Nitrogen-containing compound as well as preparation method and application thereof

Abstract

The invention provides the following compounds or pharmaceutically acceptable salts, prodrugs, deuterated compounds, hydrates, solvates, enantiomers, diastereoisomers or racemes of the compounds, and a preparation method of the compounds or the pharmaceutically acceptable salts, prodrugs, deuterated compounds, hydrates, solvates, enantiomers, diastereoisomers or racemes of the compounds. The invention also relates to application of the compound # imgabs0 # for treating depression

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a compound having a rapid antidepressant effect and application thereof. Background Art

[0002] Depression is a common mental illness characterized by significant and persistent low mood. Clinically, it can be seen that the mood is low and disproportionate to the situation. The depression can range from melancholy to grief, inferiority and depression, and even pessimism and world-weariness. There may be suicidal attempts or behaviors. In severe cases, psychotic symptoms such as hallucinations and delusions may occur. More than 350 million people suffer from depression worldwide, an increase of 18% in the past decade.

[0003] The disorder of neurotransmitters such as norepinephrine, dopamine, and 5-hydroxytryptamine (5-HT) in the brain is considered to be the main biological factor leading to depression. The main means of treating depression relies on the use of antidepressants, which are mainly divided into the following four categories according to their effects and mechanisms of action: 1) Monoamine oxidase inhibitors: such as isoprohydrazine and isocarboxazid. Since these drugs contain ingredients with greater side effects, they are now basically discontinued; 2) Tricyclic antidepressants: This type of drug has a good effect on relieving depression, but has a greater adverse effect on patients with other diseases. This drug includes clomipramine, imipramine hydrochloride, etc.; 3) Selective 5-HT reuptake inhibitors: This drug can make up for the symptoms of insufficient 5-hydroxytryptamine in depressed patients, mainly fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine; 4) 5-HT and norepinephrine reuptake inhibitors: This type of drug has a dual antidepressant mechanism and is relatively safe, such as venlafaxine, duloxetine, etc. Categories 3 and 4 are the main drugs used, while categories 1 and 2 have been basically discontinued.

[0004] Since the advent of serotonin reuptake inhibitors (SSRi), there have been dozens of generations of iterations and upgrades. Currently, there are hundreds of projects under development, mainly concentrated in SSRi, selective serotonin and norepinephrine reuptake inhibitors (SNRI), norepinephrine and specific serotonin antidepressants (NaSSA), 5-HT receptor antagonists and reuptake inhibitors (SARIs), NMDA receptor antagonists, etc. The antidepressant market is also very concentrated. So far, more than 30 SSRis varieties have been used globally. The top 10 are escitalopram, sertraline, venlafaxine, paroxetine, duloxetine, flupentixol + melitracen, mirtazapine, fluoxetine, citalopram and fluvoxamine, with a combined market share of over 90%.

[0005] However, the commonly used antidepressants in clinical practice still have serious limitations, mainly slow onset and lag, requiring 3 to 4 weeks of continuous medication to take effect. Many patients give up treatment when they cannot achieve the effect; for patients with suicidal tendencies, their lives may not be saved in time. The nasal spray formulation of ketamine (S) enantiomer (esketamine) was launched in the United States in 2019. Its single use quickly (several hours) relieves depressive symptoms and can last for 3-4 days. Although esketamine can take effect quickly, it has serious side effects, including severe drowsiness, dissociative hallucinations, and potential addiction. The FDA also issued a black box warning that esketamine must be used simultaneously with other oral antidepressants for refractory depression in adults. These deficiencies limit the clinical application of such drugs. Therefore, there is an urgent need for new antidepressants with fast onset, good efficacy, and oral administration. Summary of the invention

[0006] The purpose of the present invention includes providing a compound, such as general formula (I), and pharmaceutically acceptable salts, prodrugs, deuterated substances, hydrates, solvates, enantiomers, diastereomers or racemates thereof;

[0007] Another object of the present invention includes providing a pharmaceutical composition comprising any of the above compounds, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, and a pharmaceutically acceptable excipient or auxiliary ingredient;

[0008] Another object of the present invention also includes providing the use of the compound of the above general formula or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate, or the pharmaceutical composition described herein in the preparation of a medicament for preventing and / or treating depression.

[0009] Another object of the present invention is to provide a method for preparing the above compound.

[0010] In order to achieve the above-mentioned invention object, the technical solutions adopted include:

[0011] The present invention provides a compound represented by general formula (I') or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof:

[0012]

[0013] in,

[0014] R1 and R2 are independently selected from hydrogen, R8-(CO)-, R8-(SO)-, R8-(SO2)-, R8-O(CO)-, R8R9-N(CO)-, or a C1-C2-substituted with 0 to 8 R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0015] or R1, R2 and the nitrogen atom adjacent to them together form a C3-C4 substituted by 0 to 8 R8 15 Heterocycloalkyl or C5-C 15 heteroaryl;

[0016] R3 and R4 are independently selected from hydrogen, or C1-C2-substituted with 0 to 8 R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0017] Or R3, R4 and the carbon atoms adjacent to them together form a C3-C substituted by 0 to 8 R8 10 Cycloalkyl or C3-C 10 Heterocycloalkyl;

[0018] X is optionally selected from -CO-, -SO-, -SO2-, -CHR8-, or

[0019] R5 and R6 are independently selected from hydrogen or C1-C2-substituted by 0 to 8 R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0020] Y is selected from -CO-, -SO-, -SO2- or -CH2-;

[0021] R7 is optionally selected from hydrogen, -OR9, -NR9R 10, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of 0 to 8 R 12 replace;

[0022] R8 is optionally selected from hydrogen, halogen, oxydeoxy, -CN, -NO2, -OR9, -NR9R 10 , -SR9, -COR9, -SOR9, -SO2R9, -NR9COR 10 、-CONR9R 10 , -OCOR9, -COOR9, -OCOOR9, -OCONR9R 10 、-NR9CONR 10 R 11 、-NR9COOR 10 、-NR9SO2R 10 、-SO2NR9R 10 , -OSO2R9, -SO3R9, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of 0 to 8 R 12 replace;

[0023] R9, R 10 , R 11 are independently selected from hydrogen, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0 to 8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl;

[0024] R 12 is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0 to 8 halogen, cyano, hydroxyl, mercapto, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl.

[0025] The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof:

[0026]

[0027] R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、R8-(CH2) m -(SO)-(CH2) n -、R8-(CH2) m -O(CO)-(CH2) n -、R8R9N(CO)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12 m, n are each independently an integer of 0 to 8; or R1, R2 are each independently selected from C1-C 15 A chain alkyl group, wherein the heteroatom is selected from one or more of O, S, and N, and the C1-C 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace;

[0028] or

[0029] R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 8 R 12 replace;

[0030] R3, R4 are independently selected from hydrogen, R8-(CH2) j -、R8-(CO)O-(CH2) k -、C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12j and k are each independently 0, 1, 2 or 3; or R3, R4 are each independently selected from C1-C 15 A chain alkyl group, wherein the heteroatom is selected from one or more of O, S, and N, and the C1-C 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace;

[0031] or

[0032] R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with 0 to 8 R 12 replace;

[0033] X is selected from -CO-, -SO2-, -SO-, -CHR8- or

[0034] R5 and R6 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl or 5-15 membered heteroaryl group is optionally substituted with 0 to 8 R 12 or R5 and R6 are independently selected from C1-C 15 A chain alkyl group, wherein the heteroatom is selected from one or more of O, S, and N, and the C1-C 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace;

[0035] Y is selected from -CO-, -SO2, -SO- or -CH2-;

[0036] R7 is selected from hydrogen, -O(CH2) p R9, -NR9R 10 、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein the C1-C 15 Alkyl, C1-C15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl or 5-15 membered heteroaryl group is optionally substituted with 0 to 8 R 12 substituted; p is 0, 1, 2 or 3; or R7 is selected from C1-C 15 A chain alkyl group, wherein the heteroatom is selected from one or more of O, S, and N, and the C1-C 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace;

[0037] R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12 replace;

[0038] R9, R 10 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12 replace;

[0039] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl, optionally substituted with 0-8 halogen, oxydene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide;

[0040] Wherein, the compound represented by formula (I) does not include the following compounds:

[0041]

[0042] In some embodiments, wherein,

[0043] R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 substituted; m, n are each independently 0, 1, 2 or 3, wherein R1 and R2 are not hydrogen at the same time, and when one of R1 and R2 is hydrogen, the other of R1 and R2 is not acetyl or ethyl;

[0044] or

[0045] R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R 12 replace;

[0046] R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are each independently 0, 1, 2 or 3; R3 and R4 are not hydrogen at the same time;

[0047] or

[0048] R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace;

[0049] X is selected from -CO- or -SO2-;

[0050] R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution, wherein R5 and R6 are not hydrogen at the same time;

[0051] Y is selected from -CO- or -SO2;

[0052] R7 is selected from hydrogen, -O(CH2) p R9 or C1-C 15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution; p is 0, 1, 2 or 3;

[0053] R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0054] R9, R 10 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0055] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl, optionally substituted by 0-5 halogen, oxydene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide;

[0056] Wherein, the compound represented by formula (I) does not include the following compounds:

[0057]

[0058] In some embodiments, wherein,

[0059] R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 substituted; m, n are each independently 0, 1, 2 or 3, wherein R1 and R2 are not hydrogen at the same time, and when one of R1 and R2 is hydrogen, the other of R1 and R2 is not acetyl or ethyl;

[0060] or

[0061] R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R 12 replace;

[0062] R3, R4 are independently selected from hydrogen or R8-(CH2) j -, wherein j is 0, 1, 2 or 3; R3 and R4 are not hydrogen at the same time;

[0063] X is selected from -CO- or -SO2-;

[0064] R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution, wherein R5 and R6 are not hydrogen at the same time;

[0065] Y is selected from -CO- or -SO2;

[0066] R7 is selected from -O(CH2) p R9, wherein p is 0, 1, 2 or 3;

[0067] R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0068] R9, R 10 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0069] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

[0070] In some embodiments, wherein,

[0071] The compound represented by formula (I) is selected from the compounds represented by formula (II)

[0072]

[0073] in,

[0074] R1, R2, R3, and R4 are as defined above.

[0075] In some embodiments, wherein,

[0076] R1 is selected from R8-(CO)-, R8-(SO2)-, C1-C3 alkyl, C3-C6 cycloalkyl, 5-6-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl; R2 is hydrogen or methyl, wherein C1-C3 alkyl, C3-C6 cycloalkyl, 5-6-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl is optionally substituted by 0 to 3 R 12 Substitution; when R2 is hydrogen, R1 is not acetyl or ethyl;

[0077] or

[0078] R1, R2 and their adjacent nitrogen atoms together form a 3-8-membered nitrogen-containing heterocyclic ring or a 5-6-membered nitrogen-containing heteroaromatic ring, wherein the 3-8-membered nitrogen-containing heterocyclic ring or the 5-6-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 3 C1-C3 alkyl groups, oxydiphenyl groups, or phenyl groups; and the 3-8-membered nitrogen-containing heterocyclic ring or the 5-6-membered nitrogen-containing heteroaromatic ring contains 1 or 2 nitrogen atoms;

[0079] R3 is hydrogen; R4 is selected from hydrogen, phenyl, C1-C5 alkyl, wherein the C1-C5 alkyl is optionally substituted by 0 to 3 halogens or hydroxyl groups;

[0080] R8 is selected from C1-C3 alkylamino, phenyl, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 cycloalkyl or 5-6 membered heteroaryl, wherein phenyl, C1-C3 alkyl, C3-C6 cycloalkyl or 5-6 membered heteroaryl is optionally substituted with 0 to 3 halogens, 5-6 membered heteroaryl or 3-6 membered heterocycloalkyl;

[0081] R 12 Selected from hydrogen, halogen, oxyethylene, C1-C3 alkyl, C3-C5 cycloalkyl, wherein C1-C3 alkyl, C3-C5 cycloalkyl are optionally substituted by 0 to 3 halogens.

[0082] In some embodiments, wherein,

[0083] The compound represented by formula (I) is selected from the compounds represented by formula (III)

[0084]

[0085] in,

[0086] R1 and R2 are as defined above.

[0087] In some embodiments, wherein,

[0088] R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 Substitution; m, n are each independently 0, 1, 2 or 3;

[0089] or

[0090] R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R 12 replace;

[0091] R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are independently 0, 1, 2 or 3, wherein when one of R3 and R4 is hydrogen, the other of R3 and R4 is not methyl;

[0092] or

[0093] R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace;

[0094] X is selected from -CO- or -SO2-;

[0095] R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace;

[0096] Y is selected from -CO- or -SO2;

[0097] R7 is selected from hydrogen, -O(CH2) p R9 or C1-C 15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution, p is 0, 1, 2 or 3;

[0098] R8 is selected from -OR9, -NR9R 10 , -CO-NH2, -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0099] R9, R 10 Each independently selected from C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0100] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl, optionally substituted by 0-5 halogen, oxydene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide;

[0101] Wherein, the compound represented by formula (I) does not include the following compounds:

[0102]

[0103] In some embodiments, wherein,

[0104] R1 and R2 are independently selected from hydrogen, C1-C 15 Alkyl or R8-(CH2) m -(CO)-(CH2) n -; m, n are each independently 0, 1, 2 or 3;

[0105] R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are independently 0, 1, 2 or 3, wherein when one of R3 and R4 is hydrogen, the other of R3 and R4 is not methyl;

[0106] or

[0107] R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace;

[0108] X is selected from -CO- or -SO2-;

[0109] R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace;

[0110] Y is selected from -CO- or -SO2;

[0111] R7 is selected from hydrogen, -O(CH2) p R9, wherein p is 0, 1, 2 or 3;

[0112] R8 is selected from -OR9, -NR9R 10 , -CO-NH2, -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0113] R9, R 10 Each independently selected from C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0114] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

[0115] In some embodiments, wherein,

[0116] R1 is hydrogen; R2 is selected from hydrogen, C1-C3 alkyl or R8-(CO)-;

[0117] R3 is selected from hydrogen, C1-C3 alkyl; R4 is selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are independently 0, 1, 2 or 3, wherein when R3 is hydrogen, R4 is not methyl;

[0118] or

[0119] R3, R4 and their adjacent carbon atoms together form a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is optionally substituted by 0 to 5 R 12 replace;

[0120] X is -CO-;

[0121] R5 is hydrogen, R6 is selected from hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 0 to 5 R 12 replace;

[0122] Y is -CO-;

[0123] R7 is optionally selected from hydrogen, C1-C6 alkoxy;

[0124] R8 is selected from methylthio, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C8 aryl or 5-15 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C8 aryl or 5-15 membered heteroaryl is optionally substituted by 0 to 3 R 12 replace;

[0125] R 12 Selected from halogen, oxyethylene, hydroxyl, amino, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, C6-C8 aryl, wherein C1-C3 alkyl, C1-C3 alkoxy, C6-C8 aryl are optionally substituted by 0 to 3 halogens.

[0126] In some embodiments, wherein,

[0127] The compound represented by formula (I) is selected from the compound represented by formula (IV)

[0128]

[0129] in,

[0130] R3 and R4 are as defined above.

[0131] In some embodiments, wherein,

[0132] R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 substituted; m, n are each independently 0, 1, 2 or 3; R1 and R2 are not hydrogen at the same time;

[0133] or

[0134] R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R12 replace;

[0135] R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are each independently 0, 1, 2 or 3;

[0136] or

[0137] R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace;

[0138] X is selected from -CO- or -SO2-;

[0139] R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace;

[0140] Y is selected from -CO- or -SO2;

[0141] R7 is selected from hydrogen, -O(CH2) p R9 or C1-C 15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution; p is 0, 1, 2 or 3;

[0142] R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0143] R9, R 10 Each independently selected from C1-C 15 Alkoxy, C3-C 15Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0144] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

[0145] In some embodiments, wherein,

[0146] R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -; m, n are each independently 0, 1, 2 or 3; R1 and R2 are not hydrogen at the same time;

[0147] R3, R4 are independently selected from hydrogen or R8-(CH2) j -, where j is 0, 1, 2 or 3;

[0148] X is selected from -CO- or -SO2-;

[0149] R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace;

[0150] Y is selected from -CO- or -SO2;

[0151] R7 is selected from hydrogen, -O(CH2) p R9 or C1-C15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution; p is 0, 1, 2 or 3;

[0152] R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0153] R9, R 10 Each independently selected from C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace;

[0154] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

[0155] In some embodiments, wherein,

[0156] The compound represented by formula (I) is selected from the compounds represented by formula (V)

[0157]

[0158] in,

[0159] Y and R7 are as defined above.

[0160] In some embodiments, wherein,

[0161] The compound represented by formula (I) is selected from the compounds represented by formula (VI)

[0162]

[0163] in,

[0164] R7 is as defined above.

[0165] In some embodiments, wherein,

[0166] The compound is selected from any of the following compounds:

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173] The present invention also provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, and a pharmaceutically acceptable excipient or auxiliary ingredient.

[0174] The present invention also provides use of the compound described herein or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate, or the pharmaceutical composition described herein in the preparation of a medicament for preventing and / or treating depression.

[0175] In some embodiments, the compound or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate in the above-mentioned use, or the pharmaceutical composition is used in combination with another, two or more antidepressants simultaneously, alternately or subsequently.

[0176] In some embodiments, the drug in the above use is a fast-acting drug.

[0177] The hydrogen described herein may be in any isotopic form, including 1 H (hydrogen), 2 H (D or deuterium) and 3 H (T or tritium).

[0178] definition

[0179] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0180] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0181] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 15 carbon atoms, more preferably an alkyl group of 1 to 8 carbon atoms, and further preferably an alkyl group of 1, 2, 3, 4, 5, or 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof. The alkyl group may be optionally further substituted by one or more substituents.

[0182] "Alkoxy" refers to a group formed by linking an alkyl group to an oxygen atom. The definition of the alkyl group is the same as the definition of "alkyl" described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, cyclobutyloxy, etc. The alkoxy group may optionally be further substituted with one or more substituents.

[0183] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic substituent, and the cycloalkyl contains 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, 8 carbon atoms). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed rings, and bridged rings. The cycloalkyl may optionally be further substituted by one or more substituents.

[0184] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 6-12 membered (e.g., 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3-8 membered heterocyclic ring. 1, 2 or 3 N, S optionally substituted in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; "heterocycloalkyl" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl" include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, etc. The heterocycloalkyl may be optionally further substituted with one or more substituents.

[0185] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5-8 membered monocyclic ring (e.g., 5, 6, 7, 8 members), a 6-12 membered (e.g., 6, 7, 8, 9, 10, 11, 12 members) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 members) tricyclic ring system, which can be a bridged ring or a spiro ring, non-limiting examples include phenyl, naphthyl, etc. The aryl group may be optionally further substituted with one or more substituents.

[0186] "Heteroaryl" refers to an aromatic ring group having a conjugated planar ring system and containing heteroatoms, which can be a 5-8 membered (e.g., 5, 6, 7, 8 membered) monocyclic ring, an 8-12 membered (e.g., 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S. Non-limiting examples of heteroaryl include oxazolyl, triazolyl, pyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, etc. The heteroaryl group may be optionally further substituted with one or more substituents.

[0187] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0188] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0189] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.

[0190] Beneficial technical effects achieved:

[0191] (1) The compounds of the present invention have good rapid antidepressant activity in vivo.

[0192] (2) The compounds of the present invention have better pharmacokinetic properties than the compounds disclosed in the prior art, such as good AUC, bioavailability and other parameters.

[0193] (3) The compounds of the present invention have better plasma stability than the compounds disclosed in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0194] Figure 1 The results of the tail suspension experiment in Experimental Example 3 are shown.

[0195] Figure 2 The results of the forced swimming test in Experimental Example 4 are shown.

[0196] Figure 3 The results of the tail suspension experiment in Experimental Example 4 are shown. DETAILED DESCRIPTION

[0197] Unless otherwise specified, all raw materials, reagents, and instruments used in the examples of the present invention are conventional commercially available products.

[0198] Among them, the present invention 1 The instrument for HNMR detection is Bruker Advance 400 MHz spectrometer; the instrument for MS-ESI detection of the present invention is Agilent LCMS1260-6120.

[0199] Preparation Example 1 Preparation of Compound A-1-1-1

[0200]

[0201] first step

[0202] A-1-1-1a (7.66 g, 85.92 mmol) was dissolved in water (40 mL) and cooled to 0°C, and sodium hydroxide (5.16 g, 128.88 mmol) was added. After stirring at 0°C for 10 min, a solution of di-tert-butyl dicarbonate (24.38 g, 111.70 mmol) in tetrahydrofuran (40 mL) was added. The mixture was warmed to room temperature and stirred overnight at room temperature. After the reaction was completed, the LCMS monitoring was performed, and the aqueous phase was washed with petroleum ether (30 mL × 2), and the pH of the aqueous phase was adjusted to 1 with 1M hydrochloric acid aqueous solution. It was extracted with ethyl acetate (50 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude intermediate A-1-1-1b (15.00 g, 79.28 mmol, yield 92.3%). MS-ESI: [MH] - =188.2. 1 H NMR (400MHz, DMSO-d6) δ12.38 (s, 1H), 7.09 (d, J = 7.7Hz, 1H), 3.92 (p, J = 7.4Hz, 1H), 1.38 (s, 9H), 1.22 (d, J = 7.4Hz, 3H).

[0203] Step 2

[0204] Compound A-1-1-1b (14.00 g, 73.99 mmol) was dissolved in N,N-dimethylformamide (14 mL) and cooled to 0°C. Diisopropylethylamine (28.69 g, 221.98 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30.93 g, 81.39 mmol) were added and stirred at 0°C for 10 min. L-valine methyl ester hydrochloride (10.19 g, 77.69 mmol) was added and the temperature was raised to room temperature for 2 h. After the reaction was completed, LCMS monitoring showed that the intermediate A-1-1-1c (16.00 g, 50.26 mmol, yield 67.9%) was obtained by purification by medium pressure preparative column chromatography. MS-ESI: [M+H] + =303.1. 1H NMR(400MHz,DMSO-d6)δ7.95(d,J=8.7Hz,1H),4.20(dd,J=8.6,6.0Hz,1H),4.06(q,J=7.1Hz,1 H), 3.65 (s, 3H), 2.11–1.98 (m, 1H), 1.38 (s, 9H), 1.19 (d, J = 7.2Hz, 3H), 0.85 (d, J = 6.8Hz, 6H).

[0205] Step 3

[0206] Dissolve the intermediate A-1-1-1c (16.00 g, 50.26 mmol) in dichloromethane (40 mL), add 4M hydrogen chloride in dioxane solution (40 mL). React at room temperature for 2 h. LCMS monitoring shows that the reaction is complete. Concentrate to obtain the intermediate A-1-1-1d (11.00 g, 46.22 mmol, yield 88.4%). MS-ESI: [M+H] + =203.1.

[0207] Step 4

[0208] Dissolve the intermediate A-1-1-1d (700.0 mg, 3.46 mmol) and triethylamine (1.75 g, 17.31 mmol) in dichloromethane (7 mL) and cool to 0°C. Add cyclopropane chloride (325.62 mg, 3.11 mmol) and stir at 0°C for 1 h. After LCMS monitoring shows that the reaction is complete, add water (100 mL) to quench. Extract with dichloromethane (100 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify by preparative liquid chromatography to obtain compound A-1-1-1 (340.0 mg, 1.26 mmol, yield 36.3%). MS-ESI: [M+H] + =271.3. 1 HNMR (400MHz, DMSO-d6) δ8.25(d,J=8.0Hz,1H),8.17(d,J=8.6Hz,1H),4.47(p,J=7.2Hz,1H),4.20(dd,J=8.6,6.3Hz,1H),3.64 (s,3H),2.09–1.96(m,J=6.7Hz,1H),1.76–1.61(m,1H),1.20(d,J=7.1Hz,3H),0.85(dd,J=6.8,2.1Hz,6H),0.71–0.58(m,4H).

[0209] Preparation Example 2 Preparation of Compound A-1-1-4

[0210]

[0211] Compound A-1-1-1d (700.0 mg, 3.46 mmol) and triethylamine (1.75 g, 17.31 mmol) were dissolved in dichloromethane (7 mL) and cooled to 0°C. Isobutyryl chloride (331.9 mg, 3.11 mmol) was added and stirred at 0°C for 1 h. After LCMS monitoring showed that the reaction was complete, water was added to quench the mixture. Dichloromethane (100 mL × 3) was added to extract the mixture. The organic phases were combined and dried with anhydrous sodium sulfate and concentrated. Compound A-1-1-4 (310.0 mg, 1.14 mmol, yield 32.9%) was obtained by preparative liquid chromatography. MS-ESI: [M+H] + =273.0. 1 HNMR (400MHz, Methanol-d4) δ8.06(d,J=8.6Hz,1H),7.87(d,J=7.9Hz,1H),4.40(p,J=7.2Hz,1H),4.21(dd,J=8.6,6.2Hz,1H),3. 64(s,3H),2.44(q,J=6.9Hz,1H),2.03(q,J=6.8Hz,1H),1.20(d,J=7.1Hz,3H),0.98(d,J=6.8Hz,6H),0.85(dd,J=6.8,1.0Hz,6H).

[0212] Preparation Example 3 Preparation of Compound A-1-1-13

[0213]

[0214] Compound A-1-1-1d (500.0 mg, 2.47 mmol) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (958.0 mg, 7.41 mmol) was added, nitrogen was replaced three times, and the mixture was stirred under ice bath for 10 min. A dichloromethane solution (1.5 mL) of methylaminoformyl chloride (347.0 mg, 3.71 mmol) was slowly added dropwise. After 5 min of addition, the mixture was transferred to room temperature and reacted for 30 min. TLC showed that the reaction was complete, and sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL×3), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered and rotary evaporated. The crude product was purified by medium pressure preparative column chromatography to obtain compound A-1-1-13 (382.0 mg, 1.47 mmol, yield: 59.5%). MS-ESI: [M+H] + =260.2. 1H NMR (400MHz, DMSO-d6) δ8.22(d,J=8.5Hz,1H),6.07(d,J=8.1Hz,1H),6.00–5.80(m,1H),4.32(p,J=7.0Hz,1H),4.18(d d,J=8.5,6.4Hz,1H),3.64(s,3H),2.53(s,3H),2.10–1.91(m,1H),1.15(d,J=6.9Hz,3H),0.85(dd,J=6.8,3.6Hz,6H).

[0215] Preparation Example 4 Preparation of Compound A-1-1-14

[0216]

[0217] In a 50mL three-necked flask, add compound A-1-1-1d (500.0mg, 2.47mmol), triethylamine (1.25g, 12.35mmol), dichloromethane (20mL), cool to 0℃, add cyclopropylsulfonyl chloride (1.04g, 7.41mmol), and then return to room temperature for 2h. TLC shows that the reaction is complete, add sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane (100mL×3), combine the organic phases and wash with saturated sodium chloride aqueous solution (100mL), dry the organic phase with anhydrous sodium sulfate, filter and rotary evaporate, and purify the crude product with medium pressure preparative column chromatography to obtain oily product A-1-1-14 (405.0mg, 1.32mmol, yield 53.4%). MS-ESI: [M+H] + =307.1[M+H] + . 1 H NMR (400MHz, CDCl3) δ6.76(d,J=8.7Hz,1H),5.21(d,J=8.1Hz,1H),4.54(dd,J=8.8,4.9Hz,1H),4.12(p,J=7.2Hz,1H),3.75(s,3H),2.45(tt ,J=8.0,4.8Hz,1H),2.21(qt,J=13.5,6.8Hz,1H),1.50(d,J=7.1Hz,3H),1.24–1.12(m,2H),1.08–0.98(m,2H),0.94(dd,J=12.4,6.9Hz,6H).

[0218] Preparation Example 5 Preparation of Compound A-1-1-15

[0219]

[0220] In a 50mL three-necked flask, add compound A-1-1-1d (1.00g, 4.94mmol), triethylamine (2.50g, 24.70mmol), dichloromethane (20mL), cool to 0℃, add 1H-pyrazole-1-yl chloride (0.64g, 4.94mmol), return to room temperature and react for 2h. After LCMS and TLC monitoring show that the reaction is complete, add water to quench, extract with dichloromethane (120mL×3), combine the organic phases and wash with saturated sodium chloride aqueous solution (120mL), dry the organic phase with anhydrous sodium sulfate, filter and rotary evaporate; the crude product is purified by medium pressure preparative column chromatography to obtain compound A-1-1-15 (1.00g, 3.37mmol, yield 68.2%). MS-ESI: [M+H] + =297.2. 1 HNMR (400MHz, DMSO-d6) δ8.50(d,J=8.5Hz,1H),8.30(d,J=2.6Hz,1H),8.15(d,J=7.7Hz,1H),7.79(d,J=0.9Hz,1H),6.53(dd,J=2.6,1.6Hz,1H), 4.55(p,J=7.0Hz,1H), 4.23(dd,J=8.4,6.4Hz,1H), 3.64(s,3H), 2.06(dq,J=13.5,6.7Hz,1H), 1.39(d,J=7.0Hz,3H), 0.87(dd,J=6.8,4.1Hz,6H).

[0221] Preparation Example 6 Preparation of Compound A-1-2-1

[0222]

[0223] The intermediate A-1-1-1d (1.00 g, 4.94 mmol), iodobenzene (907.8 mg, 4.45 mmol), cuprous iodide (188.3 mg, 988.87 μmol), 2-isobutyrylcyclohexanone (664.5 mg, 3.96 mmol), cesium carbonate (3.22 g, 9.89 mmol) were dissolved in N, N-dimethylformamide (10 mL), replaced with nitrogen three times, and heated to 80 ° C for overnight reaction. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and filtered, and the filtrate was directly purified by preparative liquid chromatography to obtain compound A-1-2-1 (400.0 mg, 1.44 mmol, yield 29.1%). MS-ESI: [M+H] + =279.0. 1H NMR (400MHz, DMSO-d6) δ8.05(d,J=8.8Hz,1H),7.06(dd,J=8.5,7.2Hz,2H),6.64–6.53(m,3H),5.72(s,1H),4.20(dd,J=8 .8, 6.1Hz, 1H), 3.96 (q, J = 6.9Hz, 1H), 3.62 (s, 3H), 2.08–1.95 (m, 1H), 1.31 (d, J = 6.9Hz, 3H), 0.76 (dd, J = 6.8, 1.5Hz, 6H).

[0224] Preparation Example 7 Preparation of Compound A-1-2-2

[0225]

[0226] first step

[0227] 2-iodopyridine (4.00 g, 19.51 mmol), compound A-1-1-1a (1.91 g, 21.46 mmol), cuprous iodide (371.6 mg, 1.95 mmol), 2-isobutyrylcyclohexanone (655.6 mg, 3.90 mmol), cesium carbonate (12.72 g, 39.03 mmol) were dissolved in N,N-dimethylformamide (40 mL), replaced with nitrogen three times, and then heated to 60 ° C overnight. After LCMS monitoring showed that the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was filtered and dried, and then purified by medium pressure preparative column chromatography to obtain compound A-1-2-2a (2.40 g, 14.44 mmol, yield 74.0%). MS-ESI: [M+H] + =167.1.

[0228] Step 2

[0229] Compound A-1-2-2a (2.88 g, 17.33 mmol), L-valine methyl ester (2.73 g, 20.80 mmol), 1-hydroxybenzotriazole (1.17 g, 8.67 mmol), 4-dimethylaminopyridine (3.18 g, 26.0 mmol) were dissolved in N, N-dimethylformamide (30 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.32 g, 17.32 mmol) was added and stirred at room temperature overnight. After LCMS monitoring showed that the reaction was completed, the reaction solution was filtered and purified by medium pressure preparative column chromatography and preparative liquid chromatography to obtain compound A-1-2-2 (340.0 mg, 1.22 mmol, yield 7.02%). MS-ESI: [M+H] + =280.0. 1H NMR (400MHz, DMSO-d6) δ8.04(dd,J=28.8,8.6Hz,1H),7.93(dddd,J=6.8,5.0,2.0,0.9Hz,1H),7.4 4–7.32(m,1H),6.63(dd,J=7.5,4.0Hz,1H),6.56(ddt,J=8.4,7.4,1.0Hz,1H),6.50(dtd,J=7.1,5 .2,1.0Hz,1H),4.54–4.43(m,1H),4.19(ddd,J=8.5,6.2,1.8Hz,1H),3.61(d,J=2.5Hz,3H),2.08– 1.90(m,1H),1.28(dd,J=7.0,5.8Hz,3H),0.84(dd,J=8.6,6.8Hz,3H),0.78(dd,J=8.3,6.8Hz,3H).

[0230] Preparation Example 8 Preparation of Compound A-1-2-6

[0231]

[0232] Add 5-trifluoromethyl-2-iodopyridine (550.0 mg, 2.01 mmol), A-1-1-1d (447.0 mg, 2.21 mmol), cuprous iodide (38.0 mg, 0.20 mmol), 2-(2-methyl-1-oxopropane)cyclohexanone (67.0 mg, 0.40 mmol), and cesium carbonate (1.31 g, 4.02 mmol) into a 50 mL three-necked flask, add N,N-dimethylformamide (22 mL), replace with nitrogen three times, and stir at 60 ° C for 3 h. After LCMS and TLC monitoring showed that the reaction was complete, water was added for dilution, and ethyl acetate was used for extraction (100 mL×3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (100 mL), and the organic phases were dried over anhydrous sodium sulfate, filtered and rotary evaporated; the crude product was purified by medium-pressure preparative column chromatography to obtain compound A-1-2-6 (240.0 mg, 0.69 mmol, yield: 34.3%). MS-ESI: [M+H] + =348.1. 1H NMR (400MHz, CDCl3) δ8.35(s,1H),7.60(dd,J=8.8,2.4Hz,1H),6.90(s,1H),6.48(d,J=8.8Hz,1H),5.33(s,1H),4.54(dd ,J=9.0,4.8Hz,2H),3.69(s,3H),2.21–2.08(m,1H),1.52(d,J=7.0Hz,3H),0.89(d,J=6.9Hz,3H),0.80(d,J=6.9Hz,3H).

[0233] Preparation Example 9 Preparation of Compound A-1-2-8

[0234]

[0235] Add 3-iodopyridine (700.0 mg, 3.41 mmol), A-1-1-1d (758.0 mg, 3.75 mmol), cuprous iodide (65.0 mg, 0.34 mmol), 2-(2-methyl-1-oxopropane)cyclohexanone (114.0 mg, 0.68 mmol), and cesium carbonate (2.22 g, 6.82 mmol) into a 250 mL three-necked flask, add N,N-dimethylformamide (14 mL), replace with nitrogen three times, and stir at 80 ° C for 3 h. LCMS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated. The crude product was purified by reverse phase medium pressure preparative column chromatography to obtain product A-1-2-8 (354.0 mg, 1.27 mmol, yield: 37.2%). MS-ESI: [M+H] + =280.2. 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=8.6Hz,1H),7.89(d,J=75.5Hz,2H),7.07(s,1H),6.86(d,J=8.4Hz,1H),6.09(d,J=8.0Hz,1H),4. 19(dd,J=8.6,6.1Hz,1H),4.03(p,J=6.9Hz,1H),3.61(s,3H),2.07–2.00(m,1H),1.33(d,J=6.9Hz,3H),0.79(dd,J=6.8,2.2Hz,6H).

[0236] Preparation Example 10 Preparation of Compound A-1-2-9

[0237]

[0238] Add 4-iodopyridine (600.0 mg, 2.93 mmol), A-1-1-1d (651.0 mg, 3.22 mmol), palladium acetate (66.0 mg, 0.29 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (336.0 mg, 0.58 mmol), and cesium carbonate (1.90 g, 5.82 mmol) into a 50 mL three-necked flask, add N,N-dimethylformamide (14 mL), replace with nitrogen three times, and stir at 95 °C for 5 h. LCMS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated. The crude product was purified by medium-pressure preparative column chromatography to obtain the product A-1-2-9 (186.0 mg, 0.67 mmol, yield: 22.9%). MS-ESI: [M+H] + =280.2. 1 HNMR (400MHz, DMSO-d6) δ8.40(d,J=8.6Hz,1H),8.07(d,J=6.3Hz,2H),7.26(d,J=7.3Hz,1H),6.56(d,2H ),4.25–4.13(m,2H),3.62(s,3H),2.12–2.00(m,1H),1.34(d,J=6.9Hz,3H),0.84(dd,J=6.8,4.6Hz,6H).

[0239] Preparation Example 11 Preparation of Compound A-1-2-10

[0240]

[0241] 2-iodopyrimidine (600.0 mg, 2.91 mmol), A-1-1-1d (647.0 mg, 3.20 mmol), cuprous iodide (55.0 mg, 0.29 mmol), 2-(2-methyl-1-oxopropane)cyclohexanone (98.0 mg, 0.58 mmol), and cesium carbonate (1.90 g, 5.82 mmol) were added to a 250 mL three-necked flask, and N,N-dimethylformamide (14 mL) was added. The atmosphere was replaced with nitrogen three times and stirred at 80 °C for 3 h. LCMS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with water and extracted with ethyl acetate (100 mL×3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated. The crude product was purified by reverse phase medium pressure preparative column chromatography to obtain product A-1-2-10 (433.0 mg, 1.54 mmol, yield: 52.9%). MS-ESI: [M+H] + =281.1. 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=4.8Hz,2H),8.02(d,J=8.6Hz,1H),7.07(d,J=7.6Hz,1H),6.62(t,J=4.8Hz,1H),4.51–4. 42(m,1H),4.18(dd,J=8.7,6.4Hz,1H),3.62(s,3H),2.07–1.96(m,1H),1.32(d,J=7.1Hz,3H),0.79(dd,J=6.9,3.6Hz,6H).

[0242] Preparation Example 12 Preparation of Compound A-1-2-14

[0243]

[0244] Dissolve intermediate A-1-1-1d (1.48 g, 7.30 mmol) and triethylamine (2.22 g, 21.90 mmol) in N,N-dimethylformamide (15 mL), cool to 0°C, add bromoacetone (338.6 mg, 2.47 mmol), and stir at 0°C for 1 h. Add 1M hydrochloric acid to adjust the pH of the reaction solution to 5-6, and purify by medium pressure preparative column chromatography and preparative liquid chromatography to obtain compound A-1-2-14 (360.0 mg, 1.39 mmol, yield: 19.1%). MS-ESI: [M+H] + =259.3. 1H NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.82(d,J=8.4Hz,1H),4.28(dd,J=8.5,6.2Hz,1H),4.08(s,2H),3.94(q, J=6.9Hz,1H),3.68(s,3H),2.19(s,3H),2.14–2.00(m,1H),1.42(d,J=6.9Hz,3H),0.88(dd,J=6.9,1.3Hz,6H).

[0245] Preparation Example 13 Preparation of Compound A-1-3-2

[0246]

[0247] first step

[0248] Triethylamine (4.02 g, 39.75 mmol) was added to a solution of compound A-1-3-2a (2.00 g, 13.25 mmol) in dichloromethane (30 mL), the reaction temperature was lowered to 0°C, cyclopropylcarbonyl chloride (1.39 g, 13.25 mmol) was slowly added dropwise to the reaction solution, and the reaction was stirred at 25°C for 2 h. The reaction was slowly warmed to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate A-1-3-2b as a yellow solid (2.75 g, yield: 94.8%). MS-ESI: [M+H] + =220.1.

[0249] Step 2

[0250] Compound A-1-3-2b (2.00 g, 9.11 mmol) was dissolved in dichloromethane (20 mL) solution, and then L-valine methyl ester (1.31 g, 9.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.27 g, 11.84 mmol), 1-hydroxybenzotriazole (1.84 g, 13.67 mmol) and N,N-diisopropylethylamine (5.88 g, 45.55 mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at 25 °C for 16 h. After the reaction is completed, ethyl acetate is used for extraction (50 mL × 3), the organic phases are combined, washed with saturated sodium bicarbonate solution (50 mL × 2), saturated ammonium chloride solution (50 mL × 2), and saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by high performance liquid chromatography and freeze-dried to obtain A-1-3-2 (380.0 mg, yield: 12.1%) as a yellow solid. MS-ESI: [M+H] + =333.3. 1H NMR (400MHz, DMSO-d6) δ8.78(dd,J=35.3,8.5Hz,1H),8.61(dd,J=50.8,8.2Hz,1H),7.46–7.23(m,5H),5.74(dd,J=22.5,8. 5Hz,1H),4.17(ddd,J=14.7,8.2,6.4Hz,1H),3.66–3.54(m,3H),2.07–1.95(m,1H),1.93–1.83(m,1H),0.99–0.52(m,10H).

[0251] Preparation Example 14 Preparation of Compound A-1-3-4

[0252]

[0253] first step

[0254] Compound A-1-3-4a (1.00 g, 6.90 mmol) was dissolved in aqueous sodium hydroxide solution (7 mL, 1 M), and sodium carbonate (370.0 mg, 3.45 mmol) and cyclopropylcarbonyl chloride (790.0 mg, 7.50 mmol) were added to the solution in sequence, and the reaction was stirred at 25 ° C for 2 h. Then the pH value of the reaction solution was adjusted to 4 with hydrochloric acid (2 M), extracted with ethyl acetate (50 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 under reduced pressure to obtain a crude product A-1-3-4b (910.0 mg, yield: 62.0%), a white solid. It was used directly in the next step without purification. MS-ESI: [M+H] + =214.1.

[0255] Step 2

[0256] Compound A-1-3-4b (854.0 mg, 4.00 mmol) was dissolved in dichloromethane (8 mL), 1-hydroxybenzotriazole (812.0 mg, 6.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g, 8.00 mmol) and N,N-diisopropylethylamine (1.6 g, 12.00 mmol) were added to the solution in sequence, the reaction was stirred at 25 ° C for 1 h, and then L-valine methyl ester (630.0 mg, 4.80 mmol) was added to the reaction solution, and the reaction was continued to stir for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain A-1-3-4 (320.0 mg, yield: 24.5%) as a white solid. MS-ESI: [M+H] + =327.1. 1HNMR(400MHz,DMSO-d6)δ8.24(dd,J=10.3,9.0Hz,1H),8.07(dd,J=80.0,8.2H z,1H),4.49(dtd,J=31.5,8.5,4.4Hz,1H),4.14(ddd,J=8.3,6.5,1.5Hz,1H), 3.67–3.59(m,3H),2.02(dt,J=13.5,6.7Hz,1H),1.68–1.52(m,2H),1.52–1.3 9(m,1H),0.89(s,9H),0.88–0.83(m,6H),0.64(ddd,J=11.4,5.3,2.0Hz,4H).

[0257] Preparation Example 15 Preparation of Compound A-1-4-9

[0258]

[0259] first step

[0260] Sodium hydride (1.27 g, 52.90 mmol) was added to a toluene (30 mL) solution of compound pyrrolidone A-1-4-9a (3.00 g, 35.30 mmol) at 0°C, and the reaction was stirred at 0°C for 1 h before adding ethyl bromopropionate A-1-4-9b (12.71 g, 70.60 mmol). The reaction was slowly heated to room temperature and stirred for 5 h, quenched by adding saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (20 mL × 3), and the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 7:3) to obtain intermediate A-1-4-9c (1.10 g, yield: 16.9%), a colorless oily liquid. MS-ESI: [M+H] + =186.0.

[0261] Step 2

[0262] A-1-4-9c (1.08 g, 5.80 mmol) was dissolved in ethanol and water (V / V=1:1, 10 mL) solution, and then sodium hydroxide (0.70 g, 17.40 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 3 h. After the ethanol was dried, the pH was adjusted to 6 with 1M dilute hydrochloric acid, extracted with ethyl acetate (10 mL×3), and the aqueous phase was dried and freeze-dried to obtain A-1-4-9d (0.80 g, yield: 87.3%) as a white solid. MS-ESI: [M+H] + =158.

[0263] Step 3

[0264] To a solution of A-1-4-9d (0.78 g, 4.96 mmol) in dichloromethane (10 mL) was added L-valine methyl ester (0.83 g, 6.33 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (2.09 g, 7.44 mmol), and N-methylimidazole (1.22 g, 14.89 mmol). The reaction was stirred at room temperature for 1 h. 15 mL of water was added to the reaction solution for dilution. Extraction was performed with dichloromethane (10 mL × 2), and the organic phases were combined and concentrated under reduced pressure. Purification was performed by column chromatography (dichloromethane: methanol = 27: 4) to obtain A-1-4-9 (310.0 mg, yield: 23.0%), a colorless oily liquid. MS-ESI: [M+H] + =270.9. 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (dd, J = 29.2, 8.2Hz, 1H), 4.67 (dq, J = 21.6, 7.2Hz, 1H), 4.39–3.98 (m, 1H), 3.63 (d, J = 2.0Hz, 3H), 3.5 7–3.35(m,2H),2.28–2.16(m,2H),2.04(dq,J=13.5,6.8Hz,1H),1.96–1.83(m,2H),1.25(dd,J=7.3,3.2Hz,3H),0.97–0.77(m,6H).

[0265] Preparation Example 16 Preparation of Compound A-1-5-1

[0266]

[0267] first step

[0268] Add di-tert-butyl dicarbonate (6.02 g, 27.6 mmol) to a solution of compound A-1-3-4a (2.00 g, 13.80 mmol) in tetrahydrofuran / saturated sodium bicarbonate (V / V=1 / 1, 50 mL), and stir the reaction at room temperature for 2 h. Add ethyl acetate (20 mL) to dilute the reaction solution, adjust the pH to 3-4 with 1M hydrochloric acid solution, extract with ethyl acetate (20 mL×2), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain A-1-5-1a (3.00 g, yield: 88.8%), a yellow oily liquid. MS-ESI: [M+Na] + =268.0.

[0269] Step 2

[0270] To a solution of A-1-5-1a (2.00 g, 8.2 mmol) in dichloromethane (40 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.36 g, 12.3 mmol), 1-hydroxybenzotriazole (1.66 g, 12.3 mmol), N,N-diisopropylethylamine (5.30 g, 41 mmol) were added, and the mixture was stirred at room temperature for 10 min. L-valine methyl ester (1.29 g, 9.8 mmol) was added, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was washed with saturated citric acid solution (20 mL × 2) and saturated sodium carbonate solution (20 mL × 2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain A-1-5-1b (3.00 g crude product) as a yellow oily liquid. MS-ESI: [M+Na] + =381.0.

[0271] Step 3

[0272] A-1-5-1b (3.00 g, 8.40 mmol) was dissolved in trifluoroacetic acid / dichloromethane (V / V=1:1, 40 mL) solution, and the reaction solution was stirred at room temperature for 2 h. Saturated sodium bicarbonate solution was added to the reaction solution, and the pH value was adjusted to 9. Dichloromethane extraction (50 mL×3) was performed, and 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 obtain crude product A-1-5-1c (1.50 g, yield: 69.1%), a yellow oily liquid. MS-ESI: [M+H] + =259.0.

[0273] Step 4

[0274] Pyridine nitrogen oxide (1.07 g, 11.20 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (7.83 g, 16.80 mmol), N,N-diisopropylethylamine (2.89 g, 22.40 mmol) were added to a solution of A-1-5-1c (1.44 g, 5.60 mmol) in 1,2-dichloroethane (20 mL) in sequence, and the reaction was stirred at room temperature for 16 h. The reaction solution was poured into water (20 mL), extracted with dichloromethane (50 mL × 3), washed with saturated brine (50 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was dried, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1), and freeze-dried to obtain A-1-5-1 (600.0 mg, yield: 32.1%) as a light yellow solid. MS-ESI: [M+H] + =336.0. 1H NMR (400MHz, DMSO-d6) δ7.96–7.90(m,2H),7.39–7.35(m,1H),6.64–6.45(m,3H),4.54–4.44(m,1H),4.16–4.11(m,1H),3 .59-3.57(m,3H),2.03-1.95(m,1H),1.73-1.49(m,2H),0.91(s,9H),0.80(dd,J=10.3,6.8Hz,3H),0.73(t,J=6.5Hz,3H).

[0275] Preparation Example 17 Preparation of Compound A-1-5-2

[0276]

[0277] first step

[0278] To a solution of compound A-1-5-2a (5.00 g, 19.80 mmol) in dichloromethane (100 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.69 g, 29.70 mmol), 1-hydroxybenzotriazole (4.01 g, 29.70 mmol), and N,N-diisopropylethylamine (12.80 g, 99 mmol). After stirring at room temperature for 10 min, L-valine methyl ester (2.60 g, 19.80 mmol) was added, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was washed with saturated citric acid solution (50 mL × 2) and saturated sodium carbonate solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain A-1-5-2b (2.60 g, yield: 36.0%), a yellow oily liquid. MS-ESI: [M+Na] + =387.2.

[0279] Step 2

[0280] A-1-5-2b (2.60 g, 7.10 mmol) was dissolved in trifluoroacetic acid / dichloromethane (V / V=1:1, 40 mL) solution, and the reaction solution was stirred at room temperature for 2 h. The crude product A-1-5-2c (2.00 g) was obtained by concentration under reduced pressure, as a yellow oily liquid. MS-ESI: [M+H] + =265.1.

[0281] Step 3

[0282] Tris(dibenzylideneacetone)dipalladium (560.0 mg, 0.61 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (760.0 mg, 1.20 mmol), cesium carbonate (5.96 g, 18.30 mmol) were added to a solution of A-1-5-2c (1.60 g, 6.10 mmol) in 1,4-dioxane (20 mL) in sequence, and the mixture was ventilated three times under nitrogen protection, and the reaction was stirred at 100 ° C for 16 h. The reaction solution was filtered, the filtrate was dried, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) and freeze-dried to obtain A-1-5-2 (350.0 mg, yield: 17.0%) as a white solid. MS-ESI: [M+H] + =342.3. 1 H NMR (400MHz, DMSO-d6) δ8.56-8.47(m,1H),7.94–7.88(m,1H),7.53–7.50(m,2H),7.33–7.22(m,4H),7.08–7.02(m,1H),6.76–6 .73(m,1H),6.52–6.49(m,1H),5.82–5.78(m,1H),4.20–4.15(m,1H),3.64–3.52(m,3H),2.10–1.95(m,1H),0.89–0.70(m,6H).

[0283] Preparation Example 18 Preparation of Compound A-1-5-3

[0284]

[0285] first step

[0286] Add sodium bicarbonate (16.94 g, 201.68 mmol) to a solution of compound A-1-5-3a (12.00 g, 100.84 mmol) in dioxane (120 mL) and water (80 mL), cool the reaction to 0 ° C, add di-tert-butyl dicarbonate (32.97 g, 151.26 mmol) to the reaction solution, slowly warm the reaction to room temperature and stir for 16 hours. Adjust pH to 2 with dilute hydrochloric acid, extract with ethyl acetate (200 mL × 3). Combine the organic phases, wash with saturated sodium chloride solution (100 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product A-1-5-3b (12.00 g, yield: 54.2%), a colorless oily liquid. MS-ESI: [MH] - =218.0.

[0287] Step 2

[0288] A-1-5-3b (12.00 g, 54.79 mmol) and 1,8-diazabicyclo (5,4,0)-7-undecene (16.66 g, 109.58 mmol) were dissolved in acetonitrile (120 mL) solution, the reaction temperature was lowered to 0 ° C, and then tert-butyldimethylsilyl chloride (12.49 g, 82.18 mmol) was added to the reaction solution, and the reaction was slowly heated to room temperature and stirred for 16 hours. The pH was adjusted to 2 with dilute hydrochloric acid, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude A-1-5-3c (12.00 g, yield: 65.7%), a yellow oily liquid. MS-ESI: [MH] - =332.0.

[0289] Step 3

[0290] A-1-5-3c (12.00 g, 36.03 mmol), L-valine methyl ester (5.66 g, 43.24 mmol), N,N-diisopropylethylamine (13.94 g, 108.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.37 g, 54.04 mmol) were dissolved in dichloromethane (150 mL) solution, 1-hydroxybenzotriazole (7.30 g, 54.04 mmol) was added, and the reaction was stirred at room temperature for 2 h. Extract with dichloromethane (200 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (200 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain A-1-5-3d (6.30 g, yield: 39.4%), a yellow oily liquid. MS-ESI: [M+H] + =447.0.

[0291] Step 4

[0292] A-1-5-3d (6.30 g, 14.12 mmol) and pyridine (20 mL) were dissolved in dichloromethane (20 mL) solution, the reaction temperature was lowered to 0 ° C, and then trimethylsilyl trifluoromethanesulfonate (20 mL) was added to the reaction solution, and the reaction was slowly heated to room temperature and stirred for 2 h. The pH was adjusted to 8 with saturated sodium bicarbonate, extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude A-1-5-3e (3.60 g, yield: 73.6%), a yellow oily liquid. MS-ESI: [M+H] + =347.0.

[0293] Step 5

[0294] A-1-5-3e (3.60 g, 10.40 mmol), pyridine nitrogen oxide (1.19 g, 12.48 mmol), N, N-diisopropylethylamine (4.02 g, 31.2 mmol) were dissolved in dichloromethane (50 mL) solution, and tripyrrolidinophosphonium bromide hexafluorophosphate (14.54 g, 31.2 mmol) was added. The reaction was stirred at room temperature for 4 h. Extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified with a C18 reverse phase column to obtain A-1-5-3f (850.0 mg, yield: 19.3%), a colorless oil. MS-ESI: [M+H] + =424.3.

[0295] Step 6

[0296] A-1-5-3f (850.0 mg, 2.01 mmol) was dissolved in N, N-dimethylformamide (10 mL) solution, and then cesium fluoride (1.53 g, 10.05 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 4 h. Extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography. The obtained residue was freeze-dried to obtain A-1-5-3 (230.8 mg, yield: 37.3%) as a colorless oily liquid. MS-ESI: [M+H] + =310.1. 1 HNMR(400MHz, CDCl3)δ8.02(t,J=4.8Hz,1H),7.42(td,J=7.1,1.8Hz,1H),6.81 (dd,J=30.9,8.7Hz,1H),6.66–6.57(m,1H),6.51(t,J=7.5Hz,1H),5.51(t,J=5 .9Hz,1H),4.83–4.62(m,1H),4.56(td,J=9.0,4.9Hz,1H),3.80-3.75(m,1H),3 .76(d,J=9.7Hz,3H),2.27–2.07(m,2H),1.89–1.70(m,1H),0.96–0.83(m,6H).

[0297] Preparation Example 19 Preparation of Compound A-1-6-1

[0298]

[0299] first step

[0300] In a 100mL single-mouth bottle, A-1-6-1a (900.0mg, 4.76mmol), tetrahydrofuran (10mL), iodomethane (1351.0mg, 9.52mmol) were added in sequence. After the addition was completed, nitrogen was used to evacuate 3 times. Under nitrogen protection, sodium hydride (343.0mg, 14.28mmol) was added in batches. After the addition was completed, the reaction was allowed to react at room temperature for 2h and monitored by LCMS. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50mL×3), the organic layers were combined and washed with saturated brine (50mL), the organic layers were combined and dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain A-1-6-1b crude product (1.70g), which was directly used in the next step without purification. MS-ESI: [M+H] + =204.1.

[0301] Step 2

[0302] In a 100mL single-mouth bottle, add crude A-1-6-1b (800.0mg, 3.94mmol), L-valine methyl ester hydrochloride (793.0mg, 4.73mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2247.0mg, 5.91mmol), N,N-diisopropylethylamine (1018.0mg, 7.88mmol) and N,N-dimethylformamide (15mL) in sequence, react at room temperature for 3h after the addition is completed, and monitor by LCMS. The reaction solution is diluted with water, extracted with ethyl acetate (50mL×3), the organic layers are combined and washed with saturated sodium chloride (50mL), the organic layers are combined and dried over anhydrous sodium sulfate, filtered and rotary evaporated; the crude product is purified by medium pressure preparative column to obtain compound A-1-6-1c (800.0mg, 2.53mmol, yield 64.2%). MS-ESI:[M+H] + =317.2.

[0303] Step 3

[0304] In a 100mL single-mouth bottle, add compound A-1-6-1c (800.0mg, 2.53mmol), dichloromethane (5mL), hydrogen chloride (1,4-dioxane solution, 4.0M, 5mL), and react at room temperature for 2h. After LCMS and TLC monitoring show that the reaction is complete, the reaction solution is concentrated under reduced pressure to obtain a crude compound A-1-6-1d (700mg), which is used directly in the next step without purification. MS-ESI: [M+H] + =217.2.

[0305] Step 4

[0306] In a 50mL single-mouth bottle, add the crude compound A-1-6-1d (650.0mg, 3.01mmol), N,N-diisopropylethylamine (778.0mg, 6.02mmol), dichloromethane (10mL), cool to 0℃, slowly add cyclopropylcarbonyl chloride (378.0mg, 3.61mmol), and return to room temperature to react for 2h. After LCMS and TLC monitoring show that the reaction is complete, add water to quench, extract with dichloromethane (50mL×3), combine the organic phases and wash with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter and rotary evaporate; the crude product is purified by medium pressure preparative column to obtain compound A-1-6-1 (530.0mg, 1.86mmol, yield: 61.8%). MS-ESI: [M+H] + =285.2. 1 HNMR (400MHz, CDCl3) δ6.84(d,J=8.7Hz,1H),5.25(q,J=7.1Hz,1H),4.41(dd,J=8.8,4.6Hz,1H),3.71(s,3H),3.06(s,3H),2.17(pd,J=6.9,4.7 Hz,1H),1.78(td,J=7.8,3.9Hz,1H),1.33(d,J=7.1Hz,3H),1.23–1.13(m,1H),0.94(d,J=6.9Hz,3H),0.93–0.77(m,3H),0.86(d,J=7.0Hz,3H).

[0307] Preparation Example 20 Preparation of Compound A-3-1-1

[0308]

[0309] first step

[0310] Dissolve compound A-3-1-1a (2.00 g, 22.45 mmol) and sodium bicarbonate (7.99 g, 95.11 mmol) in water (10 mL), add acetic anhydride (4.58 g, 44.90 mmol) dropwise, and stir at room temperature for 2 h. After LCMS shows that the reaction is complete, adjust the pH to 1-2 with 1M hydrochloric acid, extract with ethyl acetate (100 mL×4), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the crude intermediate A-3-1-1b (1.20 g, 9.15 mmol, yield: 40.8%). MS-ESI: [M+H] + =132.1.

[0311] Step 2

[0312] The intermediate A-3-1-1b (1.20 g, 9.15 mmol), L-valine methyl ester (1.32 g, 10.07 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.75 g, 9.15 mmol), 1-hydroxybenzotriazole (618.3 mg, 4.58 mmol), 4-dimethylaminopyridine (1.68 g, 13.73 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature overnight. After LCMS showed that the raw material disappeared, it was filtered and purified by medium pressure preparative column to obtain A-3-1-1 (460.0 mg, 1.88 mmol, yield: 20.6%). MS-ESI: [M+H] + =245.4. 1 HNMR(400MHz,DMSO-d6)δ8.28(dd,J=81.1,8.2Hz,1H),4.25–4.16(m,1H),4.09–3.89(m,2H),3.64(d ,J=3.4Hz,3H),2.85(d,J=75.6Hz,3H),2.15–2.02(m,1H),1.95(d,J=38.3Hz,3H),0.97–0.80(m,6H).

[0313] Preparation Example 21 Preparation of Compound A-4-1-1

[0314]

[0315] Compound A-4-1-1a (0.60 g, 4.13 mmol), L-valine methyl ester (542.2 mg, 4.13 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (792 mg, 4.13 mmol), 1-hydroxybenzotriazole (279.3 mg, 2.07 mmol), 4-dimethylaminopyridine (757.5 mg, 6.20 mmol) were added to the reaction bottle, and N,N-dimethylformamide (6 mL) was added, and the mixture was reacted at room temperature for 2 h. After the reaction, the system was poured into water, extracted with ethyl acetate (50 mL × 3), washed with 1 M hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine in sequence, and then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain A-4-1-1 (1.01 g, 3.91 mmol, yield: 94.7%). MS-ESI: [M+H] + =259.3. 1H NMR(400MHz,Chloroform-d)δ6.77(d,J=8.2Hz,1H),6.55(s,1H),4.52(dd,J=8.2 ,4.4Hz,1H),3.76(s,3H),2.08(s,3H),1.63(s,6H),0.93(dd,J=14.4,6.7Hz,6H).

[0316] Preparation Example 22 Preparation of Compound A-4-1-2

[0317]

[0318] A-4-1-2a (530.0 mg, 3.70 mmol) was dissolved in N, N-dimethylformamide (9 mL), and 1-hydroxybenzotriazole (150.0 mg, 1.11 mmol), 4-dimethylaminopyridine (587.0 mg, 4.81 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (710.0 mg, 3.7 mmol) and L-valine methyl ester hydrochloride (620.0 mg, 3.7 mmol) were added in sequence at room temperature. After reacting for 16 h at room temperature, the mixture was directly subjected to medium pressure column preparation to obtain A-4-1-2 (460.0 mg, 1.79 mmol, yield: 48.0%). MS-ESI: [M+H] + =257.1. 1 HNMR (400MHz, DMSO-d6) δ8.40(s,1H),7.53(d,J=8.5Hz,1H),4.16(dd,J=8.5,6.8Hz,1H),3.65(s,3H),2.08(h,J=6.8Hz,1H ),1.86(s,3H),1.33(ddd,J=10.0,7.4,4.0Hz,1H),1.14(ddd,J=9.9,7.4,4.1Hz,1H),0.96–0.89(m,1H),0.89–0.78(m,7H).

[0319] Preparation Example 23 Preparation of Compound A-4-1-3

[0320]

[0321] first step

[0322] A-4-1-3a (2.00 g, 9.29 mmol) was dissolved in N, N-dimethylformamide (40 mL), and L-valine methyl ester hydrochloride (1.55 g, 9.29 mmol), 1-hydroxybenzotriazole (313.9 mg, 2.32 mmol), 4-dimethylaminopyridine (2.55 g, 20.87 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.11 g, 5.79 mmol) were added, and stirred at room temperature for 16 h. After the reaction was complete by LCMS, the mixture was filtered and washed with N, N-dimethylformamide, the filtrates were combined and concentrated to obtain a crude product, 40 mL of water was added, filtered and washed with ethyl acetate (80 mL × 3). The filtrates were combined, concentrated, dissolved in a little DMF, and purified by medium pressure preparative column to obtain compound A-4-1-3b (2.50 g, 4.19 mmol, yield: 82.2%) as a white solid. MS-ESI: [M+H] + =329.0.

[0323] Step 2

[0324] The intermediate A-4-1-3b (1.50 g, 4.57 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (15 mL) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete by LCMS, the reaction solution was concentrated to obtain the crude intermediate A-4-1-3c (1.00 g, 4.39 mmol, yield: 96.1%), which was directly used in the next step. MS-ESI: [M+H] + =229.3.

[0325] Step 3

[0326] Compound A-4-1-3c (1.00 g, 4.39 mmol) was dissolved in water (10 mL), sodium bicarbonate (765.0 mg, 9.11 mmol) was added, and acetic anhydride (0.93 g, 9.11 mmol) was added, and stirred at room temperature for 2 h. After the reaction was complete by LCMS, the reaction solution was extracted with dichloromethane (10 mL × 3). The organic phases were combined and concentrated, dissolved with a little DMF, and purified by medium pressure preparative column to obtain compound A-4-1-3 (500.0 mg, 1.85 mmol, yield: 42.3%), a white solid. MS-ESI: [M+H] + =271.4. 1HNMR(400MHz,Chloroform-d)δ7.49(d,J=8.6Hz,1H),6.40(s,1H),4.48(dd,J=8.6,4.8Hz,1H),3.74(s,3H),2.69(d ddd,J=13.0,6.8,3.9,1.2Hz,2H),2.37–2.12(m,3H),2.07(s,3H),2.05–1.85(m,2H),0.93(dd,J=14.1,6.9Hz,6H).

[0327] Preparation Example 24 Preparation of Compound A-4-1-5

[0328]

[0329] first step

[0330] A-4-1-5a (2.00 g, 15.20 mmol) and acetic anhydride (10.86 g, 106.40 mmol) were dissolved in water (20 mL). The reaction mixture was stirred at 70 ° C for 12 h. After the reaction was completed, water (50 mL) was added to the reaction mixture, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and concentrated to obtain A-4-1-5b (1.18 g, yield: 44.7%) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ12.07(s,1H),7.71(s,1H),2.00–1.90(m,1H),1.81(s,3H),1.25(s,3H),0.91(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H).

[0331] Step 2

[0332] A-4-1-5b (400.0 mg, 2.30 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.05 g, 2.77 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 25°C for 30 min. N,N-diisopropylethylamine (895.0 mg, 6.92 mmol) and L-valine methyl ester (465.0 mg, 2.77 mol) were added to the mixture. The reaction mixture was stirred at 25°C for 12 h. After the reaction was completed, water (50 mL) was added to the mixture, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1), and then purified by preparative HPLC to obtain A-4-1-5 (237.5 mg, yield: 36.1%) as a white solid. MS-ESI: [M+H] + =287.0. 1 H NMR(400MHz,DMSO-d6)δ7.83(d,J=8.4Hz,1H),7.59(s,1H),4.17(m,1H),3.61(s,3H),2.43–2 .38(m,1H),2.05(m,1H),1.87(s,3H),1.20(s,3H),0.89–0.83(m,9H),0.78(d,J=6.8Hz,3H).

[0333] Preparation Example 25 Preparation of Compound A-4-1-6

[0334]

[0335] first step

[0336] Compound A-4-1-6a (2.00 g, 12.69 mmol) was dissolved in methanol (12 mL), and a solution of tetramethylguanidine (4.38 g, 8.03 mmol) in methanol (6 mL) and a solution of iodomethane (1.80 g, 12.69 mmol) in tetrahydrofuran (3 mL) were added at room temperature. After the addition, the temperature was raised to 50 °C and reacted for 1 h. After the addition of acetic acid (0.762 g, 12.69 mmol), solids precipitated. The mixture was filtered, washed with ethanol (5 mL), and dried to obtain a crude intermediate A-4-1-6b (1.43 g, 10.6 mmol, yield: 83.0%).

[0337] Step 2

[0338] Dissolve the intermediate A-4-1-6b (1.00 g, 7.4 mmol) in water (12.7 mL), cool to 0 ° C, add sodium hydroxide (0.74 g, 18.49 mmol), acetic anhydride (1.36 g, 13.32 mmol) in turn, stir at 0 ° C for 30 min, then warm to room temperature for 16 h. After extraction and washing with dichloromethane (30 mL), adjust the pH of the aqueous phase to 1 with concentrated hydrochloric acid. Extract with ethyl acetate (40 mL × 3) and combine the organic phases. After drying over anhydrous sodium sulfate, concentrate to obtain the intermediate A-4-1-6c (1.10 g, 6.21 mmol, yield: 84.0%). MS-ESI: [MH] - =176.2.

[0339] Step 3

[0340] The intermediate A-4-1-6c (500.0 mg, 2.82 mmol) was dissolved in N, N-dimethylformamide (9 mL), and 1-hydroxybenzotriazole (114.4 mg, 0.85 mmol), 4-dimethylaminopyridine (448.0 mg, 3.67 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (541.0 mg, 2.82 mmol) and L-valine methyl ester hydrochloride (473.0 mg, 2.82 mmol) were added in sequence at room temperature. After reacting at room temperature for 16 h, the mixture was purified by medium pressure preparative column to obtain A-4-1-6 (601 mg, 2.07 mmol, yield: 73.0%) as a white solid. MS-ESI: [M+H] + =291.0. 1 H NMR(400MHz,DMSO-d6)δ8.42(dd,J=89.2,8.3Hz,1H),8.13(dd,J=8.5,5.1Hz,1 H),4.65(dtd,J=38.4,8.5,5.7Hz,1H),4.21(ddd,J=16.6,8.3,6.4Hz,1H),3.6 7(d,J=7.3Hz,3H),2.76(ddd,J=21.7,13.5,5.7Hz,1H),2.64–2.56(m,1H),2.1 1(d,J=3.5Hz,3H),2.10–2.02(m,1H),1.89(s,3H),0.91(td,J=7.0,1.6Hz,6H).

[0341] Preparation Example 26 Preparation of Compound A-4-1-7

[0342]

[0343] first step

[0344] A-4-1-7a (1.00 g, 7.62 mmol) was dissolved in 2M sodium hydroxide aqueous solution (20 mL), acetic anhydride (1.56 g, 15.25 mmol) was slowly added under ice bath and pH was controlled at about 10. After addition, the mixture was reacted at room temperature for 2 h. After the reaction was complete, pH was adjusted to 1, and a large amount of white solid was precipitated. Filter and dry to obtain the crude intermediate A-4-1-7b (1.32 g, 7.51 mmol, yield: 98.5%). MS-ESI: [M+H] + =174.3.

[0345] Step 2

[0346] The crude intermediate A-4-1-7b (1.20 g, 6.93 mmol), L-valine methyl ester hydrochloride (1.16 g, 6.93 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.32 g, 6.93 mmol), 1-hydroxybenzotriazole (468.06 mg, 3.46 mmol), and 4-dimethylaminopyridine (1.27 g, 10.39 mmol) were added to the reaction flask. N,N-dimethylformamide (12 mL) was added and the reaction was carried out at room temperature for 2 h. Pour into 10mL water, extract with ethyl acetate (20mL×3), combine the organic phases, wash with 1M hydrochloric acid (50mL), saturated sodium bicarbonate aqueous solution (50mL) and saturated brine (50mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify with medium pressure preparative column to obtain compound A-4-1-7 (1.01g, 3.54mmol, yield: 51.2%). MS-ESI: [M+H] + =287.4. 1 H NMR(400MHz, DMSO-d6)δ8.15(d,J=7.3Hz,1H),7.78(t,J=10.4Hz,1H),4.57–4.35(m,1H),4.11(ddd,J=16 .2,7.5,6.3Hz,1H),3.61(d,J=7.8Hz,3H),2.18–1.94(m,1H),1.88(d,J=2.7Hz,3H),0.99–0.83(m,15H).

[0347] Preparation Example 27 Preparation of Compound A-4-1-8

[0348]

[0349] first step

[0350] A-4-1-8a (1.00 g, 6.6 mmol) was dissolved in 2N sodium hydroxide aqueous solution (20 mL), acetic anhydride (1.35 g, 13.19 mmol) was slowly added under ice bath and pH was controlled at about 10. After addition, the mixture was reacted at room temperature for 2 h. After the reaction was complete, pH was adjusted to 1, and a large amount of white solid was precipitated. Filter and dry to obtain the crude intermediate A-4-1-8b (1.00 g, 6.36 mmol, yield: 96.3%). MS-ESI: [M+H] + =158.0.

[0351] Step 2

[0352] The crude intermediate A-4-1-8b (1.0 g, 6.36 mmol), L-valine methyl ester hydrochloride (1.06 g, 6.36 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.22 g, 6.36 mmol), 1-hydroxybenzotriazole (429.9 mg, 3.18 mmol), and 4-dimethylaminopyridine (1.17 g, 9.54 mmol) were added to the reaction flask. N,N-dimethylformamide (10 mL) was added and the reaction was carried out at room temperature for 2 h. After the reaction is complete, pour into 10 mL of water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify with medium pressure preparative column to obtain compound A-4-1-8 (0.72 g, 2.68 mmol, yield: 42.1%). MS-ESI: [M+H] + =271.3. 1 H NMR(400MHz,Chloroform-d)δ6.77(d,J=8.8Hz,1H),6.62–6.48(m,1H),4.54(dt,J=8.7,4.8Hz,1H),3.95(ddd,J=9.2,7.8,5.7Hz,1 H),3.75(d,J=8.6Hz,3H),2.20(dtt,J=10.1,6.9,5.1Hz,1H),2.05(s,3H),1.25–1.09(m,1H),1.04–0.86(m,6H),0.73–0.40(m,4H).

[0353] Preparation Example 28 Preparation of Compound A-4-1-9

[0354]

[0355] first step

[0356] A-4-1-9a (1.00 g, 7.74 mmol) was dissolved in 2M sodium hydroxide aqueous solution (20 mL), acetic anhydride (1.58 g, 15.49 mmol) was slowly added under ice bath and pH was controlled at about 10. After addition, the mixture was reacted at room temperature for 2 h. After the reaction was complete, pH was adjusted to 1, and a large amount of white solid precipitated. Filter and dry to obtain the crude intermediate A-4-1-9b (1.30 g, 7.59 mmol, yield: 98.1%). MS-ESI: [M+H] + =172.2.

[0357] Step 2

[0358] The crude intermediate A-4-1-9b (1.20 g, 7.01 mmol), L-valine methyl ester hydrochloride (1.17 g, 7.01 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.34 g, 7.01 mmol), 1-hydroxybenzotriazole (473.6 mg, 3.50 mmol), and 4-dimethylaminopyridine (1.28 g, 10.51 mmol) were added to the reaction flask. N,N-dimethylformamide (12 mL) was added and the reaction was carried out at room temperature for 2 h. After the reaction is complete, pour into 12 mL of water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify with medium pressure preparative column to obtain compound A-4-1-9 (699.0 mg, 2.46 mmol, yield: 35.1%). MS-ESI: [M+H] + =285.4. 1 H NMR(400MHz,Chloroform-d)δ6.24(s,1H),4.64–4.43(m,2H),3.74(d,J=3.8Hz,3H),2.75–2.57( m,1H),2.17(pt,J=6.9,5.1Hz,1H),2.04(s,5H),1.98–1.74(m,4H),0.92(dd,J=9.8,6.9Hz,6H).

[0359] Preparation Example 29 Preparation of Compound A-4-1-10

[0360]

[0361] A-4-1-10a (1.00 g, 5.03 mmol) was dissolved in N, N-dimethylformamide (20 mL), and 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (2.48 g, 6.53 mmol) and diisopropylethylamine (1.49 g, 11.56 mmol) were added. After the addition was completed, L-valine methyl ester hydrochloride (1.00 g, 6.03 mmol) was added after stirring at room temperature for 0.5 h, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, it was poured into water, and a large amount of white solid precipitated. It was filtered, and the filter cake was slurried with methanol, filtered, and dried to obtain A-4-1-10 (560.0 mg, 1.79 mmol, yield: 35.7%). MS-ESI: [M+H] + =313.4. 1 H NMR(400MHz,Chloroform-d)δ6.60(d,J=8.5Hz,1H),6.20(d,J=8.6Hz,1H),4.51(dd,J=8.5,4.9Hz,1H),4.40(dd,J=8.7,6.5Hz ,1H),3.73(s,3H),2.18(td,J=6.9,4.9Hz,1H),2.02(s,3H),1.81–1.63(m,6H),1.28–1.02(m,5H),0.94(dd,J=8.1,6.9Hz,6H).

[0362] Preparation Example 30 Preparation of Compound A-4-1-11

[0363]

[0364] Add intermediate A-4-1-11a (1.00 g, 5.18 mmol), L-valine methyl ester hydrochloride (865.0 mg, 5.18 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (989.0 mg, 5.18 mmol), 1-hydroxybenzotriazole (349.0 mg, 2.59 mmol), 4-dimethylaminopyridine (948.0 mg, 7.77 mmol) to the reaction bottle. Add N,N-dimethylformamide (20 mL) and react at room temperature for 2 h. After the reaction is complete, pour into 20 mL of water, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify with medium pressure preparative column to obtain compound A-4-1-11 (660.0 mg, 2.157 mmol, yield: 41.6%). MS-ESI: [M+H] + =307.3. 1H NMR(400MHz,Chloroform-d)δ7.45–7.28(m,5H),6.86(dd,J=107.7,7.9Hz,2H),5.66(dd,J=21.9 ,7.0Hz,1H),4.56–4.44(m,1H),3.68(d,J=39.3Hz,3H),2.02(d,J=1.1Hz,4H),0.97–0.63(m,6H).

[0365] Preparation Example 31 Preparation of Compound A-4-1-12

[0366]

[0367] C-1-1-1 (0.70 g, 2.40 mmol) and dioxane (10 mL) were added into a 50 mL three-necked flask. After fully dissolved, N,N-diisopropylethylamine (0.34 g, 2.64 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (1.00 g, 2.64 mmol) were added into the reaction flask. Deuterated methanol (5 mL) was then added dropwise into the reaction solution. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. The reaction was monitored by TLC and LCMS. After the reaction, the reaction solution was added to water (50 mL), then extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by medium pressure preparative column to obtain product A-4-1-12 (0.39 g, 1.26 mmol, yield: 52.0%). MS-ESI: [M+H] + =310.2.

[0368] 1 H NMR (400MHz, DMSO-d6) δ8.64(dd,J=24.5,21.9Hz,1H),8.50(m,1H),7.43(dd,J=21.9,7.2Hz,2H),7.37–7.19(m,3H),5.69(dd,J=2 0.5, 8.4Hz, 1H), 4.16 (ddd, J=17.0, 8.2, 6.4Hz, 1H), 2.10–1.93 (m, 1H), 1.90 (d, J=2.1Hz, 3H), 0.80 (ddd, J=29.4, 16.5, 6.8Hz, 6H).

[0369] Preparation Example 32 Preparation of Compound A-4-1-13

[0370]

[0371] first step

[0372] Add raw material A-4-1-13a (1.00 g, 6.05 mmol) and tetrahydrofuran (20 mL) into a 100 mL dry three-necked flask. After fully dissolved, add deuterated acetic acid (0.46 g, 7.26 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (2.76 g, 7.26 mmol), 1-hydroxybenzotriazole (0.82 g, 6.05 mmol), and triethylamine (1.22 g, 12.10 mmol) into the reaction flask in sequence. After the addition is completed, react at room temperature for 2 h and monitor the reaction by TLC and LCMS. After the reaction, the reaction solution was added to water (60 mL), and then extracted with ethyl acetate (50 mL×3). The organic phases were combined and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain A-4-1-13b (0.80 g, 3.80 mmol, yield: 63.0%).

[0373] Step 2

[0374] A-4-1-13b (0.80 g, 3.80 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask. After fully dissolved, lithium hydroxide aqueous solution (2.0 M, 10 mL) was added dropwise to the reaction flask. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. The reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction solution was added to water (50 mL), the aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1.0 M), and then extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product A-4-1-13c (0.55 g, 2.80 mmol, yield: 74.0%).

[0375] Step 3

[0376] A-4-1-13c (0.50 g, 2.55 mmol) and N,N-dimethylformamide (20 mL) were added into a 100 mL dry three-necked flask. After fully dissolved, L-valine methyl ester hydrochloride (0.33 g, 1.97 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.49 g, 2.55 mmol), 1-hydroxybenzotriazole (0.17 g, 1.28 mmol), and 4-dimethylaminopyridine (0.47 g, 3.83 mmol) were added into the reaction flask in sequence. After the addition was completed, the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC and LCMS. After the reaction, the reaction solution was added to water (50 mL), then extracted with ethyl acetate (50 mL × 3), the organic phases were combined, backwashed once with water (300 mL), and then washed with 1.0 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by medium pressure preparative column to obtain product A-4-1-13 (0.38 g, 1.23 mmol, yield: 48.0%). MS-ESI: [M+H] + =310.2.

[0377] 1 H NMR(400MHz,Chloroform-d)δ7.43(dd,J=7.7,1.5Hz,2H),7.36–7.28(m,3H),6.98(d,J=6.7Hz,1H),6.66(d,J=8.9 Hz,1H),5.67(d,J=6.9Hz,1H),4.50(dd,J=8.9,5.0Hz,1H),3.74(s,3H),2.23–1.91(m,1H),0.69(dd,J=6.6Hz,6H).

[0378] Preparation Example 33 Preparation of Compound A-4-1-14

[0379]

[0380] first step

[0381] A-4-1-14a (2.00 g, 11.83 mmol) was dissolved in acetonitrile (10 mL), and saturated sodium bicarbonate aqueous solution (20 mL) was added. Acetic anhydride (2.41 g, 23.66 mmol) was slowly added under ice bath and the pH was controlled at 8-9. After the addition, the reaction was allowed to react at room temperature for 2 h and the sample was sent for monitoring. After the reaction was complete, the pH was adjusted to 1 with hydrochloric acid. A large amount of white solid precipitated, which was filtered and dried to obtain the crude intermediate A-4-1-14b (1.80 g, 8.53 mmol, yield: 72.1%). MS-ESI: [M+H]+ =212.0.

[0382] Step 2

[0383] The crude intermediate A-4-1-14b (1.00 g, 4.74 mmol), L-valine methyl ester hydrochloride (791.0 mg, 4.74 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (905.0 mg, 4.74 mmol), 1-hydroxybenzotriazole (320.0 mg, 2.37 mmol), and 4-dimethylaminopyridine (867.0 mg, 7.11 mmol) were added to the reaction flask. N,N-dimethylformamide (20 mL) was added and the reaction was carried out at room temperature for 2 h. After the reaction is complete, pour into 20 mL of water, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, concentrate and purify by column chromatography to obtain compound A-4-1-14 (720.0 mg, 2.215 mmol, yield: 46.7%). MS-ESI: [M+H] + =325.3. 1 H NMR(400MHz,Chloroform-d)δ7.39(ddd,J=18.5,8.6,5.4Hz,2H),7.09–6.93(m,3H),6.73(dd,J=117.6,8.7Hz,1H),5.6 9(dd,J=23.7,7.0Hz,1H), 4.48(dt,J=8.4,4.8Hz,1H), 3.69(d,J=33.6Hz,3H), 2.04(d,J=1.8Hz,4H), 0.98–0.65(m,6H).

[0384] Preparation Example 34 Preparation of Compound A-4-1-15

[0385]

[0386] first step

[0387] A-4-1-15a (2.00 g, 11.98 mmol) was dissolved in 2M sodium hydroxide aqueous solution (20 mL), acetic anhydride (2.44 g, 23.95 mmol) was slowly added under ice bath and pH was controlled at about 10. After addition, the reaction was carried out at room temperature for 0.5 h, and then solid sodium hydroxide was added to control pH at about 12, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 1 with hydrochloric acid, and a large amount of white solid precipitated. Filter and dry to obtain the crude intermediate A-4-1-15b (2.10 g, 10.04 mmol, yield: 83.9%). MS-ESI: [M+H] + =210.0.

[0388] Step 2

[0389] The crude intermediate A-4-1-15b (1.00 g, 4.78 mmol), L-valine methyl ester hydrochloride (799 mg, 4.78 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (912.0 mg, 4.78 mmol), 1-hydroxybenzotriazole (322.0 mg, 2.39 mmol), and 4-dimethylaminopyridine (874.0 mg, 7.17 mmol) were added to the reaction flask. N,N-dimethylformamide (20 mL) was added and the reaction was carried out at room temperature for 2 h. After the reaction is complete, pour into 20 mL of water, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with 1N hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, concentrate and purify by column to obtain compound A-4-1-15 (560.0 mg, 1.74 mmol, yield: 36.4%). MS-ESI: [M+H] + =323.3. 1 HNMR(400MHz,DMSO-d6)δ9.33(s,1H),8.63–8.09(m,2H),7.37–7.02(m,2H),6.81–6.51(m,2H),5.53(dd,J=2 2.2, 8.3Hz, 1H), 4.15 (ddd, J=12.0, 8.3, 6.4Hz, 1H), 3.66–3.53 (m, 3H), 2.13–1.80 (m, 4H), 1.02–0.60 (m, 6H).

[0390] Preparation Example 35 Preparation of Compound A-4-1-21

[0391]

[0392] Dissolve the intermediate A-4-1-21a (1.00 g, 6.12 mmol) in N, N-dimethylformamide (20 mL), add L-valine methyl ester hydrochloride (1.54 g, 9.19 mmol), 1-hydroxybenzotriazole (910.8 mg, 6.74 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.29 g, 6.74 mmol). React at room temperature for 16 h. After the reaction is complete, add 20 mL of water and extract with ethyl acetate (20 mL × 3). After the organic phase is combined and concentrated, it is dissolved in a small amount of N, N-dimethylformamide and purified by medium pressure preparative column to obtain compound A-4-1-21 (400.0 mg, 1.45 mmol, yield: 23.6%). MS-ESI: [M+H] + =277.3. 1 H NMR(400MHz,Chloroform-d)δ6.83(d,J=8.7Hz,1H),6.73(d,J=7.6Hz,1H),4.68 (td,J=7.3,4.2Hz,1H),4.53(dd,J=8.6,4.8Hz,1H),3.75(s,3H),3.06(ddd,J=1 3.9,7.6,4.2Hz,1H),2.76(ddd,J=13.9,10.3,7.1Hz,1H),2.22(pd,J=6.9,4.8H z, 1H), 2.11 (s, 3H), 1.68 (dd, J = 10.3, 7.6Hz, 1H), 0.95 (dd, J = 16.0, 6.9Hz, 6H).

[0393] Preparation Example 36 Preparation of Compound A-4-1-22

[0394]

[0395] first step

[0396] A-4-1-22a (1.19 g, 9.99 mmol) was dissolved in acetic acid (10 mL), acetic anhydride (510.0 mg, 5.0 mmol) was added at room temperature, and the mixture was reacted at 90 ° C for 2 h. After the reaction was complete, it was poured into 10 mL of water and extracted with ethyl acetate (20 mL × 3). After the organic phases were combined, they were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by medium pressure preparative column to obtain the crude intermediate A-4-1-22b (560.0 mg, 3.47 mmol, yield: 34.8%). MS-ESI: [M+H] + =162.0.

[0397] Step 2

[0398] The crude intermediate A-4-1-22b (510.0 mg, 3.16 mmol), L-valine methyl ester hydrochloride (530.0 mg, 3.16 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (607.0 mg, 3.16 mmol), 1-hydroxybenzotriazole (214.0 mg, 1.58 mmol), 4-dimethylaminopyridine (580.0 mg, 4.75 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered and purified by high pressure reverse phase preparation and silica gel forward purification to obtain a white solid A-4-1-22 (315.0 mg, 1.09 mmol, yield: 34.5%). MS-ESI: [M+H] + =275.1. 1 H NMR (400MHz, DMSO-d6) δ7.96(d,J=8.1Hz,1H),7.78(d,J=8.5Hz,1H),4.86(d,J=4.9Hz,1H),4.28(dd,J=8.5,4.9Hz,1H),4.18(dd,J=8.1,6.2H z,1H),3.88(dt,J=6.4,4.9Hz,1H),3.62(s,3H),2.03(dq,J=13.3,6.7Hz,1H),1.89(s,3H),1.05(d,J=6.3Hz,3H),0.87(dd,J=6.8,5.6Hz,6H).

[0399] Preparation Example 37 Preparation of Compound A-4-1-24

[0400]

[0401] Intermediate A-4-1-24a (0.60 g, 3.45 mmol), L-valine methyl ester hydrochloride (576.2 mg, 3.45 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (658.6 mg, 3.45 mmol), 1-hydroxybenzotriazole (232.8 mg, 1.72 mmol), 4-dimethylaminopyridine (631.4 mg, 5.17 mmol) were added to N,N-dimethylformamide (20 mL) and reacted at room temperature for 2 h. After the reaction is complete, pour into water. After the reaction is complete, pour into 20 mL of water and extract with ethyl acetate (40 mL × 3). After combining the organic phases, wash with 1 M hydrochloric acid (80 mL), saturated sodium bicarbonate aqueous solution (80 mL) and saturated brine (80 mL) in sequence. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated, and purified by medium pressure preparative column to obtain compound A-4-1-24 (0.35 g, 1.22 mmol, yield: 35.4%). MS-ESI: [M+H] + =288.3. 1 H NMR(400MHz,DMSO-d6)δ8.22–7.92(m,2H),7.30(s,1H),6.90(s,1H),4.63(dt d,J=13.6,7.9,5.9Hz,1H),4.16(ddd,J=9.1,8.4,6.1Hz,1H),3.63(d,J=2.9H z,3H),2.49–2.43(m,1H),2.34(ddd,J=15.5,8.0,4.8Hz,1H),2.02(dtd,J=12 .9, 6.4, 1.9Hz, 1H), 1.83 (d, J = 1.7Hz, 3H), 0.85 (ddd, J = 6.8, 4.4, 1.6Hz, 6H).

[0402] Preparation Example 38 Preparation of Compound A-4-1-25

[0403]

[0404] A-4-1-25a (0.75 g, 4.71 mmol), L-valine methyl ester hydrochloride (789.5 mg, 4.71 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (900.7 mg, 4.71 mmol), 1-hydroxybenzotriazole (318.3 mg, 2.36 mmol), 4-dimethylaminopyridine (863.4 mg, 7.07 mmol) were added to N,N-dimethylformamide (8 mL) and reacted at room temperature for 2 h. After the reaction is complete, pour into 20 mL of water, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (80 mL), saturated sodium bicarbonate aqueous solution (80 mL) and saturated brine (80 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify by medium pressure preparative column to obtain compound A-4-1-25 (1.00 g, 3.67 mmol, yield: 77.9%). MS-ESI: [M+H] + =273.4. 1 H NMR(400MHz,DMSO-d6)δ8.24–8.09(m,1H),7.93(dd,J=8.3,5.2Hz,1H),4.3 9(dtd,J=32.6,8.4,5.5Hz,1H),4.16(ddd,J=14.4,8.2,6.4Hz,1H),3.63(d, J=7.1Hz,3H),2.03(dqd,J=13.8,6.9,1.4Hz,1H),1.83(d,J=3.2Hz,3H),1. 65–1.39(m,2H),1.28(dqd,J=12.9,7.4,6.9,2.3Hz,2H),0.95–0.80(m,9H).

[0405] Preparation Example 39 Preparation of Compound A-4-1-26

[0406]

[0407] first step

[0408] A-4-1-26a (1.28 g, 10.75 mmol) was dissolved in water (10 mL), potassium hydroxide (1.80 g, 32.14 mmol) was added at room temperature, and stirred to dissolve. After adding acetic anhydride (2.20 g, 21.54 mmol), the reaction was allowed to react at room temperature for 2 h. After the reaction was complete, it was poured into 10 mL of water and extracted with ethyl acetate (20 mL × 3). After the organic phases were combined, they were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by medium pressure preparative column to obtain the crude intermediate A-4-1-26b (660.0 mg, 4.10 mmol, yield: 38.1%), a colorless liquid. MS-ESI: [M+H] + =162.0.

[0409] Step 2

[0410] The intermediate A-4-1-26b (660.0 mg, 4.10 mmol), L-valine methyl ester (548.0 mg, 4.18 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (942.0 mg, 4.92 mmol), 1-hydroxybenzotriazole (663.0 mg, 4.92 mmol) were dissolved in N,N-dimethylformamide (13 mL). After reacting at room temperature for 2 h, the reaction solution was filtered and purified by high pressure reverse phase preparation and silica gel forward purification to obtain compound A-4-1-26 (305.0 mg, 1.11 mmol, yield 27.2%) as a white solid. MS-ESI: [M+H] + =275.1. 1 HNMR (600MHz, DMSO-d6) δ8.11(dd,J=56.6,8.2Hz,1H),7.99(t,J=9.2Hz,1H),4.42(dtd,J=34.8,8.2,5.1Hz,2H),4.22–4.09(m,1H),3.63( s,3H),3.45–3.37(m,2H),2.03(h,J=6.7Hz,1H),1.83(d,J=5.6Hz,3H),1.78(td,J=7.9,3.9Hz,1H),1.69–1.58(m,1H),0.94–0.80(m,6H).

[0411] Preparation Example 40 Preparation of Compound A-4-1-27

[0412]

[0413] first step

[0414] A-1-3-4a (1.00 g, 6.89 mmol) was dissolved in 2M sodium hydroxide aqueous solution (20 mL), acetic anhydride (1.56 g, 15.25 mmol) was slowly added under ice bath and pH was controlled at about 10. After addition, the mixture was reacted at room temperature for 2 h. After the reaction was complete, pH was adjusted to 1, and a large amount of white solid was precipitated. Filter and dry to obtain the crude intermediate A-4-1-27a (1.10 g, 5.88 mmol, yield: 85.4%). MS-ESI: [M+H] + =188.3.

[0415] Step 2

[0416] The crude intermediate A-4-1-27a (1.10 g, 5.88 mmol), L-valine methyl ester hydrochloride (982.0 mg, 5.88 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1123.0 mg, 5.88 mmol), 1-hydroxybenzotriazole (397.0 mg, 2.94 mmol), and 4-dimethylaminopyridine (1076.0 mg, 8.82 mmol) were added to the reaction bottle. N,N-dimethylformamide (12 mL) was added and the reaction was carried out at room temperature for 2 h. After the reaction is complete, pour into 10 mL of water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify with medium pressure preparative column to obtain compound A-4-1-27 (1200.0 mg, 4 mmol, yield: 68.0%). MS-ESI: [M+H] + =301.4. 1 H NMR(400MHz,Chloroform-d)δ6.98–6.05(m,2H),4.60–4.39(m,2H),3.72(d,J=6.6Hz,3H),2.17(pd,J=6.9,4.9Hz,1H ), 2.01 (d, J = 8.2Hz, 3H), 1.92 (ddd, J = 17.5, 14.4, 4.9Hz, 1H), 1.44 (ddd, J = 14.2, 7.6, 6.2Hz, 1H), 0.98–0.88 (m, 15H).

[0417] Preparation Example 41 Preparation of Compound A-4-1-30

[0418]

[0419] first step

[0420] Compound A-4-1-30a (1.00 g, 7.75 mmol) was dissolved in a saturated sodium bicarbonate aqueous solution (30 mL), and acetic anhydride (1.58 g, 15.50 mmol) was slowly added under ice bath and the pH was controlled at about 8. After the addition, the reaction was allowed to react at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 1 with hydrochloric acid, and the mixture was extracted with ethyl acetate (40 mL × 3). After the organic phases were combined, they were washed with a saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude intermediate A-4-1-30b (1.00 g, 5.84 mmol, yield: 75.5%). MS-ESI: [M+H] + =172.3.

[0421] Step 2

[0422] The crude intermediate A-4-1-30b (1.00 g, 5.84 mmol), L-valine methyl ester hydrochloride (975.0 mg, 5.84 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1115.0 mg, 5.84 mmol), 1-hydroxybenzotriazole (394.0 mg, 2.92 mmol), and 4-dimethylaminopyridine (1068.0 mg, 8.76 mmol) were added to the reaction bottle. N,N-dimethylformamide (20 mL) was added and the reaction was carried out at room temperature for 2 h. After the reaction is complete, pour into 20 mL of water, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify with medium pressure preparative column to obtain compound A-4-1-30 (1.20 g, 4.22 mmol, yield: 72.4%). MS-ESI: [M+H] + =285.4. 1 HNMR(400MHz,Chloroform-d)δ6.92–6.32(m,2H),4.67–4.44(m,2H),3.74(d,J=2.6Hz,3H),2.18(td,J=6.9,5.0Hz,1H),2.02(d,J=3.6Hz,3H),1.73( dd,J=13.8,6.9Hz,1H),1.59(dd,J=13.5,6.7Hz,1H),0.94(ddd,J=8.8,6. 9,4.4Hz,6H),0.72(s,1H),0.53–0.43(m,2H),0.11(td,J=4.7,2.0Hz,2H).

[0423] Preparation Example 42 Preparation of Compound A-4-1-31

[0424]

[0425] first step

[0426] Compound A-4-1-31a (1.00 g, 6.37 mmol) was dissolved in a saturated sodium bicarbonate aqueous solution (30 mL), and acetic anhydride (1.30 g, 12.74 mmol) was slowly added under ice bath and the pH was controlled at about 8. After the addition, the reaction was allowed to react at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 1 with hydrochloric acid, and the crude intermediate A-4-1-31b (1.00 g, 5.02 mmol, yield: 78.9%) was obtained by filtration and drying. MS-ESI: [M+H] + =200.3.

[0427] Step 2

[0428] The crude intermediate A-4-1-31b (1.00 g, 5.02 mmol), L-valine methyl ester hydrochloride (838.0 mg, 5.02 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (959.0 mg, 5.02 mmol), 1-hydroxybenzotriazole (339.0 mg, 2.51 mmol), and 4-dimethylaminopyridine (918.0 mg, 7.53 mmol) were added to the reaction bottle. N,N-dimethylformamide (20 mL) was added and the reaction was carried out at room temperature for 2 h. After the reaction is complete, pour into 20 mL of water, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify with medium pressure preparative column to obtain compound A-4-1-31 (1300.0 mg, 4.16 mmol, yield: 83.0%). MS-ESI: [M+H] + =313.4. 1 H NMR(400MHz,Chloroform-d)δ6.87–6.14(m,2H),4.50(tdd,J=10.3,5.4,3.1Hz,2H),3.73(d,J=5.8Hz,3H),2.18(td,J=6.9,4.9Hz ,1H),2.02(d,J=4.0Hz,3H),1.82(dh,J=16.5,6.5,4.6Hz,4H),1.67–1.47(m,5H),1.13(dt,J=7.2,3.7Hz,2H),0.99–0.88(m,6H).

[0429] Preparation Example 43 Preparation of Compound A-4-1-32

[0430]

[0431] first step

[0432] Compound A-4-1-32a (3.20 g, 18.69 mmol) was added to water (120 mL), and 2M sodium hydroxide aqueous solution was added dropwise until the reaction system became clear, and acetic anhydride (6.68 g, 65.41 mmol) was added, and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the pH was adjusted to 2 with hydrochloric acid at 0°C, and extracted with ethyl acetate (120 mL×3). The organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude intermediate A-4-1-32b (3.80 g, 17.82 mmol, yield: 95.3%).

[0433] Step 2

[0434] Dissolve L-valine methyl ester hydrochloride (838.0 mg, 5.00 mmol) and 4-dimethylaminopyridine (1.20 g, 10.00 mmol) in N,N-dimethylformamide (10 mL). Add the crude intermediate A-4-1-32b (1.10 g, 5.00 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.10 g, 5.50 mmol) at 0°C and react at room temperature for 16 h. After the reaction is complete, add 10 mL of water and extract with ethyl acetate (20 mL×3). Combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate and purify by preparative liquid chromatography to obtain A-4-1-32 (500.0 mg, 1.53 mmol, yield: 30.6%). MS-ESI: [M+H] + =327.4. 1 H NMR(400MHz,Chloroform-d)δ6.73–6.63(m,1H),6.00–5.94(m,1H),4.61–4.42(m,2H),3.75–3.73(m,3H),2.18( pd,J=6.8,4.8Hz,1H),2.03-2.02(m,3H),1.83–1.58(m,6H),1.50(m,1H),1.41–1.06(m,4H),1.03–0.81(m,8H).

[0435] Preparation Example 44 Preparation of Compound A-4-1-33

[0436]

[0437] first step

[0438] Add diethyl acetamidomalonate (2.20 g, 10.17 mmol) to ethanol (10 mL), stir at room temperature for 20 min, dissolve A-4-1-33a (2.40 g, 10.17 mmol) in ethanol (10 mL) and add to the reaction system, react at 80 ° C for 16 h. After the reaction is complete, concentrate and purify by preparative liquid chromatography to obtain intermediate A-4-1-33b (300.0 mg, 0.99 mmol, yield: 9.72%). MS-ESI: [M+H] + =304.1.

[0439] Step 2

[0440] Dissolve the intermediate A-4-1-33b (300 mg, 0.99 mmol) in tetrahydrofuran (3 mL), add 1M lithium hydroxide aqueous solution (3 mL), and react at room temperature for 1 h. After the reaction is complete, dilute with 3 mL of water and adjust the pH to 3 with 1M hydrochloric acid, and extract with ethyl acetate (6 mL×3). Combine the organic phases, wash with saturated brine (6 mL), dry over anhydrous sodium sulfate, and concentrate to obtain the crude intermediate A-4-1-33c (220.0 mg, 0.80 mmol, yield: 80.8%).

[0441] Step 3

[0442] Dissolve L-valine methyl ester hydrochloride (134.0 mg, 0.80 mmol) and 4-dimethylaminopyridine (195.0 mg, 1.60 mmol) in N,N-dimethylformamide (2 mL). Add the crude intermediate A-4-1-33c (220.0 mg, 0.80 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (162.0 mg, 0.85 mmol) at 0°C and react at room temperature for 16 h. After the reaction is complete, add 2 mL of water and extract with ethyl acetate (4 mL×3). Combine the organic phases, wash with saturated brine (4 mL), dry over anhydrous sodium sulfate, concentrate and purify by preparative liquid chromatography to obtain A-4-1-33 (283.0 mg, 728.67 umol, yield: 91.2%). MS-ESI: [M+H] + =389.0. 1HNMR(400MHz, DMSO-d6)δ8.42-8.29(m,1H),8.17–8.12(m,1H),7.63(dd,J=8.4,4.7Hz,2H),7.49–7.46(m,2H),4.81–4.61(m,1H),4.15(ddd, J=16.4,8.4,6.4Hz,1H),3.64–3.62(m,3H),3.01(m,1H),2.83(m,1H), 1.99(m,1H),1.76–1.74(m,3H),0.90-0.86(m,3H),0.76–0.74(m,3H).

[0443] Preparation Example 45 Preparation of Compound A-4-1-34

[0444]

[0445] first step

[0446] Compound A-4-1-34a (5.40 g, 26.34 mmol) was dissolved in anhydrous dichloromethane (100 mL), and L-valine methyl ester hydrochloride (3.50 g, 20.88 mmol), 4-dimethylaminopyridine (6.40 g, 52.68 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.10 g, 31.61 mmol) were added under ice-salt bath. After addition, the mixture was reacted at room temperature for 14 h. The consumption of the raw materials was monitored by LCMS. After the consumption of the raw materials, 100 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined and washed with saturated brine (100 mL) to obtain a crude compound A-4-1-34b (5.40 g, 16.93 mmol, yield: 64.4%), which was used directly in the next step without purification. MS-ESI: [M-(CH3)3CO] + =245.1.

[0447] Step 2

[0448] The crude product of compound A-4-1-34b (5.40 g, 16.95 mmol) was dissolved in N, N-dimethylformamide (55 mL), 4-dimethylaminopyridine (414.0 mg, 3.39 mmol) and N, N-diisopropylethylamine (6.60 g, 50.85 mmol) were added, and ethyl chloroformate (2.80 g, 25.46 mmol) was added dropwise under an ice-salt bath. After the addition, the mixture was reacted at 0-10 ° C for 10 min, and then heated to room temperature for 14 h. LCMS and TLC monitoring showed that no raw material remained. The reaction solution was poured into a saturated sodium bicarbonate solution to quench the reaction, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound A-4-1-34c (6.10 g, 15.64 mmol, yield 92.3%, purity 45.6%). MS-ESI: [M+H] + =391.1.

[0449] Step 3

[0450] Compound A-4-1-34c (6.10 g, 15.64 mmol) was dissolved in ethyl acetate solution (60 mL) of hydrochloric acid and reacted at room temperature for 2 h. LCMS monitoring showed that no raw material remained. The reaction solution was spin-dried to obtain a crude compound A-4-1-34d (4.50 g, 15.34 mmol, yield 98.1%, purity 40.4%).

[0451] Step 4

[0452] Compound A-4-1-34d (2.70 g, 9.31 mmol) was dissolved in N, N-dimethylformamide (30 mL), acetyl chloride (810.0 mg, 10.32 mmol) and triethylamine (1.90 g, 18.58 mmol) were added, and the reaction was carried out at room temperature for 14 h. The reaction was monitored by LCMS and TLC. After the reaction, 30 mL of water was added and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and dried to obtain a crude product. The compound A-4-1-34 (2.10 g, 6.14 mmol, yield: 66.3%) was obtained by medium pressure purification. MS-ESI: [M+H] + =333.4. 1H NMR(400MHz,Chloroform-d)δ6.81(d,J=8.8Hz,1H),6.45(d,J=7.4Hz,1H),4.82(dt,J=7.5,5.5Hz,1H),4.57–4.46(m,2H),4.27(dd,J=11.1, 5.7Hz,1H),4.20(q,J=7.1Hz,2H),3.74(s,3H),2.19(pd,J=6.9,5.0Hz,1H),2.06(s,3H),1.30(t,J=7.1Hz,3H),0.92(dd,J=14.3,6.9Hz,6H).

[0453] Preparation Example 46 Preparation of Compound B-1-1-1

[0454]

[0455] first step

[0456] Dissolve B-1-1-1a (10.00 g, 76.26 mmol) in anhydrous dichloromethane (100 mL), add L-valine methyl ester hydrochloride (12.80 g, 6.26 mmol), 4-dimethylaminopyridine (18.60 g, 152.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.50 g, 91.51 mmol) under ice-salt bath, and react at room temperature for 14 h. After LCMS monitoring shows that the reaction is complete, dilute with water, extract with ethyl acetate (150 mL × 3), combine the organic phases, wash with saturated brine (150 mL), dry with anhydrous sodium sulfate, and concentrate the ethyl acetate under reduced pressure to obtain compound B-1-1-1b (15.00 g, 61.40 mmol, yield: 80.5%). MS-ESI: [M+H] + =245.1.

[0457] Step 2

[0458] Compound B-1-1-1b (15.00 g, 61.40 mmol) was dissolved in anhydrous tetrahydrofuran (75 mL) and water (75 mL), and lithium hydroxide (1.80 g, 73.78 mmol) was added. After the addition, the mixture was reacted at room temperature for 2 h. LCMS monitoring showed that the reaction was complete. The solvent was dried and diluted hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with dichloromethane (150 mL × 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and dichloromethane was dried under reduced pressure to obtain compound B-1-1-1c (10.00 g, 43.47 mmol, yield: 70.7%). MS-ESI: [M+H] + =229.1.

[0459] Step 3

[0460] Compound B-1-1-1c (2.00 g, 8.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), cesium carbonate (14.20 g, 43.49 mmol) was added, 2-bromomethyl methyl ether (3.30 g, 26.09 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 14 h. LCMS monitoring showed that the reaction was complete, the reaction solution was diluted with water, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was dried, and purified by preparative liquid chromatography to obtain compound B-1-1-1 (334.0 mg, 1.22 mmol, yield: 14.0%). MS-ESI: [M+H] + =275.1. 1 HNMR(400MHz,Chloroform-d)δ6.69(d,J=8.7Hz,1H),6.06(d,J=7.4Hz,1H),5.28(dd,J=43.4,5.9Hz,2H),4.58(q,J=7.1Hz,1H),4.53( dd,J=8.7,4.7Hz,1H),3.47(s,3H),2.33–2.18(m,1H),2.03(s,3H),1.40(d,J=7.0Hz,3H),0.99(d,J=6.9Hz,3H),0.94(d,J=6.9Hz,3H).

[0461] Preparation Example 47 Preparation of Compound B-1-1-2

[0462]

[0463] Compound B-1-1-1c (2.00 g, 8.69 mmol) was dissolved in N, N-dimethylformamide (20 mL), 2-bromoethyl methyl ether (3.60 g, 26.12 mmol) and cesium carbonate (14.20 g, 43.49 mmol) were added, and the mixture was heated to 80 °C for 14 h. LCMS monitoring showed that the reaction was complete. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and dried to obtain a crude product, which was purified by preparative liquid chromatography to obtain compound B-1-1-2 (530.0 mg, 1.84 mmol, yield: 21.2%). MS-ESI: [M+H] + =289.0. 1H NMR(400MHz,Chloroform-d)δ6.74(dd,J=49.4,8.7Hz,1H),6.28(d,J=7.6Hz,1H ),4.65–4.49(m,2H),4.33(dddd,J=12.0,7.6,4.5,2.3Hz,1H),4.24(dddd,J=12. 0,8.0,5.1,4.1Hz,1H),3.61–3.56(m,2H),3.36(d,J=1.2Hz,3H),2.28–2.13(m, 1H), 2.00 (dd, J=3.6, 1.3Hz, 3H), 1.38 (dd, J=7.0, 4.4Hz, 3H), 0.98–0.89 (m, 6H).

[0464] Preparation Example 48 Preparation of Compound B-1-1-3

[0465]

[0466] Compound B-1-1-1c (2.00 g, 8.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), bromocyclopentane (3.9 g, 26.11 mmol) and cesium carbonate (14.2 g, 43.49 mmol) were added, and the mixture was heated to 80 °C for 14 h. LCMS monitoring showed that the reaction was complete. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and dried to obtain a crude product, which was purified by preparative liquid chromatography to obtain compound B-1-1-3 (810.0 mg, 2.72 mmol, yield: 31.3%). MS-ESI: [M+H] + =299.0. 1 H NMR(400MHz,Chloroform-d)δ6.69(dd,J=43.5,8.8Hz,1H),6.40–6.18(m,1H),5.25–5.16(m,1H),4.62–4.52(m,1H),4.44(ddd,J=8.7,4.7,1.5H z,1H),2.22–2.09(m,1H),2.00(d,J=3.8Hz,3H),1.91–1.80(m,2H),1.7 7–1.66(m,4H),1.63–1.54(m,2H),1.44–1.33(m,3H),0.97–0.86(m,6H).

[0467] Preparation Example 49 Preparation of Compound B-1-2-1

[0468]

[0469] first step

[0470] B-1-2-1a (2.00 g, 11.43 mmol) and n-pentanol (1.10 g, 12.57 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL), and 4-dimethylaminopyridine (2.80 g, 22.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.40 g, 12.57 mmol) were added in sequence at 0°C. After stirring at 0°C for 1 h, the mixture was warmed to room temperature overnight. After LCMS monitoring showed that the reaction was complete, a small amount of water was added to quench the reaction. The mixture was concentrated under reduced pressure to remove N,N-dimethylformamide and prepared by preparative liquid chromatography to obtain compound B-1-2-1b (2.10 g, 8.69 mmol, yield: 76.0%).

[0471] Step 2

[0472] Compound B-1-2-1b (2.10 g, 8.69 mmol) was dissolved in 4M hydrogen chloride 1,4-dioxane solution (20 mL) and stirred at room temperature for 1 h. After LCMS monitoring showed that the reaction was complete, the mixture was concentrated under reduced pressure to obtain compound B-1-2-1c (1.50 g, 8.26 mmol, yield: 93.8%). MS-ESI: [M+H] + =146.1.

[0473] Step 3

[0474] Compound B-1-2-1c (1.50 g, 8.26 mmol) and N-acetyl-D-alanine B-1-1-1a (1.30 g, 9.91 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), 4-dimethylaminopyridine (2.00 g, 16.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.90 g, 9.91 mmol) were added in sequence at 0°C, stirred at 0°C for 1 hour and then warmed to room temperature overnight. After LCMS monitoring showed that the reaction was complete, a small amount of water was added to quench, and the N,N-dimethylformamide was removed by concentration under reduced pressure and the compound B-1-2-1 (1.80 g, 6.90 mmol, yield: 83.5%) was prepared by medium pressure. MS-ESI: [M+H] + =259.3. 1H NMR(400MHz, DMSO-d6)δ8.26(t,J=6.0Hz,1H),8.05(d,J=7.7Hz,1H),4.33–4.26(m,1H),4.02(t,J=6.6Hz,2H) ,3.90–3.70(m,2H),1.83(s,3H),1.59–1.52(m,2H),1.29–1.26(m,4H),1.20–1.18(m,3H),0.88–0.85(m,3H).

[0475] Preparation Example 50 Preparation of Compound C-1-1-1

[0476]

[0477] Compound A-4-1-11 (1.00 g, 3.27 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask and fully dissolved, and then lithium hydroxide aqueous solution (2.0 M, 10 mL) was added dropwise to the reaction. After the addition was completed, the reaction was allowed to react at room temperature for 2 h, and the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction solution was added to water (50 mL), and then extracted with ethyl acetate (50 mL × 2). The aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1.0 M), and then extracted with ethyl acetate (100 mL × 5). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product C-1-1-1 (0.86 g, 2.95 mmol, yield: 90.0%). MS-ESI: [M+H] + =293.2. 1 HNMR (400MHz, DMSO-d6) δ8.53(d,J=8.3Hz,1H),8.00(dd,J=49.3,8.5Hz,1H),7.47(d,J=7.2Hz,1H),7.41(d,J=7.2Hz,1H),7.34–7.19(m,3 H),5.59(dd,J=46.2,8.3Hz,1H),3.93(ddd,J=14.9,8.5,5.0Hz,1H),2.02(ddd,J=22.2,12.8,6.8Hz,1H),1.90(s,3H),0.89–0.47(m,6H).

[0478] Preparation Example 51 Preparation of Compound A-4-1-41

[0479]

[0480] first step

[0481] To a solution of compound A-4-1-41a (3.0 g, 12.2 mmol) in dichloromethane (50 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.51 g, 18.3 mmol), 1-hydroxybenzotriazole (2.49 g, 18.3 mmol), N,N-diisopropylethylamine (7.88 g, 61 mmol) were added, and after stirring at room temperature for 10 minutes, L-valine methyl ester hydrochloride (2.45 g, 14.6 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. Concentrated under reduced pressure, purified by medium pressure preparative column chromatography to obtain intermediate A-4-1-41b (1.9 g white solid, 43.4%). MS (ESI) m / z: 381 [M+Na] + .

[0482] Step 2

[0483] The intermediate A-4-1-41b (1.9 g, 5.3 mmol) was dissolved in trifluoroacetic acid / dichloromethane (V / V=1:3, 20 mL) solution, and the reaction solution was stirred at room temperature for 2 hours. After concentration under reduced pressure and freeze drying, the intermediate A-4-1-41c (1.8 g, yellow oil, crude product) was obtained. MS (ESI) m / z: 259 [M+H] + .

[0484] Step 3

[0485] Add diisopropylethylamine (2.33 g, 18 mmol) to a solution of intermediate A-4-1-41c (1.2 g, 4.6 mmol) in dichloromethane (20 mL), cool the reaction system to 0°C, slowly add deuterated acetyl chloride (450 mg, 5.52 mmol), and stir the reaction at 25°C for 3 hours. Concentrate the reaction under reduced pressure and purify by medium pressure preparative column chromatography to obtain compound A-4-1-41 (1.036 g, 73.5%, white solid). MS (ESI) m / z: 304 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.77(d,J=7.0Hz,1H),5.84(brs,1H),4.53(td,J=8.1,4.6Hz,1H),4.44(dd,J=8.6,4.9Hz,1H ),3.73(s,3H),2.20-2.00(m,1H),1.98(dd,J=14.5,4.5Hz,1H),1.42(dd,J=14.5,7.8Hz,1H),1.06-0.82(m,15H).

[0486] Preparation Example 52 Preparation of Compound A-4-1-36

[0487]

[0488] first step

[0489] In a 200mL single-necked bottle, add compound A-4-1-36a (3.5g, 14.26mmol), N,N-dimethylformamide (100mL), cool to 0°C, add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (6.5g, 17.11mmol), add N,N-diisopropylethylamine (5.53g, 42.78mmol), stir at 0°C for 10 minutes, then add L-valine methyl ester hydrochloride (4.78g, 28.52mmol), and react at 0°C for 2 hours. After LCMS monitoring showed that the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate (50 mL×3), the organic phases were combined and washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound A-4-1-36b (4.1 g, 11.43 mmol, yield 80.15%). ESI-LCMS: m / z 359.3 [M+H] + .

[0490] Step 2

[0491] In a 200mL single-mouth bottle, add compound A-4-1-36b (4.1g, 11.43mmol), dichloromethane (50mL), hydrogen chloride (1,4-dioxane solution, 4.0M, 50mL), and react at room temperature for 2 hours. After LCMS and TLC monitoring show that the reaction is complete, the reaction solution is concentrated under reduced pressure, and the crude product is directly used for the next reaction. Compound A-4-1-36c (2.8g, 10.84mmol, yield 94.83%) is obtained. ESI-LCMS: m / z 259.2[M+H] + .

[0492] Step 3

[0493] In a 200mL single-mouth bottle, add compound A-4-1-36c (2.8g, 10.84mmol), dichloromethane (100mL), cool to -10℃, slowly add N,N-diisopropylethylamine (7.0g, 54.2mmol), stir at -10℃ for 10 minutes, slowly add acetyl chloride (1.27g, 16.26mmol), and react at -10℃ for 2 hours. After LCMS and TLC monitoring show that the reaction is complete, add water to quench, extract with dichloromethane (50mL×3), combine the organic phases and wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and chromatograph on a silica gel column to obtain compound A-4-1-36 (1.4g, 4.66mmol, yield 42.98%). ESI-LCMS: m / z 301.1[M+H] + . 1 HNMR (400MHz, CDCl3) δ6.88(d,J=8.5Hz,1H),6.19(d,J=8.3Hz,1H),4.55(td,J=8.1,4.5Hz,1H),4.43(dd,J=8.6,5.0Hz,1H),3.71( s,3H),2.22–2.12(m,1H),2.01(s,3H),1.95(dd,J=14.5,4.5Hz,1H),1.46(dd,J=14.5,7.9Hz,1H),0.96(s,9H),0.95–0.90(m,6H).

[0494] Preparation Example 53 Preparation of Compound A-4-1-39

[0495]

[0496] first step

[0497] In a dry 100mL three-necked flask, A-4-1-39a (2.00g, 7.96mmol) and dichloromethane (40mL) were fully stirred, and then L-valine methyl ester (1.57g, 11.94mmol) was added, and the temperature was lowered to about 0 degrees, and then N, N'-dicyclohexylcarbodiimide (2.46g, 11.94mmol) and 1-hydroxybenzotriazole (1.61g, 11.94mmol) were slowly added. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was reacted overnight. The reaction was monitored by TLC and LCMS. After the reaction, dichloromethane (50 mL) was added to the reaction solution, and then the reaction solution was washed with water (50 mL). The aqueous phase was extracted with dichloromethane (50 mL×3), and the organic phases were combined. The organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the product A-4-1-39b (1.72 g, 4.72 mmol, yield: 59%).

[0498] Step 2

[0499] In a dry 100mL three-necked flask, add A-4-1-39b (1.72g, 4.72mmol) and dichloromethane (20mL), then slowly drip trifluoroacetic acid (8mL). After the addition is completed, stir at room temperature for 2 hours, and monitor the reaction by TLC and LCMS. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain the product A-4-1-39c (1.20g, 4.54mmol, yield: 96%). MS m / z (ESI): 265.3 [M+H] + .

[0500] Step 3

[0501] In a dry 100mL three-necked flask, A-4-1-39c (1.00g, 3.78mmol) and dichloromethane (20mL) were fully stirred, and then deuterated acetic acid (0.36g, 5.67mmol) was added, and the temperature was lowered to about 0 degrees, and then N, N'-dicyclohexylcarbodiimide (1.17g, 5.67mmol) and 1-hydroxybenzotriazole (0.77g, 5.67mmol) were slowly added. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was reacted overnight. The reaction was monitored by TLC and LCMS. After the reaction, dichloromethane (50 mL) was added to the reaction solution, and then the reaction solution was washed with water (50 mL), the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, the organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the product A-4-1-39 (0.73 g, 2.36 mmol, yield: 62%). MS m / z (ESI): 310.3 [M + H] + . 1 H NMR (400MHz, CDCl3) δ7.43(dd,J=7.7,1.5Hz,2H),7.36–7.28(m,3H),6.98(d,J=6.7Hz,1H),6.66(d,J=8.9Hz,1 H),5.67(d,J=6.9Hz,1H),4.50(dd,J=8.9,5.0Hz,1H),3.74(s,3H),2.23–1.91(m,1H),0.69(dd,J=6.6Hz,6H).

[0502] Preparation Example 54 Synthesis of Compound A-1-1-2

[0503]

[0504] first step

[0505] A1-1-1d (440 mg, 2.18 mmol) was added to a 100 mL single-mouth bottle, anhydrous dichloromethane (8 mL) was added to dissolve it, N, N-diisopropylethylamine (842 mg, 6.53 mmol) was added, and the mixture was stirred for ten minutes under ice bath, and a dichloromethane solution (1 mL) of cyclopropaneyl chloride (274 mg, 2.62 mmol) was added, and the mixture was reacted for one hour. The reaction was confirmed to be complete by TLC and LCMS, and a saturated aqueous sodium bicarbonate solution (100 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was purified by reverse phase MPLC and freeze-dried to obtain a white solid A-1-1-2a (320 mg, 1.18 mmol, yield 54.1%). ESI-LCMS: m / z 271.2 [M+H] + .

[0506] Step 2

[0507] A-1-1-2a (292 mg, 1.08 mmol), methanol (5 mL), and lithium hydroxide aqueous solution (2.0 M, 5 mL) were added to a 100 mL single-mouth bottle in sequence, and the reaction was carried out at room temperature for 1.5 hours. The reaction was confirmed to be complete by TLC and LCMS, and the mixture was concentrated to remove methanol. After dilution with water, the pH was adjusted to 5 with dilute hydrochloric acid (1.0 M), and extracted with ethyl acetate (50 mL × 3). The organic phase was collected, dried, and concentrated to obtain the intermediate A-1-1-2b (160 mg, 0.62 mmol, yield 57.4%). ESI-LCMS: m / z 257.2 [M+H] + .

[0508] Step 3

[0509] A-1-1-2b (160 mg, 0.62 mmol), N,N-dimethylformamide (5 mL), potassium carbonate (261 mg, 1.89 mmol), deuterated iodomethane (183 mg, 1.26 mmol) were added to a 100 mL single-mouth bottle in sequence, and the mixture was reacted at room temperature for one hour. After the reaction was confirmed to be complete by TLC and LCMS, water (100 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the residue was purified by normal phase chromatography to obtain a white solid product A-1-1-2 (55 mg, 0.2 mmol, yield 32%). ESI-LCMS: m / z 274.2 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),8.19(d,J=8.6Hz,1H),4.57–4.34(m,1H),4.20(dd,J=8.6,6.3Hz, 1H),2.12–1.92(m,1H),1.75–1.61(m,1H),1.20(d,J=7.0Hz,3H),0.85(dd,J=6.8,2.1Hz,6H),0.69–0.56(m,4H).

[0510] Preparation Example 55 Synthesis of Compound A-1-1-3

[0511]

[0512] A-1-1-3a (122 mg, 1.0 mmol), A-1-1-1d (202 mg, 1.0 mmol), anhydrous dichloromethane (2 mL), DIPEA (388 mg, 3.0 mmol) were added to a 100 mL single-mouth bottle in sequence, stirred at 0°C for 5 minutes, PYBOP (677 mg, 1.3 mmol) was added, and the reaction was allowed to proceed for 30 minutes. TLC and LCMS showed that the reaction was complete, and water (100 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the residue was purified by normal phase chromatography to obtain a white solid product A-1-1-3 (14 mg, 0.05 mmol, 5%). ESI-LCMS: m / z 307.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=7.8Hz,1H),8.32(d,J=8.6Hz,1H),4.54–4.44(m,1H),4.20(dd,J=8.6,6.4Hz,1H),3. 64(s,3H),2.76–2.63(m,1H),2.09–1.95(m,1H),1.95–1.75(m,2H),1.22(d,J=7.0Hz,3H),0.85(dd,J=6.8,3.4Hz,6H).

[0513] Preparation Example 56 Synthesis of Compound A-1-1-6

[0514]

[0515] first step

[0516] Slowly add thionyl chloride (178 mg, 1.5 mmol) to a solution of A-1-1-6a (123 mg, 1 mmol) in anhydrous dichloromethane (2 mL), and stir the reaction solution at room temperature for one hour. The reaction solution was distilled under reduced pressure, dissolved in anhydrous dichloromethane (3 mL) again, and A-1-1-1d (202 mg, 1 mmol) and N,N-diisopropylethylamine (388 mg, 3 mmol) were added to the solution, and the reaction solution was stirred at room temperature for two hours. The reaction solution was concentrated, and the crude product was purified by rapid preparative chromatography to obtain compound A-1-1-6 (100 mg, 0.33 mmol, yield 32.5%). ESI-LCMS: m / z 308.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.71–8.63(m,2H),8.52(d,J=8.4Hz,1H),8.08–7.98(m,2H),7.63(ddd,J=6.9,4.8,1.8Hz,1H),4.75– 4.65(m,1H),4.22(dd,J=8.4,6.4Hz,1H),3.64(s,3H),2.12–2.01(m,1H),1.36(d,J=6.9Hz,3H),0.88(dd,J=6.8,4.1Hz,6H).

[0517] Preparation Example 57 Synthesis of Compound A-1-1-7

[0518]

[0519] A-1-1-7a (161 mg, 1.0 mmol), A-1-1-1d (202 mg, 1.0 mmol), anhydrous dichloromethane (2 mL), N, N-diisopropylethylamine (388 mg, 3.0 mmol) were added to a 100 mL single-mouth bottle in sequence, stirred at 0 ° C for 5 minutes, PYBOP (677 mg, 1.3 mmol) was added, and the reaction was continued for 30 minutes. After TLC monitoring showed that the reaction was complete, water (100 mL) was added to quench. Extracted with ethyl acetate (100 mL × 3), the organic phases were combined and dried with anhydrous sodium sulfate, concentrated, and purified by rapid preparative chromatography to obtain compound A-1-1-7 (181 mg, 0.52 mmol, yield 52.0%) ESI-LCMS: m / z 344.2 [MH] - . 1H NMR (400MHz, DMSO-d6) δ11.33(s,1H),8.28(d,J=7.7Hz,1H),8.23–8.15(m,2H),7.65(dd,J=8.6,1.7Hz,1H),7.47–7.38(m,2H),6.57–6. 50(m,1H),4.68–4.55(m,1H),4.23(dd,J=8.7,6.3Hz,1H),3.64(s,3H),2.12–1.94(m,1H),1.36(d,J=7.2Hz,3H),0.85(d,J=6.8Hz,6H).

[0520] Preparation Example 58 Synthesis of Compound A-1-1-8

[0521]

[0522] A-1-1-8a (166 mg, 1.5 mmol), A-1-1-1d (302 mg, 1.5 mmol), anhydrous dichloromethane (2 mL), N, N-diisopropylethylamine (582 mg, 4.5 mmol) were added to a 100 mL single-mouth bottle in sequence, stirred at 0 ° C for 5 minutes, PYBOP (1041 mg, 2.0 mmol) was added, and the reaction was continued for 30 minutes. After LCMS monitoring showed that the reaction was complete, water (100 mL) was added to quench. Extracted with dichloromethane (100 mL × 3), the organic phases were combined and dried with anhydrous sodium sulfate, concentrated, and purified by rapid preparative chromatography to obtain compound A-1-1-8 (147 mg, 0.50 mmol, yield 33.3%) ESI-LCMS: m / z 296.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),8.21(d,J=8.7Hz,1H),7.98(d,J=8.0Hz,1H),6.91–6.79(m,2H),6.08(dt,J=3.5,2.4Hz,1H), 4.66–4.55(m,1H),4.21(dd,J=8.6,6.4Hz,1H),3.63(s,3H),2.09–1.96(m,1H),1.31(d,J=7.1Hz,3H),0.86(dd,J=6.8,1.9Hz,6H).

[0523] Preparation Example 59 Synthesis of Compound A-1-1-9

[0524]

[0525] A-1-1-9a (165 mg, 1.0 mmol), A-1-1-1d (260 mg, 1.3 mmol), anhydrous dichloromethane (2 mL), N, N-diisopropylethylamine (504 mg, 3.9 mmol) were added to a 100 mL single-mouth bottle in sequence, stirred at 0 ° C for 5 minutes, PYBOP (885 mg, 1.7 mmol) was added, and the reaction was continued for 30 minutes. After LCMS monitoring showed that the reaction was complete, water (100 mL) was added to quench. Extracted with dichloromethane (100 mL × 3), the organic phases were combined and dried with anhydrous sodium sulfate, concentrated, and purified by rapid preparative chromatography to obtain compound A-1-1-9 (14 mg, 0.05 mmol, yield 5%) ESI-LCMS: m / z 313.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=7.8Hz,1H),8.33(d,J=8.6Hz,1H),4.57–4.45(m,1H),4.21(dd,J=8.6,6.4Hz,1H),3.64(s ,3H),3.35(d,J=11.3Hz,1H),3.30(d,J=11.4Hz,1H),2.08–1.98(m,1H),1.21(d,J=7.0Hz,3H),0.85(dd,J=6.8,3.1Hz,6H).

[0526] Preparation Example 60 Synthesis of Compound A-1-1-11

[0527]

[0528] first step

[0529] The intermediate raw material A-1-1-1d (0.51 g, 2.52 mmol) and 2-(4-(tert-butylamido)piperazin-1-yl)acetic acid (0.62 g, 2.52 mmol) were dissolved in DMF (20 mL), cooled to -20 ° C, and HOBt (0.34 g, 2.52 mmol), triethylamine (0.64 g, 6.3 mmol) and HATU (0.96 mg, 2.52 mmol) were added to the reaction solution. After the addition, the mixture was kept warm for 0.5 hours, warmed to room temperature and stirred overnight. After the reaction was completed as monitored by TLC, 20 mL of water was added, and after separation, the aqueous phase was extracted three times with ethyl acetate (100 mL×3), the organic phases were combined, the organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain A-1-1-11a (0.38 g, 0.89 mmol, yield: 35%). MS-ESI: M / Z = 429.3 [M + H] + .

[0530] Step 2

[0531] A-1-1-11a (0.38 g, 0.89 mmol) was added to tetrahydrofuran (20 mL), and a solution of hydrogen chloride in dioxane (20 mmol, 4.0 M, 5 mL) was slowly added dropwise at room temperature. After the addition was completed, stirring was continued at room temperature. After the reaction was completed by TLC monitoring, the solid in the reaction solution was filtered and washed with ethyl acetate (50 mL). The solid was dried in vacuo to obtain the product A-1-1-11 (0.17 g, 0.47 mmol, yield: 52%). MS-ESI: M / Z=329.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 2H), 4.54–4.45 (m, 1H), 4.20 (dd, J = 8.4, 6.6Hz, 1H), 4.03 (s, 2H), 3. 64(s,3H),3.58–3.22(m,9H),2.09–2.01(m,1H),1.26(d,J=7.0Hz,3H),0.86(dd,J=6.6,5.0Hz,6H).

[0532] Preparation Example 61 Synthesis of Compound A-1-2-3

[0533]

[0534] first step

[0535] A-1-2-3a (853 mg, 5.40 mmol), A-1-1-1d (1.2 g, 5.93 mmol), Xphos Pd G3 (457 mg, 0.54 mmol), sodium tert-butoxide (1.04 g, 10.8 mmol) were added to a 100 mL single-mouth bottle, and anhydrous 1,4-dioxane (20 mL) was added. After nitrogen replacement three times, the mixture was reacted at 90 ° C for 3 hours. After the completion of the reaction was confirmed by TLC and LCMS, the reaction solution was filtered and concentrated. The residue was purified by normal phase chromatography to obtain a yellow solid intermediate A1-2-3b (520 mg, 1.86 mmol, yield 34.4%). ESI-LCMS: m / z 280.2 [M+H] + .

[0536] Step 2

[0537] A1-2-3b (520 mg, 1.86 mmol), methanol (4 mL), and lithium hydroxide solution (2.0 M, 4 mL) were added to a 100 mL single-mouth bottle in sequence, and reacted at room temperature for 2 hours. After the reaction was completed by TLC and LCMS, the pH was adjusted to pH = 2 with dilute hydrochloric acid (1.0 M), concentrated under reduced pressure, dissolved with DCM / MeOH = 10 / 1 solution, filtered, collected the filtrate, and concentrated to obtain intermediate A-1-2-3c (480 mg, 1.81 mmol). ESI-LCMS: m / z 264.2 [MH] - .

[0538] Step 3

[0539] In a 100mL single-mouth bottle, add A-1-2-3c (448mg, 1.69mmol), potassium carbonate (701mg, 5.07mmol), deuterated iodomethane (490mg, 3.38mmol), anhydrous N,N-dimethylformamide (5mL) in sequence, react at room temperature for 1 hour, LCMS monitoring shows that the reaction is complete and then add water (100mL) to quench. Extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify by rapid preparative chromatography to obtain compound A-1-2-3 (104mg, 0.37mmol, yield 21.9%). ESI-LCMS: m / z 283.2[M+H] + . 1 HNMR(400MHz, DMSO-d6)δ8.06(dd,J=29.4,8.6Hz,1H),7.96–7.88(m,1H),7.43–7.30(m,1H),6.65(dd,J=7.5,3.5Hz,1H),6.59–6.43(m,2H),4 .53–4.41(m,1H),4.22–4.13(m,1H),2.08–1.94(m,1H),1.28(dd,J=7.0,5.9Hz,3H),0.83(dd,J=8.9,6.8Hz,3H),0.77(dd,J=8.3,6.8Hz,3H).

[0540] Preparation Example 62 Synthesis of Compound A-1-2-7

[0541]

[0542] Compound A-1-1-1d (0.10 g, 0.49 mmol), 2-bromo-3-trifluoromethylpyridine (0.17 g, 0.73 mmol), BrettPhos Pd G3 (44 mg, 0.05 mmol) and sodium tert-butoxide (94 mg, 0.98 mmol) were dissolved in dry dioxane (10 mL), replaced with nitrogen three times, and then heated to 100 ° C for 5 hours. After the reaction was complete as monitored by TLC and LCMS, the reaction solution was diluted with dichloromethane (100 mL), and then washed once with water. After separation, the aqueous phase was extracted with dichloromethane (100 mL×3), and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain compound A1-2-7 (87 mg, 0.25 mmol, white oil), with a yield of 50%. MS m / z (ESI): 348.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.44(d,J=8.6Hz,1H),8.29(d,J=4.8Hz,1H),7.84(d,J=7.8Hz,1H),6.76(dd,J=7.4,5.2Hz,1H),6.07(d,J=6.4Hz,1H),4.8 1(dd,J=13.6,6.8Hz,1H),4.23(dd,J=8.6,6.3Hz,1H),3.63(d,J=2.4Hz,3 H),2.11–2.02(m,1H),1.37(d,J=6.8Hz,3H),0.84(dd,J=6.8,4.2Hz,6H).

[0543] Preparation Example 63 Synthesis of Compound A-1-2-13

[0544]

[0545] The intermediate A-1-1-1d (0.21 g, 1.04 mmol) and cyclohexanone (0.11 g, 1.14 mmol) were dissolved in dichloromethane (5 mL), potassium acetate (0.13 g, 1.35 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.40 g, 1.87 mmol) was added to the reaction solution in batches, and the mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, dichloromethane (50 mL) was added to the reaction solution for dilution, and then the reaction solution was washed with water. After separation, the aqueous phase was extracted with dichloromethane (100 mL×3), and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the product A-1-2-13 (0.11 g, 0.39 mmol, yield: 38%). ESI-LCMS: 285.3 [M+H] + .1 H NMR (400MHz, CDCl3) δ7.99 (d, J=8.8Hz, 1H), 4.50 (dd, J=9.3, 4.8Hz, 1H), 3.7 3(s,3H),3.37(d,J=6.7Hz,1H),2.47–2.32(m,1H),2.27–2.19(m,1H),1.95(d ,J=12.2Hz,1H),1.84(d,J=12.7Hz,1H),1.77–1.69(m,2H),1.61(d,J=11.5Hz ,1H),1.33(d,J=7.0Hz,3H),1.30–1.00(m,6H),0.94(dd,J=12.0,6.9Hz,6H).

[0546] Preparation Example 64 Preparation of Comparative Compound ZZL-7

[0547]

[0548] first step

[0549] Add (tert-butyloxycarbonyl)-L-alanine (4.50 g, 23.78 mmol) to a dry single-necked bottle, dissolve in dichloromethane (50 mL), place in an ice bath and stir for 10 min, then add L-valine methyl ester (3.12 g, 23.78 mmol), N,N-diisopropylethylamine (6.15 g, 47.56 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.01 g, 26.16 mmol) to the bottle in sequence, and stir at room temperature for 2 h. After TLC showed that the reaction was completed, water (50 mL) was added to quench, and 2M hydrochloric acid was used to adjust to acidity, and dichloromethane (50 mL × 2) was used to extract, and the organic phases were combined, and the organic phases were adjusted to alkalinity with saturated sodium bicarbonate, and dichloromethane (50 mL × 2) was used to extract, and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain the intermediate (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.50 g, 21.50 mmol, yield: 90.4%). MS-ESI: [M+H] + =303.1

[0550] Step 2

[0551] Add (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.50 g, 21.50 mmol) to a dry single-mouth bottle and dissolve it in dichloromethane (30 mL). Then add hydrochloric acid-1.4-dioxane (10 mL, 4 M) to the bottle and stir at room temperature for 2 h. After TLC shows that the reaction is complete, concentrate the organic phase and purify it by silica gel column chromatography (dichloromethane). Alkane: Methanol =10:1) to obtain the intermediate L-alanyl-L-valine methyl ester (3.70 g, 18.32 mmol, yield: 87.2%). MS-ESI: [M+H] + =203.3. 1 HNMR (400MHz, CDCl3) δ8.13(s,3H),4.56(s,1H),4.31(s,1H),3.65(s,3H),2.15(d,J=5.3Hz,1H),1.57(s,3H),0.92(t,J=6.8Hz,6H).

[0552] Step 3

[0553] Compound L-alanyl-L-valine methyl ester (3.70 g, 18.32 mmol) and N,N-diisopropylethylamine (4.72 g, 36.64 mmol) were dissolved in tetrahydrofuran (50 mL), fully replaced with nitrogen and stirred at 0 ° C. After 10 min, acetic anhydride (2.80 g, 27.48 mmol) was slowly added dropwise, stirred at this temperature for 10 min, and stirred at room temperature for 2 h. After TLC showed that the reaction was completed, water (50 mL) was added to quench, and 2M hydrochloric acid was used to adjust to acidity, extracted with dichloromethane (50 mL × 4), and the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1). Compound acetyl-L-alanyl-L-valine methyl ester (2.60 g, 10.67 mmol, yield: 58.2%) was obtained, namely ZZL-7. MS-ESI:[M+H] + =245.3. 1 HNMR (400MHz, CDCl3) δ6.68(d,J=8.5Hz,1H),6.21(d,J=7.1Hz,1H),4.57–4.47(m,1H),4.44(dd,J=8.7,4. 9Hz,1H),3.68(s,3H),2.18–2.04(m,1H),1.94(s,3H),1.31(d,J=7.0Hz,3H),0.85(dd,J=10.1,6.9Hz,6H).

[0554] Preparation Example 65 Preparation of Compound A-4-1-37

[0555]

[0556] first step

[0557] In a 200mL single-necked bottle, add A-4-1-37a (3.0g, 12.22mmol), N,N-dimethylformamide (100mL), cool to 0℃, add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (5.57g, 14.66mmol), add N,N-diisopropylethylamine (4.73g, 36.66mmol), stir at 0℃ for 10 minutes, then add L-valine methyl ester hydrochloride (4.09g, 24.44mmol), and react at 0℃ for 2 hours. After LCMS monitoring showed that the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate (50 mL×4), the organic phases were combined and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound A-4-1-37b (3.9 g, 10.88 mmol, yield 89.02%).

[0558] ESI-LCMS: m / z 359.3 [M+H] + .

[0559] Step 2

[0560] In a 200mL single-mouth bottle, add compound A-4-1-37b (3.9g, 10.88mmol), dichloromethane (50mL), 1,4-dioxane solution of hydrogen chloride (4.0M, 50mL), and react at room temperature for 2 hours. After LCMS and TLC monitoring show that the reaction is complete, the reaction solution is concentrated under reduced pressure, and the crude product is directly used for the next reaction. Compound A-4-1-37c (2.7g, 10.45mmol, yield 96.04%) is obtained.

[0561] ESI-LCMS: m / z 259.2 [M+H] + .

[0562] Step 3

[0563] In a 200mL single-mouth bottle, add compound A-4-1-37c (2.7g, 10.45mmol), dichloromethane (100mL), cool to -10℃, slowly add N,N-diisopropylethylamine (6.75g, 52.25mmol), stir at -10℃ for 10 minutes, slowly add acetyl chloride (1.23g, 15.67mmol), and react at -10℃ for 2 hours. After LCMS and TLC monitoring show that the reaction is complete, add water to quench, extract with dichloromethane (50mL×3), combine the organic phases and wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and chromatograph on a silica gel column to obtain compound A-4-1-37 (1.5g, 4.99mmol, yield 47.75%).

[0564] ESI-LCMS: m / z 301.2 [M+H] + .

[0565] 1 H NMR (400MHz, CDCl3) δ6.80(d,J=8.6Hz,1H),6.40(d,J=8.3Hz,1H),4.53(td,J=7.9,5.0Hz,1H),4.46(dd,J=8.7,5.1Hz,1H),3.73(s,3H ), 2.21–2.12(m,1H),1.98(s,3H),1.89(dd,J=14.4,5.0Hz,1H),1.49(dd,J=14.4,7.6Hz,1H),0.95(s,9H),0.91(dd,J=6.8,4.6Hz,6H).

[0566] Experimental Example 1 Plasma Stability Determination

[0567] Mouse plasma (purchased from IPHASE, batch number 23B007) was thawed in a 37°C water bath, centrifuged to remove the upper clot, and the pH was recorded as 7-8. Take a certain volume of acetonitrile stock solution of the test compound (concentration of 10mM), dilute it to 1mM with acetonitrile, and use it as the test solution. Take a certain volume of the compound test solution, add the corresponding volume of plasma and mix evenly, so that the concentration of the test compound in the incubation system is 5μM, and the content of organic solvent acetonitrile is 0.5%. Take 50μL of mixed plasma in a 96-well plate (N=2), incubate in a 37°C water bath for a certain period of time, add 300μL of methanol solution containing the internal standard to terminate the reaction, vortex centrifuge and take the supernatant for LC-MS / MS analysis. Propantheline and ZZL-7 were used as positive controls and were treated and tested under the same conditions as the test compounds. The k value was obtained by making a curve based on the remaining percentage of the compound and the incubation time, and the half-life of each compound was calculated. The formula is as follows:

[0568]

[0569] Table 1 shows the plasma stability data of some compounds. The results show that the example compounds of the present invention exhibit excellent plasma stability, which is significantly better than ZZL-7.

[0570] Table 1 Plasma stability data of some compounds

[0571] Compound <![CDATA[T 1 / 2 (min)]]> Propantheline 25.01 ZZL-7 25.29 A-1-1-1 >372.68 A-1-2-2 >372.68 A-4-1-11 134.61 A-4-1-13 127.24 A-4-1-26 >372.68 A-4-1-37 >372.68 A-1-1-7 >372.68 A-1-1-8 >372.68 A-1-1-9 >372.68 A-1-1-11 >372.68 A-1-2-13 123.8

[0572] Note: If after 120 minutes, the remaining percentage of the compound is still greater than 80%, then T 1 / 2 Recorded as >372.68min.

[0573] Experimental Example 2 Pharmacokinetics Test

[0574] The pharmacokinetic test of the compound was carried out in 6-8 week old CD1 mice (purchased from: Sibeifu (Beijing) Biotechnology Co., Ltd.). The test compound was dissolved in a 10% hydroxypropyl-β-cyclodextrin aqueous solution containing 10% DMSO and administered by intravenous injection (10 mg / kg) or oral gavage (10 mg / kg). The concentration of the compound in the plasma sample will be analyzed by LC-MS / MS method. Pharmacokinetic calculations were performed using WinNonlin (PhoenixTM, version 8.3) or other similar software. The following pharmacokinetic parameters were calculated based on the plasma concentration and time data: Oral administration: AUC last ,, bioavailability (F). The above parameter data were statistically calculated.

[0575] Table 2 shows the area under the concentration-time curve (AUC) and bioavailability (F) data of some compounds for oral administration. The results show that the example compounds of the present invention have good pharmacokinetic properties and are significantly better than ZZL-7.

[0576] Table 2 Pharmacokinetic data of some compounds

[0577] Compound <![CDATA[AUC last (mg / mL)]]> F(％) ZZL-7 138.5 7.5 A-1-1-1 2950.3 67.4 A-1-1-13 4777.8 177.0 A-1-1-14 946.5 37.1 A-1-2-9 1211.4 79.5 A-1-2-10 1023.8 45.6 A-1-3-2 936.8 95.9 A-1-4-9 1816.1 98.6 A-4-1-11 3636.9 96.2 A-4-1-12 3494.7 77.7 A-4-1-13 4652.6 90.9 A-4-1-26 4181.4 86.9 A-4-1-36 610.5 32.5 A-4-1-39 445.2 55.2 A-4-1-41 696.1 26.7 A-4-1-37 381 22.2

[0578] Note: The dosage of ZZL-7 is 100 mg / kg, PO.

[0579] Experimental Example 3 In vivo drug efficacy detection (1)

[0580] 6-8 week old C57 / B6 mice (purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd.) were used to establish the 28-day chronic unpredictable mild stress (CUMS) model. The experimental procedure was described in the literature. [1,2]The animals were adapted for one week, and seven experiments were randomly performed within one week, including fasting and water deprivation, electrical stimulation of the soles of the feet, moist bedding, cage tilt, behavioral restraint, shaking basket, and olfactory stimulation, to achieve unpredictability. The stimulation lasted for 4 weeks. Open Field Test (OFT) [3] After the evaluation model is successful, the efficacy evaluation is carried out. The experiment is divided into a blank control group (Control), a model group (Model), a solvent control group (Vehicle), a fluoxetine control group (Fluoxetine), a ZZL-7 experimental group and a compound group. The test compound is orally administered at a dose of 25 mg / kg, and a tail suspension test (TST) is performed 2 hours later. [4,5] The depression of mice was evaluated. The prolonged immobility time of mice in TST indicated that the mice were in despair. After the data were summarized and analyzed, SPSS statistical software was used for analysis. Graph Pad software was used to draw images based on the SPSS analysis results.

[0581] The results of the tail suspension test are as follows Figure 1 As shown, the test results show that compound A-4-1-41 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in the tail suspension test, proving that the example compounds of the present invention have a rapid antidepressant effect.

[0582] Experimental Example 4 In vivo drug efficacy detection (2)

[0583] 6-8 week old C57 / B6 mice (purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd.) were used to establish the 28-day chronic unpredictable mild stress (CUMS) model. The experimental procedure was described in the literature. [1,2] The animals were adapted for one week, and seven experiments were randomly performed within one week, including fasting and water deprivation, electrical stimulation of the soles of the feet, moist bedding, cage tilt, behavioral restraint, shaking basket, and olfactory stimulation, to achieve unpredictability. The stimulation lasted for 4 weeks. Open Field Test (OFT) [3] After the evaluation model is successful, the efficacy evaluation is carried out. The experiment is divided into a blank control group (Control), a model group (Model), a solvent control group (Vehicle), a fluoxetine control group (Fluoxetine) and a compound group. The test compound is administered at a dose of 100 mg / kg by a single intravenous injection (iv) or intraperitoneal injection (ip), and a tail suspension test (TST) and a forced swimming test (FST) are performed 2 hours later. [4,5]The depression of mice was evaluated. The prolonged immobility time of mice in TST and FST indicated that the mice were in despair. After the data were summarized and analyzed, SPSS statistical software was used for analysis, and Graph Pad software was used to draw images based on the SPSS analysis results.

[0584] The results of the forced swimming test were as follows Figure 2 The results of the tail suspension experiment are shown in Figure 3 As shown, the test results show that compounds A-1-1-1, A-1-2-10, A-1-5-3, A-4-1-11, A-4-1-12 and A-4-1-27 can quickly reverse the prolonged immobility time in the forced swimming and tail suspension tests in the chronic unpredictable stress model mice, proving that the example compounds of the present invention have a rapid antidepressant effect.

[0585] References:

[0586] [1] Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 1987; 93:358–64.

[0587] [2]Chen Z, Gu J, Lin S, et al. Saffron essential oil ameliorates CUMS-induced depression-like behavior in mice via the MAPK-CREB1-BDNF signaling pathway[J]. Journal of Ethnopharmacology, 2023, 300:115719.

[0588] [3]Pentkowski, Nathan S., et al. "Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology." Neuroscience&BiobehavioralReviews 127(2021):647-658.

[0589] [4]Can,Adem,et al."The mouse forced swim test."JoVE(Journal ofVisualized Experiments)59(2012):e3638.

[0590] [5]Can,Adem,et al."The tail suspension test."JoVE(Journal ofVisualized Experiments)59(2012):e3769.

Claims

1. A compound represented by general formula (I') or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof: in, R1 and R2 are independently selected from hydrogen, R8-(CO)-, R8-(SO)-, R8-(SO2)-, R8-O(CO)-, R8R9-N(CO)-, or a C1-C2-substituted with 0 to 8 R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; or R1, R2 and the nitrogen atom adjacent to them together form a C3-C4 substituted by 0 to 8 R8 15 Heterocycloalkyl or C5-C 15 heteroaryl; R3 and R4 are independently selected from hydrogen, or C1-C2-substituted with 0 to 8 R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; Or R3, R4 and the carbon atoms adjacent to them together form a C3-C substituted by 0 to 8 R8 10 Cycloalkyl or C3-C 10 Heterocycloalkyl; X is optionally selected from -CO-, -SO-, -SO2-, -CHR8-, or R5 and R6 are independently selected from hydrogen or C1-C2-substituted by 0 to 8 R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; Y is selected from -CO-, -SO-, -SO2- or -CH2-; R7 is optionally selected from hydrogen, -OR9, -NR9R 10 , chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of 0 to 8 R 12 replace; R8 is optionally selected from hydrogen, halogen, oxydeoxy, -CN, -NO2, -OR9, -NR9R 10 , -SR9, -COR9, -SOR9, -SO2R9, -NR9COR 10 、-CONR9R 10 , -OCOR9, -COOR9, -OCOOR9, -OCONR9R 10 、-NR9CONR 10 R 11 、-NR9COOR 10 、-NR9SO2R 10 、-SO2NR9R 10 , -OSO2R9, -SO3R9, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of 0 to 8 R 12 replace; R9, R 10 , R 11 are independently selected from hydrogen, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0 to 8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl; R 12 is selected from hydrogen, halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0 to 8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl.

2. A compound represented by formula (I) or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof: R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、R8-(CH2) m -(SO)-(CH2) n -、R8-(CH2) m -O(CO)-(CH2) n -、R8R9N(CO)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12 m, n are each independently an integer of 0 to 8; or R1, R2 are each independently selected from C1-C 15 Chain alkyl, wherein The heteroatom is selected from one or more of O, S, and N. 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace; or R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 8 R 12 replace; R3, R4 are independently selected from hydrogen, R8-(CH2) j -、R8-(CO)O-(CH2) k -、C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12 j and k are each independently 0, 1, 2 or 3; or R3, R4 are each independently selected from C1-C 15 A chain alkyl group, wherein the heteroatom is selected from one or more of O, S, and N, and the C1-C 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace; or R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with 0 to 8 R 12 replace; X is selected from -CO-, -SO2-, -SO-, -CHR8- or R5 and R6 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl or 5-15 membered heteroaryl group is optionally substituted with 0 to 8 R 12 or R5 and R6 are independently selected from C1-C 15 A chain alkyl group, wherein the heteroatom is selected from one or more of O, S, and N, and the C1-C 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace; Y is selected from -CO-, -SO2, -SO- or -CH2-; R7 is selected from hydrogen, -O(CH2) p R9, -NR9R 10 、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein the C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl or 5-15 membered heteroaryl group is optionally substituted with 0 to 8 R 12 substituted; p is 0, 1, 2 or 3; or R7 is selected from C1-C 15 A chain alkyl group, wherein the heteroatom is selected from one or more of O, S, and N, and the C1-C 15 The chain alkyl group is optionally substituted with 0 to 8 R 12 replace; R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12 replace; R9, R 10 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-8 R 12 replace; R 12 is selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl, optionally substituted with 0-8 halogen, oxydene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide; Wherein, the compound represented by formula (I) does not include the following compounds:

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 substituted; m, n are each independently 0, 1, 2 or 3, wherein R1 and R2 are not hydrogen at the same time, and when one of R1 and R2 is hydrogen, the other of R1 and R2 is not acetyl or ethyl; or R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R 12 replace; R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are each independently 0, 1, 2 or 3; R3 and R4 are not hydrogen at the same time; or R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace; X is selected from -CO- or -SO2-; R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 substituted, wherein R5 and R6 are not hydrogen at the same time; Y is selected from -CO- or -SO 2- ; R7 is selected from hydrogen, -O(CH2) p R9 or C1-C 15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution; p is 0, 1, 2 or 3; R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R9, R 10 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R 12 is selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl, optionally substituted by 0-5 halogen, oxydene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide; Wherein, the compound represented by formula (I) does not include the following compounds:

4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 substituted; m, n are each independently 0, 1, 2 or 3, wherein R1 and R2 are not hydrogen at the same time, and when one of R1 and R2 is hydrogen, the other of R1 and R2 is not acetyl or ethyl; or R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R 12 replace; R3, R4 are independently selected from hydrogen or R8-(CH2) j -, wherein j is 0, 1, 2 or 3; R3 and R4 are not hydrogen at the same time; X is selected from -CO- or -SO2-; R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 substituted, wherein R5 and R6 are not hydrogen at the same time; Y is selected from -CO- or -SO2-; R7 is selected from -O(CH2) p R9, wherein p is 0, 1, 2 or 3; R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R9, R 10 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R 12 is selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (I) is selected from the compounds represented by formula (II) in, R1, R2, R3, R4 are as defined in claim 4.

6. A compound of formula (I) according to any one of claims 3 to 5, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1 is selected from R8-(CO)-, R8-(SO2)-, C1-C3 alkyl, C3-C6 cycloalkyl, 5-6-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl; R2 is hydrogen or methyl, wherein C1-C3 alkyl, C3-C6 cycloalkyl, 5-6-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl is optionally substituted by 0 to 3 R 12 Substitution; when R2 is hydrogen, R1 is not acetyl or ethyl; or R1, R2 and their adjacent nitrogen atoms together form a 3-8-membered nitrogen-containing heterocyclic ring or a 5-6-membered nitrogen-containing heteroaromatic ring, wherein the 3-8-membered nitrogen-containing heterocyclic ring or the 5-6-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 3 C1-C3 alkyl groups, oxydiphenyl groups, or phenyl groups; and the 3-8-membered nitrogen-containing heterocyclic ring or the 5-6-membered nitrogen-containing heteroaromatic ring contains 1 or 2 nitrogen atoms; R3 is hydrogen; R4 is selected from hydrogen, phenyl, C1-C5 alkyl, wherein the C1-C5 alkyl is optionally substituted by 0 to 3 halogens or hydroxyl groups; R8 is selected from C1-C3 alkylamino, phenyl, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 cycloalkyl or 5-6 membered heteroaryl, wherein phenyl, C1-C3 alkyl, C3-C6 cycloalkyl or 5-6 membered heteroaryl is optionally substituted with 0 to 3 halogens, 5-6 membered heteroaryl or 3-6 membered heterocycloalkyl; R 12 Selected from hydrogen, halogen, oxyethylene, C1-C3 alkyl, C3-C5 cycloalkyl, wherein C1-C3 alkyl, C3-C5 cycloalkyl are optionally substituted by 0 to 3 halogens.

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (I) is selected from the compounds represented by formula (III) in, R1, R2 are as defined in claim 6.

8. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 Substitution; m, n are each independently 0, 1, 2 or 3; or R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R 12 replace; R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are independently 0, 1, 2 or 3, wherein when one of R3 and R4 is hydrogen, the other of R3 and R4 is not methyl; or R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace; X is selected from -CO- or -SO2-; R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace; Y is selected from -CO- or -SO2-; R7 is selected from hydrogen, -O(CH2) p R9 or C1-C 15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution; p is 0, 1, 2 or 3; R8 is selected from -OR9, -NR9R 10 , -CO-NH2, -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R9, R 10 Each independently selected from C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R 12 is selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl, optionally substituted by 0-5 halogen, oxydene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide; Wherein, the compound represented by formula (I) does not include the following compounds:

9. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1 and R2 are independently selected from hydrogen, C1-C 15 Alkyl or R8-(CH2) m -(CO)-(CH2) n -; m, n are each independently 0, 1, 2 or 3; R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are independently 0, 1, 2 or 3, wherein when one of R3 and R4 is hydrogen, the other of R3 and R4 is not methyl; or R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace; X is selected from -CO- or -SO2-; R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace; Y is selected from -CO- or -SO2-; R7 is selected from hydrogen, -O(CH2) p R9, wherein p is 0, 1, 2 or 3; R8 is selected from -OR9, -NR9R 10 , -CO-NH2, -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R9, R 10 Each independently selected from C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R 12 is selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

10. The compound of formula (I) according to claim 8 or 9, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1 is hydrogen; R2 is selected from hydrogen, C1-C3 alkyl or R8-(CO)-; R3 is selected from hydrogen, C1-C3 alkyl; R4 is selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are independently 0, 1, 2 or 3, wherein when R3 is hydrogen, R4 is not methyl; or R3, R4 and their adjacent carbon atoms together form a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is optionally substituted by 0 to 5 R 12 replace; X is -CO-; R5 is hydrogen, R6 is selected from hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 0 to 5 R 12 replace; Y is -CO-; R7 is optionally selected from hydrogen, C1-C6 alkoxy; R8 is selected from methylthio, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C8 aryl or 5-15 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C8 aryl or 5-15 membered heteroaryl is optionally substituted by 0 to 3 R 12 replace; R 12 Selected from halogen, oxyethylene, hydroxyl, amino, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, C6-C8 aryl, wherein C1-C3 alkyl, C1-C3 alkoxy, C6-C8 aryl are optionally substituted by 0 to 3 halogens.

11. The compound of formula (I) according to claim 10 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (I) is selected from the compound represented by formula (IV) in, R3, R4 are as defined in claim 10.

12. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -、R8-(CH2) m -(SO2)-(CH2) n -、C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 substituted; m, n are each independently 0, 1, 2 or 3; R1 and R2 are not hydrogen at the same time; or R1, R2 and their adjacent nitrogen atoms together form a 3-10-membered nitrogen-containing heterocyclic ring or a 5-12-membered nitrogen-containing heteroaromatic ring, wherein the 3-10-membered nitrogen-containing heterocyclic ring or the 5-12-membered nitrogen-containing heteroaromatic ring is optionally substituted by 0 to 5 R 12 replace; R3, R4 are independently selected from hydrogen, R8-(CH2) j - or R8-(CO)O-(CH2) k -, wherein j and k are each independently 0, 1, 2 or 3; or R3, R4 and their adjacent carbon atoms together form C3-C 10 Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace; X is selected from -CO- or -SO2-; R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace; Y is selected from -CO- or -SO2-; R7 is selected from hydrogen, -O(CH2) p R9 or C1-C 15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution; p is 0, 1, 2 or 3; R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R9, R 10 Each independently selected from C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R 12 is selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

13. The compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R1, R2 are independently selected from hydrogen, R8-(CH2) m -(CO)-(CH2) n -; m, n are each independently 0, 1, 2 or 3; R1 and R2 are not hydrogen at the same time; R3, R4 are independently selected from hydrogen or R8-(CH2) j -, where j is 0, 1, 2 or 3; X is selected from -CO- or -SO2-; R5 and R6 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 replace; Y is selected from -CO- or -SO2-; R7 is selected from hydrogen, -O(CH2) p R9 or C1-C 15 Alkyl, wherein the C1-C 15 The alkyl group is optionally substituted with 0 to 5 R 12 Substitution, p is 0, 1, 2 or 3; R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R9, R 10 Each independently selected from C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl, 5-15 membered heteroaryl are optionally substituted with 0-5 R 12 replace; R 12 is selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, thiol, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl group and the 5-15 membered heteroaryl group are optionally substituted with 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (I) is selected from the compounds represented by formula (V) in, Y, R7 are as defined in claim 13.

15. The compound of formula (I) according to claim 14 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (I) is selected from the compounds represented by formula (VI) in, R7 is as defined in claim 14.

16. A compound or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, selected from any of the following compounds:

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, and a pharmaceutically acceptable excipient or auxiliary ingredient.

18. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for preventing and / or treating depression.

19. The use according to claim 18, wherein the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, or the pharmaceutical composition according to claim 17 is used in combination with another, two or more antidepressants simultaneously, alternately or subsequently.

20. The use according to claim 18, wherein the drug is a fast-acting drug.

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