Compound, preparation method therefor, and use thereof

Abstract

A compound or a pharmaceutically acceptable salt, prodrug, deuterated compound, hydrate, solvate, enantiomer, diastereomer, or racemate thereof, and a preparation method therefor. The present application further relates to the use of said compound in treating depression.

Description

Compound, preparation method and use thereof Technical Field

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

[0002] Depression, characterized by a significant and persistent low mood, is a common mental illness. Clinically, it manifests as a low mood disproportionate to one's circumstances. This depression can range from melancholy to profound grief, low self-esteem, and even pessimism and world-weariness, potentially leading to suicidal attempts or behavior. In severe cases, psychotic symptoms such as hallucinations and delusions may occur. Globally, over 350 million people suffer from depression, an 18% increase over the past decade. As of 2017, China alone had over 54 million people with depression. Major depressive disorder has a recurrence rate of 50%-85%, and a suicide rate of 4.0%-10.6%, making it the most common mental illness.

[0003] Dysregulation of neurotransmitters such as norepinephrine, dopamine, and serotonin (5-HT) in the brain is considered the primary biological factor contributing to depression. The primary treatment for depression relies on the use of antidepressants, which are broadly classified into four categories based on their effectiveness and mechanism of action: 1) Monoamine oxidase inhibitors (MAOIs), such as iprohydrazide and isocarboxazid. These drugs have been largely discontinued due to their presence of significant side effects. 2) Tricyclic antidepressants, such as clomipramine and imipramine hydrochloride, are effective in relieving depression but can have significant adverse effects on patients with other medical conditions. 3) Selective serotonin reuptake inhibitors (SRIs), such as fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine, can compensate for serotonin deficiency in depressed patients. 4) Serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine, have dual antidepressant mechanisms and are relatively safe. Categories 3 and 4 are the main medications, and categories 1 and 2 are basically discontinued.

[0004] Since their introduction, serotonin reuptake inhibitors (SSRis) have undergone dozens of iterations and upgrades. Currently, there are hundreds of research projects underway, primarily focusing on SSRis, selective serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and specific serotonin antidepressants (NaSSAs), 5-HT receptor antagonists and reuptake inhibitors (SARIs), and NMDA receptor antagonists. The antidepressant market is also highly concentrated, with over 30 SSRis currently in global use. The top 10 are escitalopram, sertraline, venlafaxine, paroxetine, duloxetine, flupentixol + melitracen, mirtazapine, fluoxetine, citalopram, and fluvoxamine, representing a combined market share exceeding 90%.

[0005] However, currently commonly used antidepressants in clinical practice still have serious limitations, mainly slow and delayed onset of action, requiring 3 to 4 weeks of continuous medication for onset of effect. Many patients give up treatment before achieving effective results; 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. A single use quickly relieves depressive symptoms (a few hours) and can last for 3-4 days. Although esketamine can act quickly, it has serious side effects, including severe drowsiness, dissociative hallucinations, and potential addiction. The FDA has also issued a black box warning, requiring esketamine to be used concomitantly with other oral antidepressants for refractory depression in adults. These shortcomings limit the clinical application of this type of drug. Therefore, there is an urgent clinical need for new antidepressants with rapid onset, good efficacy, and oral administration. Summary of the Invention

[0006] The objects of the present invention include 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 one 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 is to provide the use of the compound of the above general formula or its pharmaceutically acceptable salt, prodrug, deuterated form, 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 purpose of the invention, the technical solutions adopted include:

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

[0012] in,

[0013] R1 and R2 are independently selected from hydrogen, R8-(CO)-, R8-(SO)-, R8-(SO2)-, R8-O(CO)-, R8R9-N(CO)-, or C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0014] Or R1, R2 and the nitrogen atoms adjacent to them together form a C3-C substituted by 0 to 8 R8 15 Heterocycloalkyl or C5-C 15 heteroaryl;

[0015] R3 and R4 are independently selected from hydrogen, or C1-C ... 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0016] Or R3, R4 and their adjacent carbon atoms together form a C3-C substituted by 0 to 8 R8 10 Cycloalkyl or C3-C 10 heterocycloalkyl;

[0017] X is optionally selected from -CO-, -SO-, -SO2-, -CHR8-, or

[0018] R5 and R6 are independently selected from hydrogen or C1-C6 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;

[0019] Y is optionally selected from -CO-, -SO-, -SO2- or -CH2-;

[0020] 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;

[0021] R8 is optionally selected from hydrogen, halogen, oxyethylene, -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;

[0022] 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, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0023] R 12 is selected from hydrogen, halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, 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, sulfonate, sulfonamide, alkyl or haloalkyl.

[0024] 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:

[0025] 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 by 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, and the C1-C 15 The chain alkyl group is optionally substituted by 0 to 8 R 12 replace;

[0026] or

[0027] 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 replaced by 0-8 R 12 replace;

[0028] 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 by 0-8 R 12j and k are each independently 0, 1, 2 or 3; or R3, R4 are each independently selected from C1-C containing heteroatoms 15 Chain alkyl, 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 by 0 to 8 R 12 replace;

[0029] or

[0030] 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;

[0031] X is selected from -CO-, -SO2-, -SO-, -CHR8- or

[0032] R5, 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 Aryl or 5-15 membered heteroaryl is optionally substituted by 0-8 R 12 or R5, R6 are independently selected from C1-C containing heteroatoms 15 Chain alkyl, 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 by 0 to 8 R 12 replace;

[0033] Y is selected from -CO-, -SO2, -SO- or -CH2-;

[0034] 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 Aryl or 5-15 membered heteroaryl is optionally substituted by 0-8 R 12 Substituted; p is 0, 1, 2 or 3; or R7 is selected from C1-C containing heteroatoms 15 Chain alkyl, 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 by 0 to 8 R 12 replace;

[0035] 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 by 0-8 R 12 replace;

[0036] 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 by 0-8 R 12 replace;

[0037] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, sulfhydryl, 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, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups;

[0038] Wherein, the compound represented by formula (I) does not include the following compounds:

[0039] In some embodiments, wherein,

[0040] 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 by 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;

[0041] or

[0042] 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 replaced by 0-5 R 12 replace;

[0043] 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;

[0044] or

[0045] 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;

[0046] X is selected from -CO- or -SO2-;

[0047] 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;

[0048] Y is selected from -CO- or -SO2;

[0049] 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;

[0050] 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 by 0-5 R 12 replace;

[0051] 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 15Aryl, 5-15 membered heteroaryl are optionally substituted by 0-5 R 12 replace;

[0052] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, sulfhydryl, 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 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups;

[0053] Wherein, the compound represented by formula (I) does not include the following compounds:

[0054] In some embodiments, wherein,

[0055] 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 by 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;

[0056] or

[0057] 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 replaced by 0-5 R 12 replace;

[0058] 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;

[0059] X is selected from -CO- or -SO2-;

[0060] 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;

[0061] Y is selected from -CO- or -SO2;

[0062] R7 is selected from -O(CH2) p R9, wherein p is 0, 1, 2 or 3;

[0063] 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 by 0-5 R 12 replace;

[0064] 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 15Aryl, 5-15 membered heteroaryl are optionally substituted by 0-5 R 12 replace;

[0065] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, sulfhydryl, 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.

[0066] In some embodiments, wherein,

[0067] The compound represented by formula (I) is selected from the compound represented by formula (II)

[0068] in,

[0069] R1, R2, R3, and R4 are as defined above.

[0070] In some embodiments, wherein,

[0071] 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;

[0072] or

[0073] 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 with 0-3 C1-C3 alkyl groups, oxyethylene groups, or phenyl groups; the 3-8 membered nitrogen-containing heterocyclic ring or the 5-6 membered nitrogen-containing heteroaromatic ring contains 1 or 2 nitrogen atoms;

[0074] R3 is hydrogen; R4 is selected from hydrogen, phenyl, C1-C5 alkyl, wherein the C1-C5 alkyl is optionally substituted with 0 to 3 halogens or hydroxyl groups;

[0075] 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 0-3 halogens, 5-6 membered heteroaryl or 3-6 membered heterocycloalkyl;

[0076] R 12 Selected from hydrogen, halogen, oxyene, C1-C3 alkyl, C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by 0 to 3 halogens.

[0077] In some embodiments, wherein,

[0078] The compound represented by formula (I) is selected from the compound represented by formula (III)

[0079] in,

[0080] R1 and R2 are as defined above.

[0081] In some embodiments, wherein,

[0082] 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 by 0-5 R 12 Substitution; m and n are each independently 0, 1, 2 or 3;

[0083] or

[0084] 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 replaced by 0-5 R12 replace;

[0085] 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;

[0086] or

[0087] 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;

[0088] X is selected from -CO- or -SO2-;

[0089] 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;

[0090] Y is selected from -CO- or -SO2;

[0091] 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;

[0092] R8 is selected from -OR9, -NR9R 10 、-CO-NH2、-SR9、sulfhydryl、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 by 0-5 R 12 replace;

[0093] R9, R 10 are independently selected from C1-C 15 Alkyl, C1-C 15Alkoxy, 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 by 0-5 R 12 replace;

[0094] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, sulfhydryl, 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 0-5 halogen, oxyethylene, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate or sulfonamide groups;

[0095] Wherein, the compound represented by formula (I) does not include the following compounds:

[0096] In some embodiments, wherein,

[0097] R1 and R2 are independently selected from hydrogen, C1-C 15 Alkyl or R8-(CH2) m -(CO)-(CH2) n -; m and n are each independently 0, 1, 2 or 3;

[0098] 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;

[0099] or

[0100] R3, R4 and their adjacent carbon atoms together form C3-C 10Cycloalkyl, wherein C3-C 10 The cycloalkyl group is optionally substituted with 0 to 5 R 12 replace;

[0101] X is selected from -CO- or -SO2-;

[0102] 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;

[0103] Y is selected from -CO- or -SO2;

[0104] R7 is selected from hydrogen, -O(CH2) p R9, wherein p is 0, 1, 2 or 3;

[0105] R8 is selected from -OR9, -NR9R 10 、-CO-NH2、-SR9、sulfhydryl、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 by 0-5 R 12 replace;

[0106] R9, R 10 are 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 by 0-5 R 12 replace;

[0107] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, sulfhydryl, ether, nitro, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, C1-C 15 Alkyl, C1-C15 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.

[0108] In some embodiments, wherein,

[0109] R1 is hydrogen; R2 is selected from hydrogen, C1-C3 alkyl or R8-(CO)-;

[0110] 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;

[0111] or

[0112] 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;

[0113] X is -CO-;

[0114] R5 is hydrogen, R6 is selected from hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by 0 to 5 R 12 replace;

[0115] Y is -CO-;

[0116] R7 is optionally selected from hydrogen, C1-C6 alkoxy;

[0117] R8 is selected from methylthio, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C8 aryl or 5-15 membered heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C8 aryl or 5-15 membered heteroaryl is optionally replaced by 0-3 R 12 replace;

[0118] R 12Selected from halogen, oxyethylene, hydroxy, amino, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, C6-C8 aryl, wherein C1-C3 alkyl, C1-C3 alkoxy, C6-C8 aryl are optionally substituted with 0 to 3 halogens.

[0119] In some embodiments, wherein,

[0120] The compound represented by formula (I) is selected from the compound represented by formula (IV)

[0121] in,

[0122] R3 and R4 are as defined above.

[0123] In some embodiments, wherein,

[0124] 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 by 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;

[0125] or

[0126] 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 replaced by 0-5 R 12 replace;

[0127] 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;

[0128] or

[0129] 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;

[0130] X is selected from -CO- or -SO2-;

[0131] 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;

[0132] Y is selected from -CO- or -SO2;

[0133] 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;

[0134] 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 by 0-5 R 12 replace;

[0135] R9, R 10 are 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 by 0-5 R 12 replace;

[0136] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, sulfhydryl, 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.

[0137] In some embodiments, wherein,

[0138] 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;

[0139] R3, R4 are independently selected from hydrogen or R8-(CH2) j -, where j is 0, 1, 2 or 3;

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

[0141] 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;

[0142] Y is selected from -CO- or -SO2;

[0143] 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;

[0144] R8 is selected from -OR9, -NR9R 10 、-(CO)-NR9R 10 , -SR9, thiol, C1-C 15 Alkyl, C1-C 15Alkoxy, 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 by 0-5 R 12 replace;

[0145] R9, R 10 are 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 by 0-5 R 12 replace;

[0146] R 12 Selected from hydrogen, halogen, oxydimide, cyano, hydroxyl, sulfhydryl, 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.

[0147] In some embodiments, wherein,

[0148] The compound represented by formula (I) is selected from the compound represented by formula (V)

[0149] in,

[0150] Y and R7 are as defined above.

[0151] In some embodiments, wherein,

[0152] The compound represented by formula (I) is selected from the compound represented by formula (VI)

[0153] in,

[0154] R7 is as defined above.

[0155] In some embodiments, wherein,

[0156] The compound is selected from any one of the following compounds:

[0157] The present invention also provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer or racemate thereof, and a pharmaceutically acceptable excipient or auxiliary ingredient.

[0158] The present invention also provides use of the compound described herein or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer or racemate thereof, or the pharmaceutical composition described herein in the preparation of a medicament for preventing and / or treating depression.

[0159] In some embodiments, the compound or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate described in the above-mentioned use, or the pharmaceutical composition is used in combination with another, two or more antidepressants simultaneously, alternately or subsequently.

[0160] In some embodiments, the drug in the above use is a fast-acting drug.

[0161] The hydrogen mentioned herein may be in any isotopic form, including 1 H (hydrogen), 2 H (D or deuterium) and 3 H (T or tritium).

[0162] definition

[0163] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0164] 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 isotopes of carbon 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, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0165] "Alkyl" refers to a straight-chain 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 even more 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 optionally be further substituted with one or more substituents.

[0166] "Alkoxy" refers to a group formed by linking an alkyl group to an oxygen atom. The definition of "alkyl" is the same as that of "alkyl" described above. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, cyclobutyloxy, and the like. The alkoxy group may optionally be further substituted with one or more substituents.

[0167] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic substituent, comprising 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, 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, fused ring, and bridged rings. The cycloalkyl may optionally be further substituted with one or more substituents.

[0168] "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- to 8-membered heterocyclic ring. The 1, 2, or 3 N or S atoms optionally substituted in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; the "heterocycloalkyl" can be a bridged ring or a spirocyclic 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.

[0169] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered monocyclic ring (e.g., 5, 6, 7, 8-membered), a 6- to 12-membered (e.g., 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, non-limiting examples of which include phenyl, naphthyl, etc. The aryl group can be optionally further substituted with one or more substituents.

[0170] "Heteroaryl" refers to an aromatic ring group having a conjugated planar ring system and containing heteroatoms, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, an 8- to 12-membered (e.g., 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 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 groups include oxazolyl, triazolyl, pyridinyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, and the like. The heteroaryl group may be optionally further substituted with one or more substituents.

[0171] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0172] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, 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.

[0173] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0174] Beneficial technical effects achieved:

[0175] (1) The compounds of the present invention have good rapid antidepressant activity in vivo.

[0176] (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.

[0177] (3) The compounds of the present invention have better plasma stability than the compounds disclosed in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0178] FIG1 shows the results of the tail suspension experiment in Experimental Example 3.

[0179] FIG2 shows the results of the forced swimming test in Experimental Example 4.

[0180] FIG3 shows the results of the tail suspension experiment in Experimental Example 4. DETAILED DESCRIPTION

[0181] Unless otherwise specified, all raw materials, reagents, and instruments used in the examples of the present invention are conventional commercially available products.

[0182] Among them, the present invention 1 The instrument for HNMR detection is a Bruker Advance 400 MHz spectrometer; the instrument for MS-ESI detection in the present invention is an Agilent LCMS 1260-6120.

[0183] Preparation Example 1 Preparation of Compound A-1-1-1

[0184] first step

[0185] Dissolve A-1-1-1a (7.66 g, 85.92 mmol) in water (40 mL) and cool to 0°C. Add sodium hydroxide (5.16 g, 128.88 mmol). Stir at 0°C for 10 min, then add a solution of di-tert-butyl dicarbonate (24.38 g, 111.70 mmol) in tetrahydrofuran (40 mL). Warm to room temperature and stir overnight. After completion of the reaction, monitor by LCMS. Wash with petroleum ether (30 mL × 2), and adjust the pH of the aqueous phase to 1 with 1M aqueous hydrochloric acid. Extract with ethyl acetate (50 mL × 4), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the crude intermediate A-1-1-1b (15.00 g, 79.28 mmol, 92.3% yield). 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).

[0186] Step 2

[0187] 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 mixture was allowed to warm to room temperature for 2 h. After LCMS monitoring indicated the reaction was complete, intermediate A-1-1-1c was purified by medium-pressure preparative column chromatography to obtain intermediate A-1-1-1c (16.00 g, 50.26 mmol, yield 67.9%). MS-ESI: [M+H] + =303.1. 1 H 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).

[0188] Step 3

[0189] Dissolve intermediate A-1-1-1c (16.00 g, 50.26 mmol) in dichloromethane (40 mL) and add a 4M solution of hydrogen chloride in dioxane (40 mL). Allow to react at room temperature for 2 h. LCMS monitoring indicates the reaction is complete. Concentrate to obtain intermediate A-1-1-1d (11.00 g, 46.22 mmol, 88.4% yield). MS-ESI: [M+H] + =203.1.

[0190] Step 4

[0191] Intermediate 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. Cyclopropanoyl chloride (325.62 mg, 3.11 mmol) was added and stirred at 0°C for 1 h. After LCMS monitoring showed that the reaction was complete, water (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified 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. 1H NMR (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).

[0192] Preparation Example 2 Preparation of Compound A-1-1-4

[0193] 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 the reaction was complete, water was added to quench the mixture. Dichloromethane (100 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to obtain compound A-1-1-4 (310.0 mg, 1.14 mmol, yield 32.9%). MS-ESI: [M+H] + =273.0. 1 H NMR (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),3.6 4(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).

[0194] Preparation Example 3 Preparation of Compound A-1-1-13

[0195] Compound A-1-1-1d (500.0 mg, 2.47 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (958.0 mg, 7.41 mmol) was added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred in an ice bath for 10 min. A solution of methylaminocarbonyl chloride (347.0 mg, 3.71 mmol) in dichloromethane (1.5 mL) was slowly added dropwise. After 5 min of complete addition, the mixture was allowed to stand at room temperature and allowed to react for 30 min. TLC indicated the reaction was complete, and aqueous sodium bicarbonate was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride (100 mL), 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. 1 H 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).

[0196] Preparation Example 4 Preparation of Compound A-1-1-14

[0197] In a 50 mL three-necked flask, compound A-1-1-1d (500.0 mg, 2.47 mmol), triethylamine (1.25 g, 12.35 mmol), and dichloromethane (20 mL) were added. The temperature was lowered to 0°C, and cyclopropylsulfonyl chloride (1.04 g, 7.41 mmol) was added. The mixture was then allowed to react at room temperature for 2 h. TLC indicated that the reaction was complete. Aqueous sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride 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 the oily product A-1-1-14 (405.0 mg, 1.32 mmol, 53.4% ​​yield). MS-ESI: [M+H] + =307.1[M+H] + . 1H 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).

[0198] Preparation Example 5 Preparation of Compound A-1-1-15

[0199] In a 50 mL three-necked flask, compound A-1-1-1d (1.00 g, 4.94 mmol), triethylamine (2.50 g, 24.70 mmol), and dichloromethane (20 mL) were added. The temperature was lowered to 0°C, and 1H-pyrazole-1-yl chloride (0.64 g, 4.94 mmol) was added. After the addition was complete, the mixture was allowed to return to room temperature and react for 2 h. After LCMS and TLC monitoring showed that the reaction was complete, water was added to quench the mixture, and the mixture was extracted with dichloromethane (120 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (120 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-1-1-15 (1.00 g, 3.37 mmol, yield 68.2%). MS-ESI: [M+H] + =297.2. 1 H NMR (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).

[0200] Preparation Example 6 Preparation of Compound A-1-2-1

[0201] 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), and cesium carbonate (3.22 g, 9.89 mmol) were dissolved in N,N-dimethylformamide (10 mL). The atmosphere was replaced with nitrogen three times and the temperature was raised to 80°C for overnight reaction. LCMS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered. 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. 1 H 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).

[0202] Preparation Example 7 Preparation of Compound A-1-2-2

[0203] first step

[0204] 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), and cesium carbonate (12.72 g, 39.03 mmol) were dissolved in N,N-dimethylformamide (40 mL). The atmosphere was purged with nitrogen three times, then the temperature was raised to 60°C overnight. After LCMS monitoring indicated the reaction was complete, the reaction solution was cooled to room temperature, filtered, and dried, and 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.

[0205] Step 2

[0206] 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), and 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 indicated the reaction was complete, 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. 1 H 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).

[0207] Preparation Example 8 Preparation of Compound A-1-2-6

[0208] 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) were added to a 50 mL three-necked flask, and N,N-dimethylformamide (22 mL) was added. The atmosphere was replaced with nitrogen three times and stirred at 60 °C for 3 h. After LCMS and TLC monitoring showed the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated aqueous sodium chloride (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-1-2-6 (240.0 mg, 0.69 mmol, yield: 34.3%). MS-ESI: [M+H] + =348.1. 1 H 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).

[0209] Preparation Example 9 Preparation of Compound A-1-2-8

[0210] 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) 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 indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride (100 mL). The organic phases were 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).

[0211] Preparation Example 10 Preparation of Compound A-1-2-9

[0212] 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) were added to a 50 mL three-necked flask, and N,N-dimethylformamide (14 mL) was added. The atmosphere was replaced with nitrogen three times and stirred at 95 °C for 5 h. LCMS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride (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 product A-1-2-9 (186.0 mg, 0.67 mmol, yield: 22.9%). MS-ESI: [M+H] + =280.2. 1 H NMR (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).

[0213] Preparation Example 11 Preparation of Compound A-1-2-10

[0214] 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 indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride (100 mL). The organic phases were 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).

[0215] Preparation Example 12 Preparation of Compound A-1-2-14

[0216] Intermediate A-1-1-1d (1.48 g, 7.30 mmol) and triethylamine (2.22 g, 21.90 mmol) were dissolved in N,N-dimethylformamide (15 mL), cooled to 0°C, and bromoacetone (338.6 mg, 2.47 mmol) was added. The mixture was stirred at 0°C for 1 h. 1M hydrochloric acid was added to adjust the pH of the reaction solution to 5-6. The mixture was purified 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).

[0217] Preparation Example 13 Preparation of Compound A-1-3-2

[0218] first step

[0219] To a solution of compound A-1-3-2a (2.00 g, 13.25 mmol) in dichloromethane (30 mL) was added triethylamine (4.02 g, 39.75 mmol). The reaction temperature was lowered to 0°C, and cyclopropylcarbonyl chloride (1.39 g, 13.25 mmol) was slowly added dropwise to the reaction solution. The reaction was stirred at 25°C for 2 h. The reaction mixture 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.

[0220] Step 2

[0221] 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 completion of the reaction, extraction with ethyl acetate (50 mL × 3) was performed. The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (50 mL × 2), saturated ammonium chloride solution (50 mL × 2), and saturated sodium chloride solution (50 mL × 2). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by HPLC and lyophilized 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).

[0222] Preparation Example 14 Preparation of Compound A-1-3-4

[0223] first step

[0224] Compound A-1-3-4a (1.00 g, 6.90 mmol) was dissolved in aqueous sodium hydroxide solution (7 mL, 1 M). Sodium carbonate (370.0 mg, 3.45 mmol) and cyclopropylcarbonyl chloride (790.0 mg, 7.50 mmol) were added sequentially to the solution. The reaction was stirred at 25°C for 2 h. The pH of the reaction solution was then adjusted to 4 with hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (50 mL x 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 the crude product A-1-3-4b (910.0 mg, yield: 62.0%) as a white solid. It was used directly in the next reaction without purification. MS-ESI: [M+H] + =214.1.

[0225] Step 2

[0226] 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 sequentially to the solution. The reaction was stirred at 25°C for 1 h. L-valine methyl ester (630.0 mg, 4.80 mmol) was then added to the reaction solution, and the reaction was stirred for another 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. 1H NMR(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).

[0227] Preparation Example 15 Preparation of Compound A-1-4-9

[0228] first step

[0229] To a solution of pyrrolidone A-1-4-9a (3.00 g, 35.30 mmol) in toluene (30 mL) was added sodium hydride (1.27 g, 52.90 mmol) at 0°C. The reaction was stirred at 0°C for 1 hour before the addition of ethyl bromopropionate A-1-4-9b (12.71 g, 70.60 mmol). The reaction was slowly warmed to room temperature and stirred for 5 hours. Saturated aqueous ammonium chloride (10 mL) was added to quench the mixture. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 7:3) to afford intermediate A-1-4-9c (1.10 g, yield: 16.9%) as a colorless oil. MS-ESI: [M+H] + =186.0.

[0230] Step 2

[0231] A-1-4-9c (1.08 g, 5.80 mmol) was dissolved in ethanol and water (V / V = 1:1, 10 mL). Sodium hydroxide (0.70 g, 17.40 mmol) was then added to the reaction mixture and stirred at room temperature for 3 h. The ethanol was evaporated to dryness, and the pH was adjusted to 6 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 3). The aqueous phase was evaporated to dryness and lyophilized to afford A-1-4-9d (0.80 g, yield: 87.3%) as a white solid. MS-ESI: [M+H] + =158.

[0232] Step 3

[0233] To a solution of A-1-4-9d (0.78 g, 4.96 mmol) in dichloromethane (10 mL) were 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. The reaction mixture was diluted with 15 mL of water. Extraction was performed with dichloromethane (10 mL x 2). The combined organic phases were concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 27:4) to afford A-1-4-9 (310.0 mg, yield: 23.0%) as a colorless oil. 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).

[0234] Preparation Example 16 Preparation of Compound A-1-5-1

[0235] first step

[0236] 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) was added di-tert-butyl dicarbonate (6.02 g, 27.6 mmol), and the reaction was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate (20 mL), and the pH was adjusted to 3-4 with 1 M hydrochloric acid solution. Extraction was performed with ethyl acetate (20 mL x 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford A-1-5-1a (3.00 g, yield: 88.8%) as a yellow oil. MS-ESI: [M+Na] + =268.0.

[0237] Step 2

[0238] To a solution of A-1-5-1a (2.00 g, 8.2 mmol) in dichloromethane (40 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.36 g, 12.3 mmol), 1-hydroxybenzotriazole (1.66 g, 12.3 mmol), and N,N-diisopropylethylamine (5.30 g, 41 mmol). The mixture was stirred at room temperature for 10 min, followed by the addition of L-valine methyl ester (1.29 g, 9.8 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed sequentially with saturated citric acid solution (20 mL × 2) and saturated sodium carbonate solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford A-1-5-1b (3.00 g crude product) as a yellow oil. MS-ESI: [M+Na] + =381.0.

[0239] Step 3

[0240] A-1-5-1b (3.00 g, 8.40 mmol) was dissolved in trifluoroacetic acid / dichloromethane (V / V = 1:1, 40 mL) and the reaction mixture was stirred at room temperature for 2 h. Saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 9. The mixture was extracted with dichloromethane (50 mL x 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 crude product A-1-5-1c (1.50 g, yield: 69.1%) as a yellow oil. MS-ESI: [M+H] + =259.0.

[0241] Step 4

[0242] To a solution of A-1-5-1c (1.44 g, 5.60 mmol) in 1,2-dichloroethane (20 mL) were added pyridine N-oxide (1.07 g, 11.20 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (7.83 g, 16.80 mmol), and N,N-diisopropylethylamine (2.89 g, 22.40 mmol) in sequence. 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), and washed with saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) and lyophilized to afford 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).

[0243] Preparation Example 17 Preparation of Compound A-1-5-2

[0244] first step

[0245] 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 sequentially 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 resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain A-1-5-2b (2.60 g, yield: 36.0%) as a yellow oily liquid. MS-ESI: [M+Na] + =387.2.

[0246] Step 2

[0247] A-1-5-2b (2.60 g, 7.10 mmol) was dissolved in trifluoroacetic acid / dichloromethane (V / V=1:1, 40 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the crude product A-1-5-2c (2.00 g) as a yellow oily liquid. MS-ESI: [M+H] + =265.1.

[0248] Step 3

[0249] To a solution of A-1-5-2c (1.60 g, 6.10 mmol) in 1,4-dioxane (20 mL) were added tris(dibenzylideneacetone)dipalladium (560.0 mg, 0.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (760.0 mg, 1.20 mmol), and cesium carbonate (5.96 g, 18.30 mmol) in sequence. The mixture was purged three times under nitrogen and stirred at 100°C for 16 h. The reaction mixture was filtered, the filtrate was dried, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) and lyophilized to afford 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).

[0250] Preparation Example 18 Preparation of Compound A-1-5-3

[0251] first step

[0252] To a solution of compound A-1-5-3a (12.00 g, 100.84 mmol) in dioxane (120 mL) and water (80 mL) was added sodium bicarbonate (16.94 g, 201.68 mmol). The reaction temperature was lowered to 0°C, and di-tert-butyl dicarbonate (32.97 g, 151.26 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The pH was adjusted to 2 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product A-1-5-3b (12.00 g, yield: 54.2%) as a colorless oil. MS-ESI: [MH] - =218.0.

[0253] Step 2

[0254] 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). The reaction mixture was cooled to 0°C, and tert-butyldimethylsilyl chloride (12.49 g, 82.18 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The pH was adjusted to 2 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (200 mL x 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%) as a yellow oil. MS-ESI: [MH] - =332.0.

[0255] Step 3

[0256] 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), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.37 g, 54.04 mmol) were dissolved in dichloromethane (150 mL) solution, and 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, and concentrate the filtrate under reduced pressure. Purify by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain A-1-5-3d (6.30 g, yield: 39.4%) as a yellow oily liquid. MS-ESI: [M+H] + =447.0.

[0257] Step 4

[0258] Dissolve A-1-5-3d (6.30 g, 14.12 mmol) and pyridine (20 mL) in dichloromethane (20 mL). The reaction mixture was cooled to 0°C, then trimethylsilyl trifluoromethanesulfonate (20 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The pH was adjusted to 8 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL x 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%) as a yellow oil. MS-ESI: [M+H] + =347.0.

[0259] Step 5

[0260] A-1-5-3e (3.60 g, 10.40 mmol), pyridine N-oxide (1.19 g, 12.48 mmol), and N,N-diisopropylethylamine (4.02 g, 31.2 mmol) were dissolved in dichloromethane (50 mL). Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (14.54 g, 31.2 mmol) was added and the reaction was stirred at room temperature for 4 h. The mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were 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 on a C18 reverse phase column to obtain A-1-5-3f (850.0 mg, yield: 19.3%) as a colorless oil. MS-ESI: [M+H] + =424.3.

[0261] Step 6

[0262] A-1-5-3f (850.0 mg, 2.01 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium fluoride (1.53 g, 10.05 mmol) was then added to the reaction mixture and stirred at room temperature for 4 h. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC. The resulting residue was lyophilized to afford A-1-5-3 (230.8 mg, yield: 37.3%) as a colorless oil. MS-ESI: [M+H] + =310.1. 1 H NMR(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).

[0263] Preparation Example 19 Preparation of Compound A-1-6-1

[0264] first step

[0265] In a 100 mL single-necked flask, A-1-6-1a (900.0 mg, 4.76 mmol), tetrahydrofuran (10 mL), and iodomethane (1351.0 mg, 9.52 mmol) were added sequentially. After the addition, the mixture was evacuated with nitrogen three times. Under nitrogen protection, sodium hydride (343.0 mg, 14.28 mmol) was added in batches. After the addition, the reaction was allowed to react at room temperature for 2 h and monitored by LCMS. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 mL × 3). The organic layers were combined and washed with saturated brine (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain crude A-1-6-1b (1.70 g). The crude product was used directly in the next reaction without purification. MS-ESI: [M+H] + =204.1.

[0266] Step 2

[0267] To a 100 mL single-necked flask, crude A-1-6-1b (800.0 mg, 3.94 mmol), L-valine methyl ester hydrochloride (793.0 mg, 4.73 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2247.0 mg, 5.91 mmol), N,N-diisopropylethylamine (1018.0 mg, 7.88 mmol), and N,N-dimethylformamide (15 mL) were added sequentially. After completion of the addition, the mixture was reacted at room temperature for 3 h, monitored by LCMS. The reaction solution was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic layers were combined and washed with saturated sodium chloride (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporation. The crude product was purified by medium-pressure preparative column chromatography to obtain compound A-1-6-1c (800.0 mg, 2.53 mmol, yield 64.2%). MS-ESI:[M+H] + =317.2.

[0268] Step 3

[0269] In a 100 mL single-necked flask, compound A-1-6-1c (800.0 mg, 2.53 mmol), dichloromethane (5 mL), and hydrogen chloride (1,4-dioxane solution, 4.0 M, 5 mL) were added and allowed to react at room temperature for 2 h. After LCMS and TLC monitoring showed the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound A-1-6-1d (700 mg). The crude product was used directly in the next step without purification. MS-ESI: [M+H] + =217.2.

[0270] Step 4

[0271] In a 50 mL single-necked flask, crude compound A-1-6-1d (650.0 mg, 3.01 mmol), N,N-diisopropylethylamine (778.0 mg, 6.02 mmol), and dichloromethane (10 mL) were added. The temperature was lowered to 0°C, and cyclopropylcarbonyl chloride (378.0 mg, 3.61 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and allowed to react for 2 h. After LCMS and TLC monitoring indicated the reaction was complete, the mixture was quenched with water and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by medium-pressure preparative column chromatography to obtain compound A-1-6-1 (530.0 mg, 1.86 mmol, yield: 61.8%). MS-ESI: [M+H] + =285.2. 1 H NMR (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).

[0272] Preparation Example 20 Preparation of Compound A-3-1-1

[0273] first step

[0274] Compound A-3-1-1a (2.00 g, 22.45 mmol) and sodium bicarbonate (7.99 g, 95.11 mmol) were dissolved in water (10 mL). Acetic anhydride (4.58 g, 44.90 mmol) was added dropwise and stirred at room temperature for 2 h. After LCMS showed the reaction was complete, the pH was adjusted to 1-2 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude intermediate A-3-1-1b (1.20 g, 9.15 mmol, yield: 40.8%). MS-ESI: [M+H] + =132.1.

[0275] Step 2

[0276] 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), and 4-dimethylaminopyridine (1.68 g, 13.73 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature overnight. LCMS showed the disappearance of the starting material. The mixture was filtered and purified by medium-pressure preparative column chromatography to afford A-3-1-1 (460.0 mg, 1.88 mmol, yield: 20.6%). MS-ESI: [M+H] + =245.4. 1 H NMR(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).

[0277] Preparation Example 21 Preparation of Compound A-4-1-1

[0278] 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), and 4-dimethylaminopyridine (757.5 mg, 6.20 mmol) were added to a reaction flask. N,N-dimethylformamide (6 mL) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction, the mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The mixture was washed sequentially with 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 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).

[0279] Preparation Example 22 Preparation of Compound A-4-1-2

[0280] A-4-1-2a (530.0 mg, 3.70 mmol) was dissolved in N,N-dimethylformamide (9 mL). 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 sequentially at room temperature. The reaction was allowed to react for 16 h at room temperature and the mixture was directly purified by medium-pressure preparative column chromatography to afford A-4-1-2 (460.0 mg, 1.79 mmol, yield: 48.0%). MS-ESI: [M+H] + =257.1. 1 H NMR (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).

[0281] Preparation Example 23 Preparation of Compound A-4-1-3

[0282] first step

[0283] 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. The mixture was 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 the crude product. 40 mL of water was added, the mixture was filtered, and the mixture was washed with ethyl acetate (80 mL x 3). The filtrates were combined, concentrated, dissolved in a small amount of 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.

[0284] Step 2

[0285] 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 as determined 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 used directly in the next step. MS-ESI: [M+H] + =229.3.

[0286] Step 3

[0287] Compound A-4-1-3c (1.00 g, 4.39 mmol) was dissolved in water (10 mL), and sodium bicarbonate (765.0 mg, 9.11 mmol) was added, followed by acetic anhydride (0.93 g, 9.11 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was complete as determined by LCMS, the reaction solution was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, dissolved in a small amount of DMF, and purified by medium-pressure preparative column chromatography to obtain compound A-4-1-3 (500.0 mg, 1.85 mmol, yield: 42.3%) as a white solid. MS-ESI: [M+H] + =271.4. 1H NMR(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).

[0288] Preparation Example 24 Preparation of Compound A-4-1-5

[0289] first step

[0290] 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, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated to afford A-4-1-5b (1.18 g, yield: 44.7%) as a white solid. 1 H NMR (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).

[0291] Step 2

[0292] 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, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting 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).

[0293] Preparation Example 25 Preparation of Compound A-4-1-6

[0294] first step

[0295] Compound A-4-1-6a (2.00 g, 12.69 mmol) was dissolved in methanol (12 mL). 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 sequentially at room temperature. After complete addition, the mixture was heated to 50°C and reacted for 1 h. After the addition of acetic acid (0.762 g, 12.69 mmol), a solid precipitated. The solid was filtered, washed with ethanol (5 mL), and dried to yield the crude intermediate A-4-1-6b (1.43 g, 10.6 mmol, yield: 83.0%).

[0296] Step 2

[0297] Intermediate A-4-1-6b (1.00 g, 7.4 mmol) was dissolved in water (12.7 mL). After cooling to 0°C, sodium hydroxide (0.74 g, 18.49 mmol) and acetic anhydride (1.36 g, 13.32 mmol) were added sequentially. The mixture was stirred at 0°C for 30 min and then warmed to room temperature for 16 h. After extraction and washing with dichloromethane (30 mL), the pH of the aqueous phase was adjusted to 1 with concentrated hydrochloric acid. The organic phases were extracted with ethyl acetate (40 mL x 3) and combined. After drying over anhydrous sodium sulfate, the mixture was concentrated to afford intermediate A-4-1-6c (1.10 g, 6.21 mmol, yield: 84.0%). MS-ESI: [MH] - =176.2.

[0298] Step 3

[0299] Intermediate A-4-1-6c (500.0 mg, 2.82 mmol) was dissolved in N,N-dimethylformamide (9 mL). 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 sequentially at room temperature. After reacting at room temperature for 16 h, the mixture was purified by medium-pressure preparative column chromatography 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).

[0300] Preparation Example 26 Preparation of Compound A-4-1-7

[0301] first step

[0302] Dissolve A-4-1-7a (1.00 g, 7.62 mmol) in 2M sodium hydroxide solution (20 mL). Slowly add acetic anhydride (1.56 g, 15.25 mmol) under ice-cooling, controlling the pH to around 10. After addition, react at room temperature for 2 h. Once the reaction is complete, adjust the pH to 1, and a large amount of white solid will precipitate. Filter and dry to obtain crude intermediate A-4-1-7b (1.32 g, 7.51 mmol, yield: 98.5%). MS-ESI: [M+H] + =174.3.

[0303] Step 2

[0304] 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 a reaction flask. N,N-dimethylformamide (12 mL) was added and the mixture was allowed to react at room temperature for 2 h. Pour into 10 mL of water and extract with ethyl acetate (20 mL x 3). After combining 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. The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a medium-pressure preparative column to obtain compound A-4-1-7 (1.01 g, 3.54 mmol, 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).

[0305] Preparation Example 27 Preparation of Compound A-4-1-8

[0306] first step

[0307] Dissolve A-4-1-8a (1.00 g, 6.6 mmol) in 2N sodium hydroxide solution (20 mL). Slowly add acetic anhydride (1.35 g, 13.19 mmol) under ice-cooling, controlling the pH to around 10. After addition, react at room temperature for 2 h. Once the reaction is complete, adjust the pH to 1, and a large amount of white solid will precipitate. Filter and dry to obtain crude intermediate A-4-1-8b (1.00 g, 6.36 mmol, yield: 96.3%). MS-ESI: [M+H] + =158.0.

[0308] Step 2

[0309] 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 a reaction flask. N,N-dimethylformamide (10 mL) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was poured into 10 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a 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).

[0310] Preparation Example 28 Preparation of Compound A-4-1-9

[0311] first step

[0312] A-4-1-9a (1.00 g, 7.74 mmol) was dissolved in 2M sodium hydroxide solution (20 mL). Acetic anhydride (1.58 g, 15.49 mmol) was slowly added under ice-cooling, and the pH was controlled at approximately 10. After addition, the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the 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.

[0313] Step 2

[0314] 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 a reaction flask. N,N-dimethylformamide (12 mL) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was poured into 12 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a 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).

[0315] Preparation Example 29 Preparation of Compound A-4-1-10

[0316] 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 stirring at room temperature for 0.5 h, L-valine methyl ester hydrochloride (1.00 g, 6.03 mmol) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was poured into water, whereupon a large amount of white solid precipitated. The solid 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).

[0317] Preparation Example 30 Preparation of Compound A-4-1-11

[0318] 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), and 4-dimethylaminopyridine (948.0 mg, 7.77 mmol) were added to a reaction flask. N,N-dimethylformamide (20 mL) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was poured into 20 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a 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).

[0319] Preparation Example 31 Preparation of Compound A-4-1-12

[0320] C-1-1-1 (0.70 g, 2.40 mmol) and dioxane (10 mL) were added to 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 to the reaction flask. Deuterated methanol (5 mL) was then added dropwise to 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 chromatography to obtain product A-4-1-12 (0.39 g, 1.26 mmol, yield: 52.0%). MS-ESI: [M+H] + =310.2.

[0321] 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).

[0322] Preparation Example 32 Preparation of Compound A-4-1-13

[0323] first step

[0324] The raw material A-4-1-13a (1.00 g, 6.05 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL dry three-necked flask. After sufficient dissolution, deuterated acetic acid (0.46 g, 7.26 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (2.76 g, 7.26 mmol), 1-hydroxybenzotriazole (0.82 g, 6.05 mmol), and triethylamine (1.22 g, 12.10 mmol) were added to the reaction flask in sequence. 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, 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%).

[0325] Step 2

[0326] A-4-1-13b (0.80 g, 3.80 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask. After complete dissolution, a 2.0 M aqueous lithium hydroxide solution (10 mL) was added dropwise to the reaction flask. The mixture was allowed to react at room temperature for 2 h and monitored by TLC and LCMS. After completion of the reaction, the reaction solution was added to water (50 mL). The aqueous phase was adjusted to a pH of approximately 4 with dilute hydrochloric acid (1.0 M), 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%).

[0327] Step 3

[0328] A-4-1-13c (0.50 g, 2.55 mmol) and N,N-dimethylformamide (20 mL) were added to a 100 mL dry three-necked flask. After sufficient dissolution, 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 to the reaction flask in sequence. 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 (50 mL × 3). The organic phases were combined and backwashed once with water (300 mL). The organic phase was then washed sequentially with 1.0 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure preparative column chromatography to obtain product A-4-1-13 (0.38 g, 1.23 mmol, yield: 48.0%). MS-ESI: [M+H] + =310.2.

[0329] 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).

[0330] Preparation Example 33 Preparation of Compound A-4-1-14

[0331] first step

[0332] Dissolve A-4-1-14a (2.00 g, 11.83 mmol) in acetonitrile (10 mL) and add saturated aqueous sodium bicarbonate (20 mL). Slowly add acetic anhydride (2.41 g, 23.66 mmol) under ice-cooling, controlling the pH between 8 and 9. Allow to react at room temperature for 2 hours, then sample for monitoring. After the reaction is complete, adjust the pH to 1 with hydrochloric acid. A large amount of white solid precipitates, which is 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.

[0333] Step 2

[0334] 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 a reaction flask. N,N-dimethylformamide (20 mL) was added and the mixture was reacted at room temperature for 2 h. After the reaction was complete, the mixture was poured into 20 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified 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 HNMR(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).

[0335] Preparation Example 34 Preparation of Compound A-4-1-15

[0336] first step

[0337] A-4-1-15a (2.00 g, 11.98 mmol) was dissolved in 2M aqueous sodium hydroxide solution (20 mL). Acetic anhydride (2.44 g, 23.95 mmol) was slowly added under ice-cooling, and the pH was controlled at approximately 10. After addition, the mixture was allowed to react at room temperature for 0.5 h. Solid sodium hydroxide was then added to control the pH to approximately 12, and the reaction was continued 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.

[0338] Step 2

[0339] 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 a reaction flask. N,N-dimethylformamide (20 mL) was added and the mixture was allowed to react at room temperature for 2 h. 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 1N hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL) in sequence. The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound A-4-1-15 (560.0 mg, 1.74 mmol, yield: 36.4%). MS-ESI: [M+H] + =323.3. 1 H NMR(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=22 .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).

[0340] Preparation Example 35 Preparation of Compound A-4-1-21

[0341] Intermediate A-4-1-21a (1.00 g, 6.12 mmol) was dissolved in N,N-dimethylformamide (20 mL), and L-valine methyl ester hydrochloride (1.54 g, 9.19 mmol), 1-hydroxybenzotriazole (910.8 mg, 6.74 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g, 6.74 mmol) were added. The reaction was allowed to react at room temperature for 16 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were concentrated, dissolved in a small amount of N,N-dimethylformamide, and purified by medium-pressure preparative column chromatography to obtain compound A-4-1-21 (400.0 mg, 1.45 mmol, yield: 23.6%). MS-ESI: [M+H] + =277.3. 1H 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).

[0342] Preparation Example 36 Preparation of Compound A-4-1-22

[0343] first step

[0344] 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 allowed to react at 90°C for 2 h. After the reaction was complete, the mixture was poured into 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure preparative column chromatography to obtain the crude intermediate A-4-1-22b (560.0 mg, 3.47 mmol, yield: 34.8%). MS-ESI: [M+H] + =162.0.

[0345] Step 2

[0346] Dissolve 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), and 4-dimethylaminopyridine (580.0 mg, 4.75 mmol) in N,N-dimethylformamide (20 mL). Allow to react at room temperature for 2 h. After the reaction is complete, the reaction mixture is filtered and purified by high-pressure reverse phase preparative chromatography followed by silica gel forward chromatography to afford A-4-1-22 (315.0 mg, 1.09 mmol, yield: 34.5%) as a white solid. MS-ESI: [M+H] + =275.1. 1H 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).

[0347] Preparation Example 37 Preparation of Compound A-4-1-24

[0348] 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), and 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, concentrated, and purified by medium-pressure preparative column chromatography 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).

[0349] Preparation Example 38 Preparation of Compound A-4-1-25

[0350] 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), and 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 was complete, the mixture was poured into 20 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (80 mL), saturated aqueous sodium bicarbonate solution (80 mL), and saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure preparative column chromatography 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).

[0351] Preparation Example 39 Preparation of Compound A-4-1-26

[0352] first step

[0353] 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. Acetic anhydride (2.20 g, 21.54 mmol) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was poured into 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure preparative column chromatography to obtain the crude intermediate A-4-1-26b (660.0 mg, 4.10 mmol, yield: 38.1%) as a colorless liquid. MS-ESI: [M+H] + =162.0.

[0354] Step 2

[0355] 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), and 1-hydroxybenzotriazole (663.0 mg, 4.92 mmol) were dissolved in N,N-dimethylformamide (13 mL). After reacting at room temperature for 2 hours, the reaction mixture was filtered and purified using high-pressure reverse phase preparative and silica gel forward chromatography to obtain compound A-4-1-26 (305.0 mg, 1.11 mmol, 27.2% yield) as a white solid. MS-ESI: [M+H] + =275.1. 1 H NMR (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).

[0356] Preparation Example 40 Preparation of Compound A-4-1-27

[0357] first step

[0358] Dissolve A-1-3-4a (1.00 g, 6.89 mmol) in 2M sodium hydroxide solution (20 mL). Slowly add acetic anhydride (1.56 g, 15.25 mmol) under ice-cooling, controlling the pH to around 10. After addition, react at room temperature for 2 h. Once the reaction is complete, adjust the pH to 1, and a large amount of white solid will precipitate. Filter and dry to obtain crude intermediate A-4-1-27a (1.10 g, 5.88 mmol, yield: 85.4%). MS-ESI: [M+H] + =188.3.

[0359] Step 2

[0360] 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 a reaction flask. N,N-dimethylformamide (12 mL) was added and the mixture was reacted at room temperature for 2 h. After the reaction was complete, the mixture was poured into 10 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a 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).

[0361] Preparation Example 41 Preparation of Compound A-4-1-30

[0362] first step

[0363] Compound A-4-1-30a (1.00 g, 7.75 mmol) was dissolved in a saturated aqueous sodium bicarbonate solution (30 mL). Acetic anhydride (1.58 g, 15.50 mmol) was slowly added under ice-cooling, and the pH was controlled at approximately 8. 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 x 3). The combined organic phases were washed with a saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and concentrated to afford the crude intermediate A-4-1-30b (1.00 g, 5.84 mmol, yield: 75.5%). MS-ESI: [M+H] + =172.3.

[0364] Step 2

[0365] 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 a reaction flask. N,N-dimethylformamide (20 mL) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was poured into 20 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a 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 H NMR (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).

[0366] Preparation Example 42 Preparation of Compound A-4-1-31

[0367] first step

[0368] Compound A-4-1-31a (1.00 g, 6.37 mmol) was dissolved in a saturated aqueous sodium bicarbonate solution (30 mL). Acetic anhydride (1.30 g, 12.74 mmol) was slowly added under ice-cooling, and the pH was controlled at approximately 8. The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 1 with hydrochloric acid, and the mixture was filtered and dried to obtain the crude intermediate A-4-1-31b (1.00 g, 5.02 mmol, yield: 78.9%). MS-ESI: [M+H] + =200.3.

[0369] Step 2

[0370] 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 a reaction flask. N,N-dimethylformamide (20 mL) was added and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was poured into 20 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined and washed sequentially with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a 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).

[0371] Preparation Example 43 Preparation of Compound A-4-1-32

[0372] first step

[0373] Compound A-4-1-32a (3.20 g, 18.69 mmol) was added to water (120 mL). 2M aqueous sodium hydroxide solution was added dropwise until the reaction system became clear. Acetic anhydride (6.68 g, 65.41 mmol) was then added and allowed to react at room temperature for 16 h. After the reaction was complete, the pH was adjusted to 2 with hydrochloric acid at 0°C, and the mixture was extracted with ethyl acetate (120 mL x 3). The organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, and concentrated to afford crude intermediate A-4-1-32b (3.80 g, 17.82 mmol, yield: 95.3%).

[0374] Step 2

[0375] L-Valine methyl ester hydrochloride (838.0 mg, 5.00 mmol) and 4-dimethylaminopyridine (1.20 g, 10.00 mmol) were dissolved in N,N-dimethylformamide (10 mL). 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) were added at 0°C and allowed to react for 16 h at room temperature. After the reaction was complete, 10 mL of water was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to afford 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).

[0376] Preparation Example 44 Preparation of Compound A-4-1-33

[0377] first step

[0378] Add diethyl acetamidomalonate (2.20 g, 10.17 mmol) to ethanol (10 mL) and stir at room temperature for 20 min. Dissolve A-4-1-33a (2.40 g, 10.17 mmol) in ethanol (10 mL) and add it to the reaction system. React at 80°C for 16 h. After the reaction is complete, concentrate the mixture and purify it 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.

[0379] Step 2

[0380] Intermediate A-4-1-33b (300 mg, 0.99 mmol) was dissolved in tetrahydrofuran (3 mL), and 1M aqueous lithium hydroxide solution (3 mL) was added. The reaction was allowed to react at room temperature for 1 h. After the reaction was complete, the mixture was diluted with 3 mL of water and the pH was adjusted to 3 with 1M hydrochloric acid. The mixture was then extracted with ethyl acetate (6 mL x 3). The organic phases were combined, washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and concentrated to afford the crude intermediate A-4-1-33c (220.0 mg, 0.80 mmol, yield: 80.8%).

[0381] Step 3

[0382] L-Valine methyl ester hydrochloride (134.0 mg, 0.80 mmol) and 4-dimethylaminopyridine (195.0 mg, 1.60 mmol) were dissolved in N,N-dimethylformamide (2 mL). 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) were added at 0°C and allowed to react for 16 h at room temperature. After the reaction was complete, 2 mL of water was added and the mixture was extracted with ethyl acetate (4 mL x 3). The combined organic phases were washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to afford A-4-1-33 (283.0 mg, 728.67 μmol, yield: 91.2%). MS-ESI: [M+H] + =389.0. 1H NMR (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).

[0383] Preparation Example 45 Preparation of Compound A-4-1-34

[0384] first step

[0385] Compound A-4-1-34a (5.40 g, 26.34 mmol) was dissolved in anhydrous dichloromethane (100 mL). 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. The mixture was allowed to react at room temperature for 14 h. The starting material consumption was monitored by LCMS. Once the material was consumed, the mixture was diluted with 100 mL of water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL) to obtain crude compound A-4-1-34b (5.40 g, 16.93 mmol, yield: 64.4%). The crude product was used directly in the next step without purification. MS-ESI: [M-(CH3)3CO] + =245.1.

[0386] Step 2

[0387] The crude product of compound A-4-1-34b (5.40 g, 16.95 mmol) was dissolved in N,N-dimethylformamide (55 mL), and 4-dimethylaminopyridine (414.0 mg, 3.39 mmol) and N,N-diisopropylethylamine (6.60 g, 50.85 mmol) were added. Ethyl chloroformate (2.80 g, 25.46 mmol) was added dropwise under an ice-salt bath. After completion of the addition, the mixture was reacted at 0-10°C for 10 minutes and then at room temperature for 14 hours. LCMS and TLC monitoring showed no residual starting material. The reaction solution was poured into saturated sodium bicarbonate solution to quench the reaction, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the resulting 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.

[0388] Step 3

[0389] Compound A-4-1-34c (6.10 g, 15.64 mmol) was dissolved in ethyl acetate (60 mL) with hydrochloric acid and allowed to react at room temperature for 2 h. LCMS monitoring indicated no residual starting material. The reaction mixture was then dried to afford crude compound A-4-1-34d (4.50 g, 15.34 mmol, 98.1% yield, 40.4% purity).

[0390] Step 4

[0391] Compound A-4-1-34d (2.70 g, 9.31 mmol) was dissolved in N,N-dimethylformamide (30 mL), and acetyl chloride (810.0 mg, 10.32 mmol) and triethylamine (1.90 g, 18.58 mmol) were added. The reaction was allowed to react at room temperature for 14 h, and the reaction was monitored by LCMS and TLC. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. The product was purified by medium pressure to obtain compound A-4-1-34 (2.10 g, 6.14 mmol, yield: 66.3%). 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).

[0392] Preparation Example 46 Preparation of Compound B-1-1-1

[0393] first step

[0394] 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), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.50 g, 91.51 mmol) under ice-salt bath. Allow to react at room temperature for 14 h. After LCMS monitoring indicated completion of the reaction, dilute with water and extract with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated under reduced pressure to yield compound B-1-1-1b (15.00 g, 61.40 mmol, yield: 80.5%). MS-ESI: [M+H] + =245.1.

[0395] Step 2

[0396] Compound B-1-1-1b (15.00 g, 61.40 mmol) was dissolved in anhydrous tetrahydrofuran (75 mL) and water (75 mL). Lithium hydroxide (1.80 g, 73.78 mmol) was added and allowed to react at room temperature for 2 h. LCMS monitoring indicated the reaction was complete. The solvent was evaporated and dilute hydrochloric acid was added to adjust the pH to 3. The mixture was extracted with dichloromethane (150 mL x 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and the dichloromethane was evaporated 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.

[0397] Step 3

[0398] 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, and 2-bromomethyl methyl ether (3.30 g, 26.09 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 14 h. LCMS monitoring indicated the reaction was complete. The reaction solution was diluted with water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was then 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 H NMR(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(d d,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).

[0399] Preparation Example 47 Preparation of Compound B-1-1-2

[0400] Compound B-1-1-1c (2.00 g, 8.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 2-bromoethyl methyl ether (3.60 g, 26.12 mmol) and cesium carbonate (14.20 g, 43.49 mmol) were added. 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. The product 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).

[0401] Preparation Example 48 Preparation of Compound B-1-1-3

[0402] Compound B-1-1-1c (2.00 g, 8.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and cyclopentane bromide (3.9 g, 26.11 mmol) and cesium carbonate (14.2 g, 43.49 mmol) were added. The mixture was heated to 80°C for 14 h. LCMS monitoring indicated 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. The product was then 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).

[0403] Preparation Example 49 Preparation of Compound B-1-2-1

[0404] first step

[0405] 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 sequentially 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 the compound B-1-2-1b (2.10 g, 8.69 mmol, yield: 76.0%) was prepared by preparative liquid chromatography.

[0406] Step 2

[0407] Compound B-1-2-1b (2.10 g, 8.69 mmol) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL) and stirred at room temperature for 1 h. LCMS monitoring indicated that the reaction was complete, and the mixture was concentrated under reduced pressure to give compound B-1-2-1c (1.50 g, 8.26 mmol, yield: 93.8%). MS-ESI: [M+H] + =146.1.

[0408] Step 3

[0409] 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 sequentially at 0°C. The mixture was 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 the reaction. The mixture was concentrated under reduced pressure to remove N,N-dimethylformamide and the mixture was heated under medium pressure to obtain compound B-1-2-1 (1.80 g, 6.90 mmol, yield: 83.5%). MS-ESI: [M+H] + =259.3. 1 H 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).

[0410] Preparation Example 50 Preparation of Compound C-1-1-1

[0411] 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. A 2.0 M aqueous lithium hydroxide solution (10 mL) was then added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. The reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction solution was added to water (50 mL) and extracted with ethyl acetate (50 mL x 2). The aqueous phase was adjusted to a pH of approximately 4 with dilute hydrochloric acid (1.0 M), and then extracted with ethyl acetate (100 mL x 5). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain product C-1-1-1 (0.86 g, 2.95 mmol, yield: 90.0%). MS-ESI: [M+H] + =293.2. 1 H NMR (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).

[0412] Preparation Example 51 Preparation of Compound A-4-1-41

[0413] first step

[0414] To a solution of compound A-4-1-41a (3.0 g, 12.2 mmol) in dichloromethane (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.51 g, 18.3 mmol), 1-hydroxybenzotriazole (2.49 g, 18.3 mmol), and N,N-diisopropylethylamine (7.88 g, 61 mmol). 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. The mixture was concentrated under reduced pressure and 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] + .

[0415] Step 2

[0416] Intermediate A-4-1-41b (1.9 g, 5.3 mmol) was dissolved in trifluoroacetic acid / dichloromethane (V / V = 1:3, 20 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and freeze-dried to give intermediate A-4-1-41c (1.8 g, yellow oil, crude product). MS (ESI) m / z: 259 [M+H] + .

[0417] Step 3

[0418] To a solution of intermediate A-4-1-41c (1.2 g, 4.6 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.33 g, 18 mmol). The reaction system was cooled to 0°C and deuterated acetyl chloride (450 mg, 5.52 mmol) was slowly added. The reaction was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by medium-pressure preparative column chromatography to give 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).

[0419] Preparation Example 52 Preparation of Compound A-4-1-36

[0420] first step

[0421] In a 200 mL single-necked bottle, add compound A-4-1-36a (3.5 g, 14.26 mmol) and N,N-dimethylformamide (100 mL), cool to 0°C, add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (6.5 g, 17.11 mmol), add N,N-diisopropylethylamine (5.53 g, 42.78 mmol), stir at 0°C for 10 minutes, then add L-valine methyl ester hydrochloride (4.78 g, 28.52 mmol), and react at 0°C for 2 hours. After LCMS monitoring showed that the reaction was complete, the reaction solution was diluted with water and 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 purified by 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] + .

[0422] Step 2

[0423] In a 200 mL single-necked flask, compound A-4-1-36b (4.1 g, 11.43 mmol), dichloromethane (50 mL), and hydrogen chloride (1,4-dioxane solution, 4.0 M, 50 mL) were added and allowed to react at room temperature for 2 hours. After LCMS and TLC monitoring showed the reaction was complete, the reaction solution was concentrated under reduced pressure and the crude product was used directly in the next reaction. Compound A-4-1-36c (2.8 g, 10.84 mmol, yield 94.83%) was obtained. ESI-LCMS: m / z 259.2 [M+H] + .

[0424] Step 3

[0425] In a 200 mL single-necked flask, compound A-4-1-36c (2.8 g, 10.84 mmol) and dichloromethane (100 mL) were added, cooled to -10°C, and N,N-diisopropylethylamine (7.0 g, 54.2 mmol) was slowly added. After stirring at -10°C for 10 minutes, acetyl chloride (1.27 g, 16.26 mmol) was slowly added and allowed to react at -10°C for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound A-4-1-36 (1.4 g, 4.66 mmol, yield 42.98%). ESI-LCMS: m / z 301.1 [M+H] + . 1H NMR (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).

[0426] Preparation Example 53 Preparation of Compound A-4-1-39

[0427] first step

[0428] 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. 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 complete, the temperature was slowly raised to room temperature and the reaction was allowed to react 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 phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product A-4-1-39b (1.72 g, 4.72 mmol, yield: 59%) was obtained by MPLC purification.

[0429] Step 2

[0430] In a dry 100 mL three-necked flask, A-4-1-39b (1.72 g, 4.72 mmol) and dichloromethane (20 mL) were added, followed by the slow dropwise addition of trifluoroacetic acid (8 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours and monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to afford the product A-4-1-39c (1.20 g, 4.54 mmol, yield: 96%). MS m / z (ESI): 265.3 [M+H] + .

[0431] Step 3

[0432] In a dry 100mL three-necked flask, A-4-1-39c (1.00g, 3.78mmol) and dichloromethane (20mL) were thoroughly stirred, and then deuterated acetic acid (0.36g, 5.67mmol) was added. 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 complete, the temperature was slowly raised to room temperature and the reaction was allowed to react 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, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain 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).

[0433] Preparation Example 54 Synthesis of Compound A-1-1-2

[0434] first step

[0435] A1-1-1d (440 mg, 2.18 mmol) was added to a 100 mL single-necked flask and dissolved in anhydrous dichloromethane (8 mL). N,N-diisopropylethylamine (842 mg, 6.53 mmol) was added and stirred in an ice bath for 10 minutes. A solution of cyclopropaneyl chloride (274 mg, 2.62 mmol) in dichloromethane (1 mL) was added and allowed to react for one hour. Completion of the reaction was confirmed by TLC and LCMS. Saturated aqueous sodium bicarbonate solution (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The residue was purified by reverse phase MPLC and lyophilized to obtain A-1-1-2a (320 mg, 1.18 mmol, 54.1% yield) as a white solid. ESI-LCMS: m / z 271.2 [M+H] + .

[0436] Step 2

[0437] A-1-1-2a (292 mg, 1.08 mmol), methanol (5 mL), and lithium hydroxide aqueous solution (2.0 M, 5 mL) were added sequentially to a 100 mL single-necked flask and reacted at room temperature for 1.5 hours. The reaction was confirmed to be complete by TLC and LCMS. The mixture was concentrated to remove methanol, diluted with water, and adjusted to pH 5 with dilute hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, dried, and concentrated to obtain intermediate A-1-1-2b (160 mg, 0.62 mmol, yield 57.4%). ESI-LCMS: m / z 257.2 [M+H] + .

[0438] Step 3

[0439] A-1-1-2b (160 mg, 0.62 mmol), N,N-dimethylformamide (5 mL), potassium carbonate (261 mg, 1.89 mmol), and deuterated iodomethane (183 mg, 1.26 mmol) were added sequentially to a 100 mL single-necked bottle and reacted at room temperature for one hour. After completion of the reaction was confirmed by TLC and LCMS, water (100 mL) was added to quench the reaction 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 the white solid product A-1-1-2 (55 mg, 0.2 mmol, yield 32%). ESI-LCMS: m / z 274.2 [M+H] + . 1 H NMR (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).

[0440] Preparation Example 55 Synthesis of Compound A-1-1-3

[0441] A-1-1-3a (122 mg, 1.0 mmol), A-1-1-1d (202 mg, 1.0 mmol), anhydrous dichloromethane (2 mL), and DIPEA (388 mg, 3.0 mmol) were added to a 100 mL single-necked bottle in sequence. The mixture was stirred at 0°C for 5 minutes, and PYBOP (677 mg, 1.3 mmol) was added. The reaction was allowed to react for 30 minutes. TLC and LCMS showed that the reaction was complete. 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 the 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).

[0442] Preparation Example 56 Synthesis of Compound A-1-1-6

[0443] first step

[0444] To a solution of A-1-1-6a (123 mg, 1 mmol) in anhydrous dichloromethane (2 mL) was slowly added thionyl chloride (178 mg, 1.5 mmol) dropwise, and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was distilled under reduced pressure and redissolved in anhydrous dichloromethane (3 mL). To this solution were added A-1-1-1d (202 mg, 1 mmol) and N,N-diisopropylethylamine (388 mg, 3 mmol), and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was concentrated, and the crude product was purified by flash 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] + . 1H 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).

[0445] Preparation Example 57 Synthesis of Compound A-1-1-7

[0446] A-1-1-7a (161 mg, 1.0 mmol), A-1-1-1d (202 mg, 1.0 mmol), anhydrous dichloromethane (2 mL), and N,N-diisopropylethylamine (388 mg, 3.0 mmol) were added to a 100 mL single-necked bottle in sequence. The mixture was stirred at 0°C for 5 minutes, and PYBOP (677 mg, 1.3 mmol) was added. The reaction was allowed to proceed for 30 minutes. After TLC monitoring showed that the reaction was complete, water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by flash preparative chromatography to obtain compound A-1-1-7 (181 mg, 0.52 mmol, yield 52.0%). ESI-LCMS: m / z 344.2 [MH] - . 1 H 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).

[0447] Preparation Example 58 Synthesis of Compound A-1-1-8

[0448] A-1-1-8a (166 mg, 1.5 mmol), A-1-1-1d (302 mg, 1.5 mmol), anhydrous dichloromethane (2 mL), and N,N-diisopropylethylamine (582 mg, 4.5 mmol) were added to a 100 mL single-necked bottle in sequence. The mixture was stirred at 0°C for 5 minutes, and PYBOP (1041 mg, 2.0 mmol) was added. The reaction was allowed to proceed for 30 minutes. After LCMS monitoring showed that the reaction was complete, water (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by flash 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).

[0449] Preparation Example 59 Synthesis of Compound A-1-1-9

[0450] A-1-1-9a (165 mg, 1.0 mmol), A-1-1-1d (260 mg, 1.3 mmol), anhydrous dichloromethane (2 mL), and N,N-diisopropylethylamine (504 mg, 3.9 mmol) were added to a 100 mL single-necked bottle in sequence. The mixture was stirred at 0°C for 5 minutes, and PYBOP (885 mg, 1.7 mmol) was added. The reaction was allowed to proceed for 30 minutes. After LCMS monitoring showed that the reaction was complete, water (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Compound A-1-1-9 (14 mg, 0.05 mmol, yield 5%) was obtained by flash preparative chromatography. ESI-LCMS: m / z 313.0 [M+H] + . 1H 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).

[0451] Preparation Example 60 Synthesis of Compound A-1-1-11

[0452] first step

[0453] The intermediate raw material A-1-1-1d (0.51 g, 2.52 mmol) and 2-(4-(tert-butyramido)piperazin-1-yl)acetic acid (0.62 g, 2.52 mmol) were dissolved in DMF (20 mL) and cooled to -20°C. 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, then warmed to room temperature and stirred overnight. After the reaction was completed as monitored by TLC, 20 mL of water was added. After separation, the aqueous phase was extracted three times with ethyl acetate (100 mL×3). 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 A-1-1-11a (0.38 g, 0.89 mmol, yield: 35%). MS-ESI: M / Z = 429.3 [M+H] + .

[0454] Step 2

[0455] 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 complete, stirring was continued at room temperature. After the reaction was completed, the solid was filtered and washed with ethyl acetate (50 mL) and dried under vacuum to obtain the product A-1-1-11 (0.17 g, 0.47 mmol, yield: 52%). MS-ESI: M / Z = 329.3 [M+H] + . 1H 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).

[0456] Preparation Example 61 Synthesis of Compound A-1-2-3

[0457] first step

[0458] 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), and sodium tert-butoxide (1.04 g, 10.8 mmol) were added to a 100 mL single-necked bottle. Anhydrous 1,4-dioxane (20 mL) was added. After nitrogen replacement three times, the reaction was carried out at 90°C for 3 hours. After the reaction was confirmed to be complete by TLC and LCMS, the reaction solution was filtered and concentrated. The residue was purified by normal phase column 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] + .

[0459] Step 2

[0460] A1-2-3b (520 mg, 1.86 mmol), methanol (4 mL), and lithium hydroxide solution (2.0 M, 4 mL) were added sequentially to a 100 mL single-necked bottle and reacted at room temperature for 2 hours. After the reaction was confirmed to be complete 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, and the filtrate was collected and concentrated to obtain intermediate A-1-2-3c (480 mg, 1.81 mmol). ESI-LCMS: m / z 264.2 [MH] - .

[0461] Step 3

[0462] In a 100 mL single-necked flask, A-1-2-3c (448 mg, 1.69 mmol), potassium carbonate (701 mg, 5.07 mmol), deuterated iodomethane (490 mg, 3.38 mmol), and anhydrous N,N-dimethylformamide (5 mL) were added in sequence. The reaction was allowed to react at room temperature for 1 hour. After LCMS monitoring showed that the reaction was complete, water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by flash preparative chromatography to obtain compound A-1-2-3 (104 mg, 0.37 mmol, yield 21.9%). ESI-LCMS: m / z 283.2 [M+H] + . 1 H NMR(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).

[0463] Preparation Example 62 Synthesis of Compound A-1-2-7

[0464] 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). After nitrogen substitution three times, the temperature was raised to 100°C and the reaction was allowed to proceed for 5 hours. After completion of the reaction as monitored by TLC and LCMS, the reaction solution was diluted with dichloromethane (100 mL) and washed once with water. After separation, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification by MPLC, compound A1-2-7 (87 mg, 0.25 mmol, white oil) was obtained in a 50% yield. MS m / z (ESI): 348.2 [M+H] + . 1H NMR (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).

[0465] Preparation Example 63 Synthesis of Compound A-1-2-13

[0466] Intermediate A-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 portionwise to the reaction mixture and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with dichloromethane (50 mL) and then washed with water. After separation, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After MPLC purification, the product A-1-2-13 (0.11 g, 0.39 mmol, yield: 38%) was obtained. 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).

[0467] Preparation Example 64 Preparation of Comparative Compound ZZL-7

[0468] first step

[0469] Add (tert-Butyloxycarbonyl)-L-alanine (4.50 g, 23.78 mmol) to a dry single-necked flask, 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 flask in sequence and stir at room temperature for 2 h. After TLC showed the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was adjusted to acidity with 2M hydrochloric acid. The mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined and adjusted to alkalinity with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (50 mL x 2). The organic phases were 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

[0470] Step 2

[0471] To a dry, single-necked flask, add (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.50 g, 21.50 mmol) and dissolve in dichloromethane (30 mL). Then, add hydrochloric acid-1,4-dioxane (10 mL, 4 M) and stir at room temperature for 2 h. After TLC indicated completion of the reaction, the organic phase was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford 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).

[0472] Step 3

[0473] 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). The mixture was thoroughly purged with nitrogen and stirred at 0°C. After 10 minutes, acetic anhydride (2.80 g, 27.48 mmol) was slowly added dropwise. The mixture was stirred at the same temperature for 10 minutes and then moved to room temperature and stirred for 2 hours. After TLC indicated the reaction was complete, water (50 mL) was added to quench the reaction. The mixture was acidified with 2M hydrochloric acid and extracted with dichloromethane (50 mL x 4). The combined organic phases were 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). This afforded acetyl-L-alanyl-L-valine methyl ester (2.60 g, 10.67 mmol, yield: 58.2%), 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).

[0474] Preparation Example 65 Preparation of Compound A-4-1-37

[0475] first step

[0476] In a 200 mL single-necked bottle, add A-4-1-37a (3.0 g, 12.22 mmol) and N,N-dimethylformamide (100 mL), cool to 0°C, add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (5.57 g, 14.66 mmol), add N,N-diisopropylethylamine (4.73 g, 36.66 mmol), stir at 0°C for 10 minutes, then add L-valine methyl ester hydrochloride (4.09 g, 24.44 mmol), and react at 0°C for 2 hours. After LCMS monitoring showed that the reaction was complete, the reaction solution was diluted with water and 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%).

[0477] ESI-LCMS: m / z 359.3 [M+H] + .

[0478] Step 2

[0479] In a 200 mL single-necked flask, compound A-4-1-37b (3.9 g, 10.88 mmol), dichloromethane (50 mL), and a 4.0 M solution of hydrogen chloride in 1,4-dioxane (50 mL) were added and allowed to react at room temperature for 2 hours. After LCMS and TLC monitoring indicated completion of the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was used directly in the next reaction. This afforded compound A-4-1-37c (2.7 g, 10.45 mmol, 96.04% yield).

[0480] ESI-LCMS: m / z 259.2[M+H] + .

[0481] Step 3

[0482] In a 200 mL single-necked flask, compound A-4-1-37c (2.7 g, 10.45 mmol) and dichloromethane (100 mL) were added, cooled to -10°C, and N,N-diisopropylethylamine (6.75 g, 52.25 mmol) was slowly added. After stirring at -10°C for 10 minutes, acetyl chloride (1.23 g, 15.67 mmol) was slowly added, and the mixture was allowed to react at -10°C for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound A-4-1-37 (1.5 g, 4.99 mmol, yield 47.75%).

[0483] ESI-LCMS: m / z 301.2[M+H] + .

[0484] 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).

[0485] Experimental Example 1 Plasma stability determination

[0486] 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. A certain volume of acetonitrile stock solution of the test compound (concentration of 10mM) was taken and diluted to 1mM with acetonitrile as the test solution. A certain volume of the test solution of the compound was taken, and the corresponding volume of plasma was added and mixed evenly so that the concentration of the test compound in the incubation system was 5μM and the content of organic solvent acetonitrile was 0.5%. 50μL of mixed plasma was placed in a 96-well plate (N=2), incubated in a 37°C water bath for a certain period of time, and then 300μL of methanol solution containing the internal standard was added to terminate the reaction. The supernatant was vortexed and centrifuged to obtain 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. A curve was drawn using the remaining percentage of the compound and the incubation time to obtain the k value and calculate the half-life of each compound. The formula is as follows:

[0487] 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.

[0488] Table 1 Plasma stability data of some compounds Note: If the remaining percentage of the compound is still greater than 80% after 120 minutes, then T 1 / 2 Recorded as >372.68min.

[0489] Experimental Example 2 Pharmacokinetics Test

[0490] 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.

[0491] Table 2 shows the area under the concentration-time curve (AUC) and bioavailability (F) data of some compounds after oral administration. The results show that the example compounds of the present invention have good pharmacokinetic properties and are significantly better than ZZL-7.

[0492] Table 2 Pharmacokinetic data of some compounds Note: The dosage of ZZL-7 is 100 mg / kg, PO.

[0493] Experimental Example 3 In vivo drug efficacy test (1)

[0494] 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 acclimated for one week, and seven experiments were randomly performed within one week, including food and water deprivation, electrical stimulation of the sole of the foot, moist bedding, cage tilt, behavioral restraint, rocking basket, and olfactory stimulation, to achieve unpredictability. The stimulation was continued for 4 weeks. [3] After the model was successfully evaluated, the efficacy was evaluated. The experiment was 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 was administered orally at a dose of 25 mg / kg, and a tail suspension test (TST) was performed 2 hours later. [4,5] To assess the depression of mice, prolonged immobility during the TST indicated behavioral despair. Data were aggregated and analyzed using SPSS statistical software, and graphs were plotted using Graph Pad software based on the SPSS analysis results.

[0495] The results of the tail suspension test are shown in FIG1 . 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.

[0496] Experimental Example 4 In vivo drug efficacy test (2)

[0497] 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 acclimated for one week, and seven experiments were randomly performed within one week, including food and water deprivation, electrical stimulation of the sole of the foot, moist bedding, cage tilt, behavioral restraint, rocking basket, and olfactory stimulation, to achieve unpredictability. The stimulation was continued for 4 weeks.[3] After the model was successfully evaluated, the efficacy was evaluated. The experiment was 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 was administered intravenously (iv) or intraperitoneally (ip) at a dose of 100 mg / kg. After 2 hours, the tail suspension test (TST) and forced swimming test (FST) were performed. [4,5] Depression in mice was assessed by prolonged immobility in the TST and FST, indicating behavioral despair. Data were aggregated and analyzed using SPSS statistical software, and graphs were plotted using Graph Pad software based on the SPSS analysis results.

[0498] The results of the forced swimming test are shown in Figure 2, and the results of the tail suspension test are shown in Figure 3. 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, demonstrating that the example compounds of the present invention have a rapid antidepressant effect.

[0499] References:

[0500] [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.

[0501] [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.

[0502] [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&Biobehavioral Reviews 127(2021):647-658.

[0503] [4]Can,Adem,et al."The mouse forced swim test."JoVE(Journal of Visualized Experiments)59(2012):e3638.

[0504] [5]Can,Adem,et al."The tail suspension test."JoVE(Journal of Visualized 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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