed cells per well to 384 well plates. Galacton-

And diluting the substrate by 50 times by using Reaction Buffer, balancing to room temperature, adding a 384-well plate into 20 mu l of each well, mixing uniformly, incubating at 25 ℃ for 30min in a dark place, and detecting a chemiluminescent signal. The origin7.5 assay was used to fit the EC50 and calculate the maximum pharmacodynamic activity (Efficacy (%)) of the compound. Efficacy (%) = maximum pharmacodynamic activity of compound/maximum pharmacodynamic activity of positive compound × 100%. The positive compound was TRV-130. The test results are shown in Table 2.

TABLE 2 in vitro beta-arrestin Activity assay results

"-" indicates no activity.

And (4) conclusion: the compound of the invention has no obvious activity on beta-arrestin and has good preference.

3. Mouse hot plate experiment

Female C57 mice 18-22g were purchased from Duoduosho laboratory animals, inc. The temperature of the hot plate apparatus was set to 56 ℃ and the experiment was started after 30min of stabilization after temperature rise. Sequentially placing the animals into a hot plate instrument for testing, and observing the foot reaction of the animals after licking, wherein the foot reaction is used as an index of pain reaction; recording the time from the animal entering the hot plate to the time of the animal licking the hindpaw caused by the thermal stimulus, and according with Animals with group entry criteria (paw response time below 25s after licking) were group-numbered. Grouped by baseline threshold, 10 per group. Compounds at different concentrations were given subcutaneously at 10ml/kg for 15min and the reaction time was recorded with 30 seconds as the cut-off time. And (3) carrying out statistical analysis on the result, and calculating the% MPE value according to a formula: % MPE = (Tn-T0)/(30-T0), (Tn is the animal's time to lick the foot after administration, T0 is the animal's time to lick the foot before administration). And the ED was fitted by analyzing the data with origin7.5 software ₅₀ The value is obtained. The results are shown in Table 3.

TABLE 3 results of the experiment

And (4) conclusion: the compound has obvious analgesic effect in a hot plate pain model.

4. Colon motility experiment of mice

Male C57 mice, 18-22g, were purchased from Duoduoshu laboratory animals, inc. Fasting was not prohibited overnight. On the day of the experiment, 10 animals were randomized into groups. The compound was formulated in terms of 5% DMSO,95% physiological saline to 0.03mg/ml,0.1mg/ml,0.3mg/ml,1mg/ml,3mg/ml,5mg/ml (free base concentration), and the amount of compound administered was 10ml/kg. Animals were weighed and administered subcutaneously. After 30min, the mice were anesthetized with a small animal anesthetic (Matrx, VME 2), 5% isoflurane (rewarded life technologies ltd.) for 0.5-1min, the mice were taken out of the anesthesia machine and glass beads (2 mm in diameter) were inserted into the anus of the mice, advancing by 2cm. The time for which the mice expelled the glass beads from the body was observed and recorded. Maximum observation time 240min. Maximum effect (MPE (%)) was calculated using Office Excel software. And the ED was fitted using origin7.5 software analysis ₅₀ The value is obtained. MPE = (test group time-blank group time)/(240-blank group time) × 100%. The results are shown in Table 4.

TABLE 4 mouse Colon motility test results

Example numbering	ED ₅₀ (mg/kg)
		Compound 28	22.3
TRV-130	32.6
		Morphine (morphine)	4.1

And (4) conclusion: the compounds of the present invention, particularly compound 28, had less effect on colonic motility.

While the examples have described the compounds described herein, those skilled in the art will recognize that various modifications may be made without departing from the spirit and scope thereof.

Claims

1. A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

wherein

A is selected from

B is pyridyl;

R ₁ is selected from H;

R ₂₁ selected from-OCHF ₂ 、-CH ₂ OCH ₃ An ethynyl group;

n is selected from 2; m is selected from 1;

or when n =2,m =2, a is selected from

B is pyridyl, R ₂₁ Ethynyl and methoxy, respectively.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is

B is

R ₁ Is selected from H;

n is selected from 2.

3. A compound, or a pharmaceutically acceptable salt thereof,

4. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the salt is selected from the hydrochloride, sulfate, acetate, benzenesulfonate or p-toluenesulfonate salt.

5. A pharmaceutical composition, said composition comprising: an effective dose of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or further comprising one or more other therapeutic agents and a pharmaceutically acceptable carrier or excipient.

6. The composition of claim 5, further comprising at least one additional analgesic, anti-constipation agent.

7. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a composition according to claim 5, in the manufacture of a medicament for the prevention or treatment of pain.