Nitrogen-containing heterocyclic compound, and preparation method and use therefor

Abstract

A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, and a preparation method and use therefor. The compound can be used for preparing quick-acting antidepressant drugs.

Description

A nitrogen-containing heterocyclic compound, its preparation method and application 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 purpose of the present invention includes providing a nitrogen-containing heterocyclic compound, and a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof;

[0007] Another object of the present invention includes providing a pharmaceutical composition comprising a therapeutically effective amount of 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;

[0008] Another object of the present invention includes providing 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 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 compound of the above general formula.

[0010] To achieve the above-mentioned purpose, the technical solutions adopted by the present invention include:

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

[0012] in:

[0013] X is a bond or CHR5;

[0014] Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time;

[0015] Z3 is CHR6 or carbonyl;

[0016] Z4, Z5 and Z6 are independently selected from CR6, N;

[0017] n is an integer from 0 to 4; R1 is hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7-N(CO)-, or C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C4-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 Heteroaryl; R2 is optionally selected from carboxyl, C1-C 15 Chain alkoxycarbonyl, C1-C 15 Heterochain alkoxycarbonyl, C3-C 15 Cycloalkoxycarbonyl, C4-C 15 Heterocycloalkoxycarbonyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0018] R3 and R4 are independently selected from hydrogen or 0 to 8 C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C4-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0019] R5 is optionally selected from hydrogen, C1-C5 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl;

[0020] R6 is optionally selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -COR7, -SOR7, -SO2R7, -NR7COR8, -CONR7R8, -OCOR7, -COOR7, -OCOOR7, -OCONR7R8, -NR7CONR8R9, -NR7COOR8, -NR7SO2R8, -SO2NR7R8, -OSO2R7, -SO3R7, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of 0 to 8 R 10 replace;

[0021] R7, R8, and R9 are independently selected from hydrogen, linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is independently substituted with 0 to 8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl, or haloalkyl groups;

[0022] R 10 is selected from hydrogen, halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently substituted with 0 to 8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl, or haloalkyl groups;

[0023] Wherein, the general formula (IA) does not contain compounds Formula (IB) does not include compounds

[0024] The present invention also provides a compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer or racemate thereof:

[0025] in:

[0026] X is a bond or CHR5;

[0027] Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time;

[0028] Z3 is CHR6 or carbonyl;

[0029] Z4, Z5 and Z6 are independently selected from CR6 or N;

[0030] n is an integer from 0 to 4;

[0031] R1 is selected from hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7N(CO)-, 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 R6; or, R1 is 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 R6;

[0032] R2 is selected from -(CO)O-(CH2) m R6, wherein m is an integer from 0 to 4, or R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 Aryl or 5-15 membered heteroaryl is optionally substituted with 0 to 8 R6;

[0033] R3, R4 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 R6, R3 and R4 are not hydrogen at the same time; or, R3, R4 are 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 R6;

[0034] R5 is selected from hydrogen, C1-C5 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocycloalkyl;

[0035] R6 is selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -(CO)-R7, -(SO)-R7, -(SO2)-R7, -NR7-(CO)-R8, -(CO)-NR7R8, -O(CO)-R7, -(CO)OR 7. -O(CO)OR7, -O(CO)-NR7R8, -NR7-(CO)-NR8R9, -NR7-(CO)OR8, -NR7-(SO2)-R8, -(SO2)-NR7R8, -O(SO2)-R7, -(SO2)OR7, 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 10 Substituted; or, R6 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 10 replace;

[0036] R7, R8, and R9 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 is optionally substituted by 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl; or R7, R8, R9 are independently selected from C1-C1 containing heteroatoms 15Chain 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 with 0 to 8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0037] R 10 Selected from hydrogen, halogen, 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 or 5-15 membered heteroaryl group is optionally substituted with 0-8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0038] Wherein, formula (Ia) does not include the following compounds:

[0039] Formula (Ib) does not include the following compounds:

[0040] In some embodiments, wherein,

[0041] X is a bond;

[0042] Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time;

[0043] Z3 is CHR6 or carbonyl;

[0044] Z4, Z5 and Z6 are independently selected from CR6 or N;

[0045] n is an integer from 0 to 4;

[0046] R1 is selected from hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7N(CO)-, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C15 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 with 0 to 8 R6;

[0047] R2 is selected from -(CO)O-(CH2) m R6, wherein m is an integer from 0 to 4, or R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 Aryl or 5-15 membered heteroaryl is optionally substituted with 0 to 8 R6;

[0048] R3 and R4 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted with 0 to 8 R6; R3 and R4 are not hydrogen at the same time;

[0049] R6 is selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -(CO)-R7, -(SO)-R7, -(SO2)-R7, -NR7-(CO)-R8, -(CO)-NR7R8, -O(CO)-R7, -(CO)OR 7. -O(CO)OR7, -O(CO)-NR7R8, -NR7-(CO)-NR8R9, -NR7-(CO)OR8, -NR7-(SO2)-R8, -(SO2)-NR7R8, -O(SO2)-R7, -(SO2)OR7, 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 10 replace;

[0050] R7, R8, and R9 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C15 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 0-8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0051] R 10 Selected from hydrogen, halogen, 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 or 5-15 membered heteroaryl group is optionally substituted with 0-8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups.

[0052] In some embodiments, wherein,

[0053] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-1), and the compound represented by formula (Ib) is a compound represented by the following formula (Ib-1)

[0054] wherein R1, R2, Z1, Z2, Z3, Z4, Z5, Z6 and n are as defined above.

[0055] In some embodiments, wherein,

[0056] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-1'),

[0057] wherein R1, R2, R3, and R4 are as defined above.

[0058] In some embodiments, wherein,

[0059] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-2),

[0060] wherein R1 and R2 are as defined above.

[0061] In some embodiments, wherein,

[0062] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-3),

[0063] wherein R2 is as defined above.

[0064] In some embodiments, wherein,

[0065] R2 is selected from -(CO)O-(CH2) m R6, wherein m is an integer from 0 to 4.

[0066] In some embodiments, wherein,

[0067] R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 The aryl or 5-15 membered heteroaryl is optionally substituted with 0 to 8 R6.

[0068] In some embodiments, wherein,

[0069] R2 is selected from:

[0070] In some embodiments, wherein,

[0071] X is a bond;

[0072] Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time;

[0073] Z3 is CHR6 or carbonyl;

[0074] Z4, Z5 and Z6 are independently selected from CR6 or N;

[0075] n is an integer from 0 to 4;

[0076] R1 is selected from hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7N(CO)-, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl is optionally substituted by 0 to 8 R6;

[0077] R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 Aryl or 5-15 membered heteroaryl is optionally substituted with 0 to 8 R6;

[0078] R3, R4 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 R6; R3 and R4 are not hydrogen at the same time;

[0079] R6 is selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -(CO)-R7, -(SO)-R7, -(SO2)-R7, -NR7-(CO)-R8, -(CO)-NR7R8, -O(CO)-R7, -(CO)OR 7. -O(CO)OR7, -O(CO)-NR7R8, -NR7-(CO)-NR8R9, -NR7-(CO)OR8, -NR7-(SO2)-R8, -(SO2)-NR7R8, -O(SO2)-R7, -(SO2)OR7, 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 10 replace;

[0080] R7, R8, and R9 are independently selected from hydrogen, C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl or 5-15 membered heteroaryl group is optionally substituted with 0-8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0081] R 10 Selected from hydrogen, halogen, 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 or 5-15 membered heteroaryl group is optionally substituted with 0-8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups.

[0082] In some embodiments, wherein,

[0083] The compound represented by formula (Ia) is a compound represented by formula (Ia-4) below, and the compound represented by formula (Ib) is a compound represented by formula (Ib-2) below

[0084] wherein R1, R2, R3, Z1, Z2, Z3, Z4, Z5, Z6 and n are as defined above.

[0085] In some embodiments, wherein,

[0086] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-5)

[0087] wherein R1, R2, and R3 are as defined above.

[0088] In some embodiments, wherein,

[0089] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-6)

[0090] wherein R2 and R3 are as defined above.

[0091] In some embodiments, wherein,

[0092] The compound is selected from any one of the following compounds:

[0093] In some embodiments, wherein,

[0094] The compound is selected from any one of the following compounds:

[0095] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound described herein, its pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer or racemate, and a pharmaceutically acceptable excipient or auxiliary ingredient.

[0096] 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 in the preparation of a medicament for preventing and / or treating depression.

[0097] In some embodiments, the drug in the above use is a fast-acting drug.

[0098] 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).

[0099] definition

[0100] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0101] 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.

[0102] "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.

[0103] "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.

[0104] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic substituent, and the cycloalkyl group contains 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, 8 carbon atoms). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include cycloalkyl groups of spirocycles, fused rings, and bridged rings. The cycloalkyl group may optionally be further substituted with one or more substituents.

[0105] "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.

[0106] "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 bicyclic ring (e.g., 6, 7, 8, 9, 10, 11, 12-membered), 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.

[0107] "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.

[0108] "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.

[0109] "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.

[0110] "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.

[0111] In this article, when When expressing chemical bonds, A chemical bond connected to a chiral center of a compound indicates that the chiral center of the compound has a single configuration, but the absolute configuration is unknown.

[0112] Beneficial technical effects achieved:

[0113] (1) The compounds of the present invention have good rapid antidepressant activity in vivo.

[0114] (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. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] FIG1 and FIG2 show the results of the tail suspension experiment in Experimental Example 5.

[0116] FIG3 shows the results of the forced swimming test in Experimental Example 6.

[0117] FIG4 shows the results of the tail suspension experiment in Experimental Example 6. DETAILED DESCRIPTION

[0118] Unless otherwise specified, all raw materials, reagents, and instruments used in the examples of the present invention are conventional commercially available products.

[0119] 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.

[0120] Preparation Example 1 Preparation of Compound A-1-7

[0121] first step

[0122] L-Valine methyl ester hydrochloride (779 mg, 4.65 mmol) and 4-dimethylaminopyridine (1.3 g, 10.80 mmol) were dissolved in N,N-dimethylformamide (10 mL), cooled to 0°C, and compound A-1-7a (600 mg, 5.40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 g, 5.94 mmol) were added. The reaction was allowed to react at room temperature for 16 hours, and TLC indicated the reaction was complete. The mixture was diluted with water (50 mL) and extracted with ethyl acetate three times (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was then purified by preparative HPLC to obtain compound A-1-7 (580 mg, 2.59 mmol, yield 47.89%). MS-ESI calculated value [M+H] + : 225.12; measured value: 224.9.

[0123] Preparation Example 2 Preparation of Compound A-1-1

[0124] first step

[0125] L-Valine methyl ester hydrochloride (686 mg, 4.09 mmol) and 4-dimethylaminopyridine (1.2 g, 9.52 mmol) were dissolved in N,N-dimethylformamide (10 mL). The mixture was cooled to 0°C and compound A-1-1a (600 mg, 4.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.32 mmol) were added. The mixture was reacted at room temperature for 16 hours. TLC indicated the reaction was complete. The mixture was diluted with water (50 mL) and extracted with ethyl acetate three times (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This was then purified by preparative HPLC to obtain compound A-1-1 (750 mg, 3.13 mmol, yield 65.8%). MS-ESI calculated value [M+H] + : 240.1; measured value: 240.0.

[0126] Preparation Example 3 Preparation of Compound A-2-1

[0127] first step

[0128] A-2-1a (5.00 g, 49.45 mmol), di-tert-butyl dicarbonate (12.95 g, 59.34 mmol), and ethanol (60 mL) were added to a 200 mL dry three-necked flask. After thorough stirring, sodium hydroxide (1.98 g, 49.45 mmol) was dissolved in water (25 mL) and added to the reaction system. The reaction was allowed to react at room temperature for 16 hours. After completion, as monitored by LCMS, the reaction was diluted with water (60 mL) and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford intermediate A-2-1b (8.60 g, 42.74 mmol, 86% yield).

[0129] Step 2

[0130] L-valine methyl ester hydrochloride (7.52 g, 44.86 mmol), 4-dimethylaminopyridine (10.45 g, 85.45 mmol), and N,N-dimethylformamide (80 mL) were added to a 200 mL dry three-necked flask. The temperature was lowered to 0°C, and compound A-2-1b (8.60 g, 42.74 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.83 g, 51.29 mmol) were added. The mixture was reacted at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed sequentially with water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to obtain intermediate A-2-1c (13.80 g, 43.90 mmol).

[0131] Step 3

[0132] The compound intermediate A-2-1c (13.80 g, 43.90 mmol) was dissolved in hydrogen chloride ethyl acetate solution (4.0 M, 100 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated and purified by medium pressure preparation to obtain intermediate A-2-1d (7.56 g, 35.28 mmol, yield 80%).

[0133] Step 4

[0134] Intermediate A-2-1d (1.0 g, 4.67 mmol) was dissolved in dichloromethane (10 ml). Acetic anhydride (6.7 g, 65.41 mmol) was added and allowed to react at room temperature for 16 hours. TLC indicated the reaction was complete. The temperature was lowered to 0°C and the pH was adjusted to 2 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate three times (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This was then purified by reverse phase preparative chromatography to obtain compound A-2-1 (500 mg, 1.95 mmol, yield 41.80%). MS-ESI calculated value [M+H] + : 257.2; measured value: 257.0.

[0135] Preparation Example 4 Preparation of Compound A-2-2

[0136] Intermediate A-2-1d (1.00 g, 4.67 mmol) was dissolved in dry dichloromethane (20 mL), and cyclopropylcarbonyl chloride (0.54 g, 5.14 mmol) was added, followed by the dropwise addition of triethylamine (1.18 g, 11.68 mmol). After the addition was complete, the reaction was allowed to react at room temperature for 1 hour. After LCMS monitoring, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure preparative purification to obtain compound A-2-2 (0.49 g, 1.74 mmol, 37% yield). MS-ESI calculated value [M+H] + : 283.2; measured value: 283.3. 1 H NMR (400MHz, DMSO-d6) δ8.58–8.21(m,1H),5.13–4.66(m,1H),4.32–4.10(m,2H),3.86–3.71(m,1H),3.64(dd,J= 6.7,4.2Hz,3H),2.48–2.30(m,1H),2.25–1.93(m,2H),1.61–1.16(m,1H),0.92–0.80(m,6H),0.80–0.51(m,4H).

[0137] Preparation Example 5 Preparation of Compound A-2-4

[0138] first step

[0139] Compound A-2-1 (0.92 g, 3.59 mmol) and THF (10 mL) were added to a 50 mL dry three-necked flask, followed by a slow dropwise addition of a 2 M sodium hydroxide aqueous solution (3 mL). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was adjusted to acidity (pH = 5) with dilute hydrochloric acid and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford the crude intermediate A-2-4a (0.80 g, 3.31 mmol, 92% yield).

[0140] Step 2

[0141] The crude intermediate A-2-4a (0.80 g, 3.31 mmol) and deuterated methanol (5 mL) were added to a 50 mL dry three-necked flask, followed by the slow addition of concentrated sulfuric acid (0.36 g, 3.64 mmol). The reaction was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was adjusted to neutral (pH = 7) with sodium hydroxide (2.0 M) and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure preparative purification to obtain the product A-2-4 (0.25 g, 0.98 mmol, 30% yield). MS-ESI calculated value [M+H] + : 260.2; measured value: 260.2. 1 H NMR(400MHz, DMSO)δ8.42(ddd,J=28.1,13.8,6.7Hz,1H),4.97–4.64(m,1H),4.32–4.13(m,1H),4.08–3.9 3(m,1H),3.83–3.62(m,1H),2.41–2.29(m,1H),2.16–1.91(m,2H),1.83–1.56(m,3H),0.96–0.77(m,6H).

[0142] Preparation Example 6 Preparation of Compound A-2-5

[0143] Intermediate A-2-1d (1.00 g, 4.67 mmol), 2-iodopyridine (1.91 g, 9.34 mmol), and N,N-dimethylformamide (30 mL) were added to a 100 mL dry three-necked flask. Pd2(dba)3 (0.85 g, 0.93 mmol), Xantphos (0.54 g, 0.93 mmol), and cesium carbonate (4.55 g, 14.01 mmol) were then added sequentially. After nitrogen replacement three times, the temperature was raised to 110°C and the reaction was allowed to proceed for 6 hours. After completion of the reaction, monitored by LCMS, the mixture was diluted with water (20 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure preparative purification to obtain product A-2-5 (0.27 g, 0.93 mmol, 20% yield). MS-ESI calculated value [M+H] + : 292.2; measured value: 292.2. 1H NMR (400MHz, DMSO-d6) δ8.71 (dd, J=87.4, 8.3Hz, 1H), 8.07 (d, J=4.0Hz, 1H), 7.63–7.52(m,1H),6.72(ddd,J=23.9,12.0,5.5Hz,1H),6.43(dd,J=8.3,5.8H z,1H),4.69(dd,J=16.5,8.5Hz,1H),4.29–4.20(m,1H),3.95–3.72(m,2H),3. 64(d,J=9.0Hz,3H),2.46–2.35(m,2H),2.16–2.00(m,1H),0.91–0.79(m,6H).

[0144] Preparation Example 7 Preparation of Compound A-2-6

[0145] first step

[0146] A-2-6a (5.00 g, 49.45 mmol), di-tert-butyl dicarbonate (12.95 g, 59.34 mmol), and ethanol (60 mL) were added to a 200 mL dry three-necked flask. After thorough stirring, sodium hydroxide (1.98 g, 49.45 mmol) was dissolved in water (25 mL) and added to the reaction system. The reaction was allowed to react at room temperature for 16 hours. After completion of the reaction, as monitored by LCMS, the product was diluted with water (60 mL) and adjusted to pH 3 with 1.0 M dilute hydrochloric acid. The product was then extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford intermediate A-2-6b (8.60 g, 42.74 mmol, 86% yield).

[0147] Step 2

[0148] L-Valine methyl ester hydrochloride (7.52 g, 44.86 mmol), 4-dimethylaminopyridine (10.45 g, 85.45 mmol), and N,N-dimethylformamide (80 mL) were added to a 200 mL dry three-necked flask. After cooling to 0°C, Intermediate A-2-6b (8.60 g, 42.74 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.83 g, 51.29 mmol) were added. The reaction was allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed sequentially with water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to obtain crude Intermediate A-2-6c (13.80 g, 43.90 mmol).

[0149] Step 3

[0150] Dissolve the crude intermediate A-2-6c (13.80 g, 43.90 mmol) in 4.0 M hydrogen chloride in ethyl acetate (100 mL) and allow to react at room temperature for 2 hours. After completion of the reaction, monitored by LCMS, the product was concentrated and purified by medium-pressure preparative purification to afford intermediate A-2-6d (7.56 g, 35.28 mmol, 80% yield).

[0151] Step 4

[0152] Intermediate A-2-6d (1.00 g, 4.67 mmol) and dichloromethane (15 mL) were added to a 50 mL dry three-necked flask, followed by the slow addition of acetic anhydride (4.76 g, 46.70 mmol). The reaction was allowed to react overnight at room temperature. After completion of the reaction, monitored by LCMS, saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution, stirred for 0.5 hours, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure preparative purification to obtain product A-2-6 (0.92 g, 3.59 mmol, 76% yield). MS-ESI calculated value [M+H] + : 257.1; measured value: 257.2. 1 H NMR (400MHz, CDCl3) δ8.31 (d, J=7.4Hz, 1H), 4.93 (dd, J=9.3, 6.5Hz, 1H), 4.41 (dd, J=8.1, 5.0Hz, 1H), 4.08 (t, J=7.7Hz, 2H) ,3.74(d,J=5.0Hz,3H),2.81–2.61(m,1H),2.47–2.34(m,1H),2.25–2.13(m,1H),1.93(s,3H),0.93(dd,J=8.5,6.9Hz,6H).

[0153] Preparation Example 8 Preparation of Compound A-2-7

[0154] first step

[0155] Compound A-2-7a (5.00 g, 49.45 mmol), di-tert-butyl dicarbonate (12.95 g, 59.34 mmol), and ethanol (60 mL) were added to a 200 mL dry three-necked flask. After thorough stirring, sodium hydroxide (1.98 g, 49.45 mmol) was dissolved in water (25 mL) and added to the reaction system. The reaction was allowed to react at room temperature for 16 hours. After completion, as monitored by LCMS, the reaction was diluted with water (60 mL) and the pH was adjusted to 3 with 1.0 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford intermediate A-2-7b (8.60 g, 42.74 mmol, 86% yield).

[0156] Step 2

[0157] L-valine methyl ester hydrochloride (7.52 g, 44.86 mmol), 4-dimethylaminopyridine (10.45 g, 85.45 mmol), and N,N-dimethylformamide (80 mL) were added to a 200 mL dry three-necked flask. The temperature was lowered to 0°C, and intermediate A-2-7b (8.60 g, 42.74 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.83 g, 51.29 mmol) were added. The mixture was reacted at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed sequentially with water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to obtain crude intermediate A-2-7c (13.80 g, 43.90 mmol).

[0158] Step 3

[0159] Dissolve the crude intermediate A-2-7c (13.80 g, 43.90 mmol) in 4.0 M hydrogen chloride in ethyl acetate (100 mL) and allow to react at room temperature for 2 hours. After completion of the reaction, monitored by LCMS, the product was concentrated and purified by medium-pressure preparative purification to afford intermediate A-2-7d (7.56 g, 35.28 mmol, 80% yield).

[0160] Step 4

[0161] Intermediate A-2-7d (1.00 g, 4.67 mmol) and dichloromethane (15 mL) were added to a 50 mL dry three-necked flask, followed by the slow addition of acetic anhydride (4.76 g, 46.70 mmol). The reaction was allowed to react overnight at room temperature. After completion of the reaction, LCMS was used to monitor the reaction. Saturated aqueous sodium bicarbonate (50 mL) was added to the reaction solution, stirred for 0.5 hours, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed sequentially with water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure preparative purification to obtain product A-2-7 (0.92 g, 3.59 mmol, yield 76%). MS-ESI calculated value [M+H] + : 257.1; measured value: 257.2. 1 H NMR (400MHz, CDCl3) δ8.28(d,J=7.9Hz,1H),4.91(dd,J=9.5,6.6Hz,1H),4.48(dd,J=8.4,4.9Hz,1H),4.13–4.00(m,2 H),3.73(s,3H),2.73–2.58(m,1H),2.52–2.35(m,1H),2.30–2.15(m,1H),1.95(s,3H),0.96(dd,J=16.1,6.9Hz,6H).

[0162] Preparation Example 9 Preparation of Compound A-2-8

[0163] Intermediate A-2-6d (1.4 g, 6.5 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (3.38 g, 26.2 mmol) was added. The nitrogen atmosphere was replaced three times, and the reaction mixture was cooled to 0°C before the dropwise addition of deuterated acetyl chloride (0.58 g, 7.19 mmol). The reaction mixture was stirred at 20°C for 1 hour, and then saturated sodium bicarbonate solution (20 mL) was added. The mixture was extracted with dichloromethane three times (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to obtain product A-2-8 (1.31 g, 5.05 mmol, yield 77.3%). MS-ESI calculated value [M+H] + : 260.2; measured value: 260. 1H NMR (400MHz, CDCl3) δ8.31(d,J=7.2Hz,1H),4.93(dd,J=9.2,6.5Hz,1H),4.41(dd,J=8.0,5.0Hz,1H),4.08(t,J=7.7Hz,2H),3.73(s,3H ), 2.71(ddd,J=19.2,13.4,7.7Hz,1H), 2.41(ddd,J=16.3,12.0,7.8Hz,1H), 2.20(td,J=13.6,6.8Hz,1H), 0.93(dd,J=8.3,7.1Hz,6H).

[0164] Preparation Example 10 Preparation of Compound A-2-9

[0165] Intermediate A-2-7d (1.5 g, 7.0 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (4.52 g, 35 mmol) was added. The mixture was purged three times under nitrogen. The reaction mixture was cooled to 0°C and deuterated acetyl chloride (630 mg, 7.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and then saturated aqueous sodium bicarbonate solution (20 mL) was added and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain product A-2-9 (1.1 g, 4.24 mmol, yield 60.6%). MS-ESI theoretical value [M+H] + : 260.2; measured value: 260.1. 1 H NMR (400MHz, CDCl3) δ8.28 (d, J=7.4Hz, 1H), 4.91 (dd, J=9.4, 6.6Hz, 1H), 4.47 (dd, J=8.4, 4.9Hz, 1H), 4.12–4. 03(m,2H),3.72(s,3H),2.70-2.60(m,1H),2.47–2.38(m,1H),2.28–2.15(m,1H),0.95(dd,J=16.2,6.9Hz,6H).

[0166] Preparation Example 11 Preparation of Compound A-2-10

[0167] Compound A-2-10 is intermediate A-2-1d, and its preparation is shown in Preparation Example 3.

[0168] Preparation Example 12 Preparation of Compound A-2-11

[0169] Compound A-2-11 is intermediate A-2-6d, and its preparation is shown in Preparation Example 7.

[0170] Preparation Example 13 Preparation of Compound A-2-12

[0171] Compound A-2-12 is intermediate A-2-7d, and its preparation is shown in Preparation Example 8.

[0172] Preparation Example 14 Preparation of Compound A-2-15

[0173] first step

[0174] Compound A-2-15a (480 mg, 3.69 mmol) and L-valine methyl ester hydrochloride (680 mg, 4.06 mmol, 1.1 eq) were dissolved in anhydrous N,N-dimethylformamide (10 mL). 4-Dimethylaminopyridine (900 mg, 7.38 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (780 mg, 4.06 mmol) were added sequentially at 0°C. After stirring at 0°C for 1 hour, the mixture was warmed to room temperature and allowed to react overnight. A small amount of water was added to quench the mixture, and after concentration to remove N,N-dimethylformamide, the mixture was dissolved in water and acetonitrile and subjected to medium pressure to obtain compound A-2-15 (347 mg, 1.43 mmol, yield 38.6%). MS-ESI calculated value [M+H] + : 244.1; measured value 244.1.

[0175] Preparation Example 15 Preparation of Compound A-2-16

[0176] first step

[0177] Compound A-2-16a (440 mg, 3.07 mmol) and L-valine methyl ester hydrochloride (567 mg, 3.38 mmol, 1.1 eq) were dissolved in anhydrous N,N-dimethylformamide (10 mL). 4-Dimethylaminopyridine (750 mg, 6.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (650 mg, 3.38 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 1 hour, then warmed to room temperature and allowed to react overnight. A small amount of water was added to quench the mixture, and after concentration to remove N,N-dimethylformamide, the mixture was dissolved in water and acetonitrile and subjected to medium pressure to obtain compound A-2-16 (465 mg, 1.81 mmol, yield 59.0%). MS-ESI calculated value [M+H] + : 257.2; measured value 257.0.

[0178] Preparation Example 16 Preparation of Compound A-2-17

[0179] first step

[0180] Compound A-2-17a (10.0 g, 41.9 mmol) was dissolved in N,N-dimethylformamide (80 mL), potassium carbonate (14.3 g, 103.47 mmol) was added thereto, and then (2-aminoethyl) benzyl carbamate (12.2 g, 62.9 mmol) was added at 0°C. The reaction solution was reacted at 100°C for 6 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain compound A-2-17b (5.8 g, yield: 39%). MS-ESI calculated value [M+H] + : 353.17; measured value: 353.16.

[0181] Step 2

[0182] Compound A-2-17b (5.8 g, 16.5 mmol) was dissolved in methanol (40 mL), and palladium carbon (580 mg) was added thereto. The reaction solution was reacted at 25°C under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium carbon was removed by filtration, di-tert-butyl dicarbonate (5.4 g, 24.8 mmol) was added to the filtrate, and the reaction was continued at room temperature for 2 hours. After the reaction was completed, the product was concentrated, and the obtained residue was separated and purified by silica gel column (dichloromethane / methanol = 20 / 1) to obtain compound A-2-17c (3.0 g, yield: 62%). MS-ESI calculated value [M+H] + : 273.14; measured value: 272.85.

[0183] Step 3

[0184] Compound A-2-17c (3.0 g, 11 mmol) was dissolved in methanol (30 mL) and lithium hydroxide (0.4 g, 16.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then lyophilized and recrystallized from methanol to obtain compound A-2-17d (2.6 g, yield: 96.6%). MS-ESI calculated value [M+H] + : 245.11; measured value: 245.11.

[0185] Step 4:

[0186] Compound A-2-17d (2.6 g, 10.6 mmol) was dissolved in N,N-dimethylformamide (30 mL), and L-valine methyl ester hydrochloride (3.54 g, 21.2 mmol), 1-hydroxybenzotriazole (2.86 g, 21.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.05 g, 21.2 mmol), and N,N-diisopropylethylamine (4.12 g, 31.8 mmol) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The product was separated and purified by silica gel column (dichloromethane / methanol = 15 / 1) and then subjected to preparative HPLC to obtain two isomers of the target product, compounds A-2-17e1 (300 mg) and A-2-17e2 (200 mg). MS-ESI calculated value [M+H] + : 358.20; measured value: 358.02.

[0187] Step 5:

[0188] Compound A-2-17e1 (300 mg, 0.84 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added thereto. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by spin drying and lyophilized to obtain compound A-2-17A (155 mg). MS-ESI calculated value [M+H] + : 258.14; measured value: 258.05. 1 H NMR(400MHz,DMSO-d6)δ9.34(s,2H),8.82-8.80(m,1H),8.66-8.61(m,1H),4.81-4.75(m,1H), 4.30-4.27(m,1H),3.68-3.66(m,3H),3.42-3.32(m,4H),2.13-2.07(m,1H),0.91-0.89(m,6H).

[0189] Compound A-2-17e2 (200 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added thereto. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by spin drying, and compound A-2-17B (73 mg) was obtained by preparative HPLC. MS-ESI calculated value [M+H] + : 258.14; measured value: 258.00. 1H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.81(d,J=8.4Hz,1H),8.63(d,J=18.0Hz,1H),4.781(d,J=26.4H z,1H),4.33-4.27(m,1H),3.68-3.67(m,3H),3.42-3.32(m,4H),2.13-2.07(m,1H),0.91-0.89(m,6H).

[0190] Preparation Example 17 Preparation of Compound A-2-20

[0191] first step

[0192] Compound A-2-7a (10.00 g, 98.91 mmol) was dissolved in ethanol (100 mL), and then di-tert-butyl dicarbonate (43.17 g, 197.82 mmol) was added. The mixture was stirred at room temperature and 4-dimethylaminopyridine (1.74 g, 14.27 mmol) was slowly added in portions. Sodium hydroxide (3.96 g, 98.91 mmol) was dissolved in water (100 mL) and added to the reaction system. The mixture was stirred at room temperature. After 4 hours, TLC monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction system to dilute it, and the pH was adjusted to 3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude intermediate A-2-7b (22.10 g). MS-ESI theoretical value [MH] - : 200.1; measured value: 200.1.

[0193] Step 2

[0194] At room temperature, intermediate A-2-7b (10.00 g, 49.70 mmol) and L-valine methyl ester hydrochloride (10.00 g, 59.64 mmol) were added to a single-necked flask and dissolved in dichloromethane (150 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (22.68 g, 59.64 mmol) and triethylamine (10.06 g, 99.40 mmol) were then added sequentially. After stirring at room temperature for 16 hours, TLC indicated the reaction was complete. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed sequentially with water (500 mL × 3) and saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 2) to obtain intermediate A-2-7c (13.84 g, 44.02 mmol, yield 88.6%).

[0195] Step 3

[0196] Add intermediate A-2-7c (3.00 g, 9.54 mmol) to a single-necked flask, followed by a hydrochloric acid ethyl acetate solution (3.0 M, 5 mL). Stir at room temperature for 4 hours. After TLC indicates the reaction is complete, concentrate to obtain intermediate A-2-20a (2.02 g, 8.07 mmol, 84.4% yield). MS-ESI theoretical value [M+H] + : 215.1; measured value: 215.3.

[0197] Step 4

[0198] To a dry three-necked flask, add cyclopropylcarboxylic acid (0.12 g, 1.44 mmol), N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (0.67 g, 2.40 mmol), N-methylimidazole (0.20 g, 2.40 mmol), and triethylamine (0.20 g, 1.98 mmol). Add dichloromethane (5 mL) and stir for 0.5 hours. Then, add intermediate A-2-20a (0.30 g, 1.20 mmol) and react at room temperature for 2 hours. After completion of the reaction, spin dry the solvent, add water (10 mL), and extract with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-20 (135.3 mg, 0.48 mmol, yield: 40.1%). MS-ESI theoretical value [M+H] + : 283.2; measured value: 283.3. 1 H NMR(400MHz,Chloroform-d)δ8.25(d,J=8.5Hz,1H),4.91(dd,J=9.5,6.5Hz,1H), 4.47(dd,J=8.2,4.8Hz,1H),4.20(q,J=6.5,4.5Hz,2H),3.72(s,3H),2.67(d,J=9 .6Hz,1H),2.59–2.37(m,1H),2.30–2.08(m,1H),1.44(tq,J=11.2,6.9,5.7Hz,1H ), 1.03 (dt, J=11.7, 5.2Hz, 2H), 0.93 (dd, J=20.5, 6.9Hz, 6H), 0.87–0.78 (m, 2H).

[0199] Preparation Example 18 Preparation of Compound A-2-21

[0200] first step

[0201] In a dry three-necked flask, compound A-2-6a (5.20 g, 51.43 mmol) was added to a sodium hydroxide aqueous solution (1 M, 50 mL) at 0°C. After dissolution, ethanol (50 mL) was added. Di-tert-butyl dicarbonate (13.47 g, 61.72 mmol) was added dropwise at this temperature, and the reaction was stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to 4-5 with saturated citric acid solution, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate A-2-6b (9.59 g, 47.66 mmol, yield 92.7%). MS-ESI theoretical value [MH] - : 200.1; measured value: 200.1. 1 H NMR (400MHz, Chloroform-d) δ9.19 (s, 1H), 4.77 (s, 1H), 3.94 (q, J = 7.7Hz, 2H), 2.48 (s, 2H), 1.46 (s, 9H).

[0202] Step 2

[0203] In a dry three-necked flask, dissolve N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (22.68 g, 59.64 mmol) and triethylamine (10.00 g, 99.40 mmol) in dichloromethane (100 mL) at 0°C and cool to 0°C. Add intermediate A-2-6b (9.59 g, 47.66 mmol) and stir for half an hour before adding L-valine methyl ester hydrochloride (7.82 g, 59.64 mmol). React at room temperature for 16 hours. After completion of the reaction, add water (100 mL) and extract with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain intermediate A-2-6c (11.50 g, 36.58 mmol, yield 76.8%). MS-ESI theoretical value [MH] - : 313.2; measured value: 313.0. 1H NMR(400MHz,DMSO-d6)δ8.17(d,J=8.3Hz,1H),4.72–4.50(m,1H),4.22(dd,J=8.2,6.1Hz,1H),3.85– 3.66(m,2H),3.64(s,3H),2.36(s,1H),2.13–1.82(m,2H),1.42–1.27(m,9H),0.88(d,J=6.8Hz,6H).

[0204] Step 3

[0205] In a dry three-necked flask, dissolve intermediate A-2-6c (2.50 g, 7.95 mmol) in 5 mL of dichloromethane at 0°C and add a 4 M solution of hydrogen chloride in dioxane (20 mL) dropwise. After addition, bring the mixture to room temperature and continue stirring. After the reaction is complete, concentrate to obtain intermediate A-2-21a (2.00 g, 7.95 mmol, 100%). MS-ESI theoretical value [M+H] + : 215.1; measured value: 215.3.

[0206] Step 4

[0207] To a dry three-necked flask, add cyclopropylcarboxylic acid (0.15 g, 1.20 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.23 g, 1.20 mmol), 1-hydroxybenzotriazole (0.16 g, 1.20 mmol), and triethylamine (0.20 g, 1.60 mmol). Add dichloromethane (5 mL) and stir for 0.5 hours. Then add intermediate A-2-21a (0.25 g, 1.00 mmol) and react at room temperature for 2 hours. After completion of the reaction, concentrate, add water (10 mL), and extract with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-21 (99.1 mg, 0.35 mmol, yield: 35.2%). MS-ESI theoretical value [M+H] + : 283.2; measured value: 283.3. 1H NMR(400MHz,Chloroform-d)δ8.42(d,J=8.2Hz,1H),4.93(dd,J=9.4,6.4Hz,1H),4.40(dd,J= 8.2,5.0Hz,1H),4.20(ddd,J=12.0,8.9,4.8Hz,2H),3.63(s,3H),2.74(ddd,J=12.5,9.2,6.2H z,1H),2.44(dtd,J=11.9,9.2,5.5Hz,1H),2.18(td,J=7.2,5.3Hz,1H),1.42(td,J=8.0,4.1H z, 1H), 1.01 (q, J = 3.8Hz, 2H), 0.90 (dd, J = 16.3, 6.9Hz, 6H), 0.82 (dtd, J = 9.3, 5.9, 2.7Hz, 2H).

[0208] Preparation Example 19 Preparation of Compound A-2-22

[0209] Benzoic acid (146.5 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (299.0 mg, 1.56 mmol), and 1-hydroxybenzotriazole (210.8 mg, 1.56 mmol) were added to a single-necked flask and dissolved in dichloromethane (5 mL). The mixture was stirred at 0°C for 0.5 hours. Intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (465.3 mg, 3.60 mmol) were then added sequentially. The mixture was stirred at room temperature overnight and the reaction progress was monitored by TLC. After TLC indicated the reaction was complete, water (10 mL) was added to quench the reaction, followed by extraction and separation. The aqueous phase was then extracted with dichloromethane (10 mL x 2). The organic phase was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to give product A-2-22 (227.0 mg, 0.71 mmol, yield 59.59%). MS-ESI theoretical value [M+H] + : 319.2; measured value: 319.3. 1H NMR(400MHz,Chloroform-d)δ7.61-7.57(m,2H),7.46-7.41(m,1H),7.37(dd,J=8.1,6.5Hz,2H),5.09-4.98(m,1H),4.47(dd,J=8.6,4.9Hz,1H ), 4.30(td,J=8.9,5.6Hz,1H),4.06(q,J=8.1Hz,1H),3.64(s,3H),2.69(s,1H),2.43(s,1H),2.23-2.09(m,1H),0.89(dd,J=21.6,6.9Hz,6H).

[0210] Preparation Example 20 Preparation of Compound A-2-23

[0211] Benzoic acid (0.19 g, 1.54 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.29 g, 1.54 mmol), 1-hydroxybenzotriazole (0.21 g, 1.54 mmol), and triethylamine (0.26 g, 2.56 mmol) were added to a dry three-necked flask. Dichloromethane (5 mL) was added and the mixture was stirred for 0.5 hours. Intermediate A-2-21a (0.32 g, 1.28 mmol) was then added and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated, water (10 mL) was added, and extraction was performed with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-23 (69.0 mg, 0.22 mmol, yield: 17.0%). MS-ESI theoretical value [M+H] + : 319.2; measured value: 319.3. 1 H NMR(400MHz,Chloroform-d)δ8.09-7.85(m,1H),7.65-7.60(m,2H),7.50(t,J=7.2Hz,1H),7.43(t,J=7.4Hz,2H),5.12(t,J=8.1Hz,1H),4.48(dd,J=8.4 ,5.0Hz,1H),4.36(td,J=8.9,5.6Hz,1H),4.14(q,J=8.2Hz,1H),3.74(s,3H) , 2.84(s,1H),2.44(s,1H),2.29–2.09(m,1H),0.92(dd,J=12.3,6.9Hz,6H).

[0212] Preparation Example 21 Preparation of Compound A-2-24

[0213] In a single-necked flask, 4-trifluoromethylbenzoic acid (228.1 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.30 g, 1.56 mmol), and 1-hydroxybenzotriazole (0.21 g, 1.56 mmol) were added and dissolved in dichloromethane (5 mL). The mixture was stirred at 0°C for 0.5 hours. Intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (0.47 g, 3.60 mmol) were then added sequentially. The mixture was stirred at room temperature overnight and the reaction progress was monitored by TLC. After TLC indicated the reaction was complete, water (10 mL) was added to quench the reaction, followed by extraction and separation. The aqueous phase was then extracted with dichloromethane (10 mL x 2). The organic phase was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to give product A-2-24 (218.0 mg, 0.56 mmol, yield 47.15%). MS-ESI theoretical value [M+H] + : 387.1; measured value: 387.4. 1 H NMR(400MHz,Chloroform-d)δ7.86(d,J=7.2Hz,1H),7.77(d,J=8.2Hz,2H),7.70(d,J=8.2Hz,2H),5.16–5.07(m,1H),4.54(dd,J=8.6,4.8Hz,1H),4 .36(td,J=8.9,5.7Hz,1H),4.12(q,J=8.2Hz,1H),3.70(s,3H),2.79(s,1H ),2.61–2.45(m,1H),2.23(q,J=6.6Hz,1H),0.96(dd,J=23.5,6.9Hz,6H).

[0214] Preparation Example 22 Preparation of Compound A-2-25

[0215] To a dry three-necked flask, add 4-trifluoromethylbenzoic acid (0.18 g, 0.96 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.18 g, 0.96 mmol), 1-hydroxybenzotriazole (0.13 g, 0.96 mmol), and triethylamine (0.16 g, 1.60 mmol). Add dichloromethane (5 mL) and stir for 0.5 hours. Add intermediate A-2-21a (0.20 g, 0.80 mmol). React at room temperature for 2 hours, concentrate, add water (10 mL), and extract with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-25 (130.0 mg, 0.34 mmol, yield: 42.2%). MS-ESI theoretical value [M+H] + : 387.2; measured value: 387.4. 1 H NMR (400MHz, Chloroform-d) δ7.88 (d, J=8.4Hz, 1H), 7.73 (q, J=8.3Hz, 4H), 5.13 (dd, J=9.4, 6.4Hz, 1H), 4.49 (dd, J=8.4, 4.9Hz, 1H), 4.37 (td, J=9. 0,5.6Hz,1H),4.22–4.03(m,1H),3.75(s,3H),2.85(d,J=16.4Hz,1H),2. 48(d,J=10.0Hz,1H), 2.21(q,J=6.6Hz,1H), 0.92(dd,J=13.2,6.9Hz,6H).

[0216] Preparation Example 23 Preparation of Compound A-2-26

[0217] In a single-necked flask, p-fluorobenzoic acid (168.1 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (300 mg, 1.56 mmol), and 1-hydroxybenzotriazole (0.21 g, 1.56 mmol) were added and dissolved in dichloromethane (5 mL). The mixture was stirred at 0°C for 0.5 hours. Intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (0.47 g, 3.60 mmol) were then added sequentially. The mixture was stirred at room temperature overnight and the reaction progress was monitored by TLC. After TLC indicated the reaction was complete, water (10 mL) was added to quench the reaction, followed by extraction and separation. The aqueous phase was then extracted with dichloromethane (10 mL x 2). The organic phase was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10% to 60%) to give product A-2-26 (270.0 mg, 0.88 mmol, yield 59.34%). MS-ESI theoretical value [M+H] + : 337.2; measured value: 337.4. 1 H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.62(dd,J=8.6,5.3Hz,2H),7.05(t,J=8.5Hz,2H),5.08–4.99(m,1H),4.47(dd,J=8.6,4.9Hz,1H),4. 30(td,J=8.8,5.5Hz,1H),4.14–4.02(m,1H),3.64(s,3H),2.70(s,1H), 2.44 (s, 1H), 2.15 (dq, J = 13.9, 6.7 Hz, 1H), 0.89 (dd, J = 21.8, 6.9 Hz, 6H).

[0218] Preparation Example 24 Preparation of Compound A-2-27

[0219] 4-Fluorobenzoic acid (0.13 g, 0.96 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.18 g, 0.96 mmol), 1-hydroxybenzotriazole (0.13 g, 0.96 mmol), and triethylamine (0.16 g, 1.60 mmol) were added to a dry three-necked flask. Dichloromethane (5 mL) was added and the mixture was stirred for 0.5 hours. Intermediate A-2-21a (0.20 g, 0.80 mmol) was then added. The reaction was allowed to proceed at room temperature for 2 hours, then concentrated, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-27 (99.4 mg, 0.28 mmol, yield: 35.3%). MS-ESI theoretical value [M+H] + : 337.2; measured value: 337.4. 1 H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.75–7.62(m,2H),7.12(t,J=8.6Hz,2H),5.11(s,1H),4.47(dd,J=8.4,5.0Hz,1H),4.42– 4.29(m,1H),4.15(d,J=7.9Hz,1H),3.74(s,3H),2.84(s,1H),2.44(s,1H),2.20(pd,J=7.0,5.1Hz,1H),0.91(dd,J=11.7,6.9Hz,6H).

[0220] Preparation Example 25 Preparation of Compound A-2-28

[0221] In a single-necked flask, p-chlorobenzoic acid (187.9 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.30 g, 1.56 mmol), and 1-hydroxybenzotriazole (0.21 g, 1.56 mmol) were added and dissolved in dichloromethane (5 mL). The mixture was stirred at 0°C for 0.5 hours. Intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (0.47 g, 3.60 mmol) were then added sequentially. The mixture was stirred at room temperature overnight and the reaction progress was monitored by TLC. After TLC indicated the reaction was complete, water (10 mL) was added to quench the reaction, followed by extraction and separation. The aqueous phase was then extracted with dichloromethane (10 mL x 2). The organic phase was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to give product A-2-28 (218.0 mg, 0.56 mmol, yield 47.15%). MS-ESI theoretical value [M+H] + : 353.1; measured value: 353.4. 1 H NMR(400MHz,Chloroform-d)δ7.83(s,1H),7.58(d,J=8.3Hz,2H),7.39(d,J=8.2Hz,2H),5.11–5.02(m,1H),4.50(dd,J=8.6,4.9Hz,1H),4.33( td,J=8.9,5.6Hz,1H),4.11(q,J=7.5,6.5Hz,1H),3.68(s,3H),2.74(s,1H),2.48(s,1H),2.19(h,J=6.8Hz,1H),0.93(dd,J=22.1,6.9Hz,6H).

[0222] Preparation Example 26 Preparation of Compound A-2-29

[0223] To a dry three-necked flask, add 4-chlorobenzoic acid (0.30 g, 1.92 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.37 g, 1.92 mmol), 1-hydroxybenzotriazole (0.26 g, 1.92 mmol), and triethylamine (0.32 g, 3.20 mmol). Add dichloromethane (5 mL), stir and react for 0.5 hours, then add intermediate A-2-21a (0.40 g, 1.60 mmol). React at room temperature for 2 hours, concentrate, add water (10 mL), and extract with ethyl acetate (10 mL × 3 L). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-29 (64.6 mg, 0.18 mmol, yield: 11.5%). MS-ESI theoretical value [M+H] + : 353.1; measured value: 353.3. 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=8.3Hz,1H),7.77–7.51(m,2H),7.41(d,J=8.3Hz,2H),5.10(t,J=8.0Hz,1H),4.47(dd,J=8.3,5.0Hz,1 H), 4.35 (q, J = 8.9, 8.4Hz, 1H), 4.15 (t, J = 8.1Hz, 1H), 3.74 (s, 3H), 2.84 (s, 1H), 2.44 (s, 1H), 2.29–2.05 (m, 1H), 0.91 (dd, J = 12.0, 6.8Hz, 6H).

[0224] Preparation Example 27 Preparation of Compound A-2-30

[0225] In a single-necked flask, furan-2-carboxylic acid (165.9 mg, 1.48 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.37 g, 1.92 mmol), and 1-hydroxybenzotriazole (0.26 g, 1.92 mmol) were added and dissolved in dichloromethane (5 mL). The mixture was stirred at 0°C for 0.5 hours. Intermediate A-2-20a (370.0 mg, 1.48 mmol) and diisopropylethylamine (0.57 g, 4.44 mmol) were then added sequentially. The mixture was stirred at room temperature overnight and the reaction progress was monitored by TLC. After TLC indicated the reaction was complete, water (10 mL) was added to quench the reaction, followed by extraction and separation. The aqueous phase was then extracted with dichloromethane (10 mL x 2). The organic phase was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to give compound A-2-30 (270.0 mg, 0.88 mmol, yield 59.34%). MS-ESI theoretical value [M+H] + : 309.1; measured value: 309.3. 1 H NMR(400MHz,Chloroform-d)δ8.09(s,1H),7.46(s,1H),7.08(d,J=3.5Hz,1H),6.45(dd,J=3.5,1.7Hz,1H),5.03(t,J= 8.4Hz,1H),4.44(dd,J=14.4,7.2Hz,3H),3.64(s,3H),2.70(s,1H),2.49(s,1H),2.24–2.10(m,1H),1.09–0.84(m,6H).

[0226] Preparation Example 28 Preparation of Compound A-2-31

[0227] To a dry three-necked flask, add 2-furancarboxylic acid (0.13 g, 1.20 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.23 g, 1.20 mmol), 1-hydroxybenzotriazole (0.16 g, 1.20 mmol), and triethylamine (0.20 g, 1.60 mmol). Add dichloromethane (5 mL) and stir for 0.5 hours. Then add intermediate A-2-21a (0.25 g, 1.00 mmol). After reacting at room temperature for 2 hours, concentrate, add water (10 mL), and extract with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-31 (182.2 mg, 0.57 mmol, yield: 57.2%). MS-ESI theoretical value [M+H] + : 309.1; measured value: 309.3. 1 H NMR(400MHz,Chloroform-d)δ8.25(s,1H),7.53(s,1H),7.14(d,J=3.5Hz,1H),6.51(dd,J=3.6,1.8Hz,1H),5.21–4.93(m,1 H), 4.47 (d, J = 13.1Hz, 3H), 3.73 (s, 3H), 2.84 (s, 1H), 2.50 (s, 1H), 2.19 (td, J = 6.9, 5.1Hz, 1H), 0.92 (dd, J = 8.1, 6.8Hz, 6H).

[0228] Preparation Example 29 Preparation of Compound A-2-32

[0229] Thiophene-2-carboxylic acid (306.0 mg, 2.39 mmol) was added to a single-necked flask and dissolved in dichloromethane (10 mL). Intermediate A-2-20a (500.0 mg, 1.99 mmol), 2-(7-azabenzotriazole)-tetramethyluronium hexafluorophosphate (500.0 mg, 2.59 mmol), and triethylamine (402 mg, 3.98 mmol) were then added sequentially. The mixture was stirred at room temperature overnight, and the reaction progress was monitored by TLC. After TLC indicated completion of the reaction, water (10 mL) was added to quench the reaction, followed by extraction and separation. The aqueous phase was further extracted with dichloromethane (10 mL x 2). The organic phase was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to give product A-2-32 (302.2 mg, 0.95 mmol, yield 46.7%). MS-ESI theoretical value [M+H] + : 325.1; measured value: 325.3. 1 H NMR(400MHz,Chloroform-d)δ8.09(s,1H),7.52(dd,J=7.5,4.2Hz,2H),7.16–6.98(m,1H),5.08(dd,J=9.4,6.5Hz,1H),4.54 –4.24(m,3H),3.66(s,3H),2.78(s,1H),2.57(d,J=27.1Hz,1H),2.17(dp,J=13.5,6.8Hz,1H),0.92(dd,J=17.5,6.6Hz,6H).

[0230] Preparation Example 30 Synthesis of Compound A-2-33

[0231] To a dry three-necked flask, 2-thiophenecarboxylic acid (0.15 g, 1.20 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.23 g, 1.20 mmol), 1-hydroxybenzotriazole (0.16 g, 1.20 mmol), and triethylamine (0.20 g, 1.60 mmol) were added. Dichloromethane (5 mL) was added and the reaction was stirred for 0.5 hours. Intermediate A-2-21a (0.25 g, 1.00 mmol) was then added. After reacting at room temperature for 2 hours, the mixture was concentrated, water (10 mL) was added, and extraction was performed with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-33 (77.2 mg, 0.24 mmol, yield: 23.9%). MS-ESI theoretical value [M+H] + : 325.1; measured value: 325.2. 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.75–7.37(m,2H),7.12(dd,J=5.0,3.8Hz,1H),5.13(dd,J=9.4,6.3Hz,1H),4.4 1(dtd,J=17.3,8.4,5.9Hz,3H),3.73(s,3H),2.86(s,1H),2.51(s,1H),2.20(pd,J=6.9,5.1Hz,1H),0.92(t,J=6.7Hz,6H).

[0232] Preparation Example 31 Preparation of Compound A-2-34

[0233] first step

[0234] Compound A-2-34a (3 g, 13.81 mmol) and dichloromethane (50 ml) were added to a dry, single-necked flask and stirred in an ice bath for 10 minutes. Cyclopentylmethanol (2.07 g, 20.71 mmol), 4-dimethylaminopyridine (1.69 g, 13.81 mmol), and N,N'-dicyclohexylcarbodiimide (4.27 g, 20.71 mmol) were then added in sequence. The reaction was allowed to proceed at room temperature for 12 hours, and TLC indicated the reaction was complete. Water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml x 3). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate A-2-34b (3.2 g, 10.68 mmol, 77.4% yield). 1H NMR (400MHz, CDCl3) δ5.07(d,J=8.8Hz,1H),4.25(dd,J=9.1,4.6Hz,1H),4.04(qd,J=10.6,7.2Hz,2H),2.25(dd,J=15.1,7.5Hz,1H),2.2 0–2.09(m,1H),1.78(dt,J=7.7,2.9Hz,2H),1.70–1.53(m,4H),1.47(s,9H),1.33–1.20(m,2H),1.02–0.97(m,3H),0.92(d,J=6.9Hz,3H).

[0235] Step 2

[0236] To a dry, single-necked flask, add intermediate A-2-34b (3.2 g, 10.68 mmol) and dichloromethane (20 ml). Then, add 4 M hydrogen chloride solution in dioxane (20 mL) and stir at room temperature for 2 hours. After TLC indicates the reaction is complete, concentrate the reaction mixture to obtain crude intermediate A-2-34c, which is used directly in the next step.

[0237] Step 3

[0238] Dissolve the crude intermediate A-2-34c and intermediate A-2-7b (1.98 g, 9.94 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (3.85 g, 29.82 mmol), N-hydroxy-7-azabenzotriazole (1.35 g, 9.94 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.91 g, 9.94 mmol) in an ice bath. Continue stirring in an ice bath for 1 hour and then transfer to room temperature overnight. TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate A-2-34d (2.4 g, 6.27 mmol, total yield of two steps 58.7%). 1H NMR (400MHz, CDCl3) δ4.79–4.64(m,1H),4.59(dd,J=8.9,4.6Hz,1H),4.17–4.02(m ,2H),4.01–3.92(m,1H),3.85(dd,J=14.0,8.5Hz,1H),2.51(d,J=6.2Hz,1H),2.40 (s,1H),2.31–2.19(m,2H),1.79(d,J=10.4Hz,2H),1.61(ddd,J=26.9,13.8,6.0Hz ,4H),1.49(s,9H),1.36–1.25(m,2H),1.00(d,J=6.8Hz,3H),0.95(d,J=6.9Hz,3H).

[0239] Step 4

[0240] In a dry, single-necked flask, add Intermediate A-2-34d (1.2 g, 3.13 mmol), dichloromethane (5 ml), and a 4M solution of hydrogen chloride in dioxane (10 ml). The mixture was reacted at room temperature for 2 hours. After TLC indicated the reaction was complete, the mixture was concentrated to afford the crude product of Intermediate A-2-34e.

[0241] Step 5

[0242] The crude intermediate A-2-34e was dissolved in tetrahydrofuran (20 ml) and N,N-diisopropylethylamine (1.22 g, 9.42 mmol) was added. Acetic anhydride (0.64 g, 6.28 mmol) was slowly added dropwise in an ice bath and the reaction was continued for 30 minutes. The mixture was then brought to room temperature and the reaction was continued for 2 hours. After TLC, ethanol (5 mL) was added, the mixture was concentrated, and the product A-2-34 (0.7 g, 2.16 mmol, 68.8% yield) was obtained by silica gel column chromatography. MS-ESI theoretical value [M+H] + : 325.2; measured value: 325.2. 1H NMR (400MHz, CDCl3) δ8.20 (d, J=8.4Hz, 1H), 4.85 (dd, J=9.5, 6.6Hz, 1H), 4.42 (dd, J=8.6,4.7Hz,1H),4.00(t,J=6.4Hz,2H),3.98–3.87(m,2H),2.67–2.51(m,1H),2. 44–2.28(m,1H),2.20(d,J=4.8Hz,2H),1.87(s,3H),1.68(dd,J=12.1,5.0Hz,2H), 1.60–1.44(m,4H),1.23–1.14(m,2H),0.92(d,J=6.9Hz,3H),0.87(d,J=6.9Hz,3H).

[0243] Preparation Example 32 Preparation of Compound A-2-35

[0244] first step

[0245] Compound A-2-34a (3 g, 13.81 mmol) and dichloromethane (50 ml) were added to a dry, single-necked flask and stirred in an ice bath for 10 minutes. Cyclohexanol (2.07 g, 20.71 mmol), 4-dimethylaminopyridine (1.69 g, 13.81 mmol), and N,N'-dicyclohexylcarbodiimide (4.27 g, 20.71 mmol) were then added in sequence. The reaction was continued at room temperature for 12 hours, after which TLC indicated completion. Water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to yield intermediate A-2-35a (3.5 g, 11.68 mmol, 84.66% yield). 1 H NMR (400MHz, CDCl3) δ5.08(d,J=8.8Hz,1H),4.93–4.79(m,1H),4.23(dd,J=9.0,4.4Hz,1H),2.18(dd,J=11.6,6.7Hz,1H),1.93–1.83(m,2 H), 1.76 (dd, J = 7.4, 4.3Hz, 2H), 1.57 (dd, J = 8.4, 3.6Hz, 2H), 1.48 (s, 9H), 1.46–1.28 (m, 4H), 1.00 (d, J = 6.9Hz, 3H), 0.92 (d, J = 6.9Hz, 3H).

[0246] Step 2

[0247] In a dry one-necked flask, add intermediate A-2-35a (3.5 g, 11.68 mmol), dichloromethane (20 ml), and 4M hydrogen chloride in dioxane solution (20 ml). React at room temperature for 2 hours. After TLC shows the reaction is complete, concentrate to obtain crude intermediate A-2-35b.

[0248] Step 3

[0249] The crude intermediate A-2-35b and intermediate A-2-7b (1.98 g, 9.94 mmol) were dissolved in dichloromethane (40 ml). N,N-diisopropylethylamine (3.85 g, 29.82 mmol), N-hydroxy-7-azabenzotriazole (1.35 g, 9.94 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.91 g, 9.94 mmol) were added under ice-cooling. After reacting for 1 hour, the mixture was brought to room temperature overnight. Upon completion of the reaction by TLC, water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml x 3). The combined organic phases were washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to afford intermediate A-2-35c (2.4 g, 6.27 mmol, 53.7% total yield for two steps). 1 H NMR (400MHz, CDCl3) δ4.93–4.82(m,1H),4.74–4.63(m,1H),4.56(dd,J=9.0,4.6Hz, 1H),3.97(dd,J=16.3,8.2Hz,1H),3.90–3.79(m,1H),2.45(d,J=45.1Hz,2H),2.30– 2.18(m,1H),1.93–1.82(m,2H),1.79–1.68(m,2H),1.61–1.51(m,2H),1.49(s,9H), 1.46–1.38(m,2H),1.37–1.26(m,2H),1.00(d,J=6.9Hz,3H),0.95(d,J=6.9Hz,3H).

[0250] Step 4

[0251] In a dry one-necked flask, add intermediate A-2-35c (1.2 g, 3.13 mmol), dichloromethane (5 ml), and 4M hydrogen chloride in dioxane solution (10 ml). React at room temperature for 2 hours. TLC shows the reaction is complete. Concentrate to obtain the crude intermediate A-2-35d.

[0252] Step 5

[0253] Dissolve the crude intermediate A-2-35d in tetrahydrofuran (20 ml) and add N,N-diisopropylethylamine (1.22 g, 9.42 mmol) under ice-cooling. Then slowly add acetic anhydride (0.64 g, 6.28 mmol) dropwise. Continue the reaction for 30 minutes and then at room temperature for 2 hours. After TLC, add ethanol (5 mL), concentrate, and purify by silica gel column chromatography to obtain product A-2-35 (0.7 g, 2.16 mmol, yield 68.8%). MS-ESI theoretical value [M+H] + : 325.2; measured value: 325.2. 1 H NMR (400MHz, CDCl3) δ8.19 (d, J=8.4Hz, 1H), 4.85 (dd, J=9.5, 6.5Hz, 1H), 4.80–4.6 9(m,1H),4.41(dd,J=8.7,4.6Hz,1H),4.00(t,J=7.7Hz,2H),2.67–2.54(m,1H),2.3 7(ddt,J=9.4,8.4,7.0Hz,1H),2.25–2.11(m,1H),1.87(s,3H),1.81–1.71(m,2H), 1.69–1.57(m,2H),1.49–1.23(m,6H),0.92(d,J=6.9Hz,3H),0.87(d,J=6.9Hz,3H).

[0254] Preparation Example 33 Preparation of Compound A-2-37

[0255] Nicotinic acid (0.12 g, 0.96 mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.18 g, 0.96 mmol), 1-hydroxybenzotriazole (0.13 g, 0.96 mmol), and triethylamine (0.16 g, 1.60 mmol) were added to a dry three-necked flask. Dichloromethane (5 mL) was added, and the reaction was stirred for 0.5 hours. Intermediate A-2-21a (0.20 g, 0.80 mmol) was then added. After reacting at room temperature for 2 hours, the mixture was concentrated, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product A-2-37 (53.5 mg, 0.17 mmol, yield: 21.0%). MS-ESI theoretical value [M+H] + : 320.2; measured value: 320.3. 1H NMR(400MHz,Chloroform-d)δ8.88(s,1H),8.74(d,J=4.6Hz,1H),8.04(d,J=7.8Hz,1H),7.84(d,J=8.2Hz,1H),7.44(dd,J=7.9,4.7Hz,1H),5.14(t, J=8.0Hz,1H),4.69–4.37(m,2H),4.21(q,J=8.3Hz,1H),3.75(s,3H),2.88 (s,1H),2.49(s,1H),2.20(d,J=14.9Hz,1H),0.92(dd,J=12.7,6.8Hz,6H).

[0256] Preparation Example 34 Preparation of Compound B-2-1

[0257] first step

[0258] The raw material B-2-1a (5.00 g, 48.54 mmol) was dissolved in 1,4-dioxane / water (50 mL / 10 mL), and a solution of 1,4-dioxane / water (50 mL / 10 mL) of benzyloxycarbonyl succinimide (12.10 g, 48.54 mmol) was slowly added thereto. The reaction solution was reacted at 25 ° C for 16 hours. After the reaction was completed, ethyl acetate was added to dilute (200 mL), and then washed with 5% sodium bicarbonate solution and 5% citric acid solution respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude intermediate B-2-1b (10.40 g, 43.83 mmol, yield 90.3%). MS-ESI theoretical value [M+H] + : 238.2; measured value: 238.1.

[0259] Step 2

[0260] Intermediate B-2-1b (10.40 g, 43.83 mmol) was dissolved in ethyl acetate (300 mL), and Dess-Martin periodinane (22.30 g, 52.60 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction, the reaction mixture was filtered through celite, the filtrate was concentrated, and the mixture was filtered through a silica gel column to obtain intermediate B-2-1c (8.76 g, 37.25 mmol, yield 85%). MS-ESI theoretical value [M+H] + : 236.1; measured value 236.1.

[0261] Step 3

[0262] Intermediate B-2-1c (7.0 g, 29.79 mmol) and glyoxal solution (15.4 mL, 119.16 mmol) were dissolved in methanol (70 mL). Aqueous ammonia (18.9 mL, 148.95 mmol) was slowly added, maintaining the temperature below 10°C during the addition. The reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and the precipitated solid was collected by filtration. The filter cake was washed with water and dried to obtain intermediate B-1-2d (6.3 g, 23.05 mmol, yield 77%). MS-ESI theoretical value [M+H] + : 274.1; measured value: 274.1.

[0263] Step 4

[0264] Intermediate B-2-1d (3.00 g, 10.98 mmol) was dissolved in methanol (75 mL), followed by the addition of palladium on carbon (0.3 g, 10 wt.%). The mixture was purged with hydrogen three times, and the reaction mixture was allowed to react at 25°C under a hydrogen atmosphere for 16 hours. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated to obtain the crude intermediate B-2-1e (1.2 g, 8.62 mmol, 78% yield). MS-ESI theoretical value [M+H] + : 140.0; measured value: 140.1.

[0265] Step 5

[0266] Intermediate B-2-1e (1.2 g, 8.62 mmol) and A-2-1b (1.82 g, 9.05 mmol) were dissolved in N,N-dimethylformamide (12 mL). 1-Hydroxybenzotriazole (1.40 g, 10.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.97 g, 10.34 mmol) were added at -20°C. The reaction solution was stirred at 0°C for 3 hours. After completion, the reaction solution was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified on a silica gel column (dichloromethane / methanol = 15 / 1) and then purified by reverse preparative purification to obtain intermediate B-2-1f (0.90 g, 2.80 mmol, yield 32%). MS-ESI theoretical value [M+H] + : 323.2; measured value: 323.1.

[0267] Step 6

[0268] Intermediate B-2-1f (0.90 g, 2.80 mmol) was dissolved in ethyl acetate (20 mL). A solution of hydrogen chloride in dioxane (4.0 M, 3 ml) was slowly added dropwise with stirring at room temperature. Stirring was continued at room temperature for 12 hours after completion of the addition. The reaction was monitored for completion and concentrated to dryness to obtain the crude intermediate B-2-1g (0.60 g, 2.33 mmol, yield 86%). MS-ESI theoretical value [M+H] + : 223.1; measured value: 223.2.

[0269] Step 7

[0270] Dissolve intermediate B-2-1g (0.60g, 2.33mmol) in toluene (10mL), add acetic anhydride (2.38g, 23.30mmol), heat to 110℃, react for 8 hours, monitor the reaction completion, and concentrate to dryness. The resulting residue is separated and purified using a silica gel column (dichloromethane / methanol = 15 / 1) and then purified by reverse preparative purification to obtain product B-2-1 (0.20g, 0.76mmol, yield 33%). MS-ESI theoretical value [M+H] + : 265.2; measured value: 265.2. 1 H NMR (400MHz, DMSO) δ11.84(d,J=42.0Hz,1H),8.58–8.11(m,1H),7.02–6.71(m,2H),4.95–4.62(m,2H),4.03(t,J=7.7Hz,1H),3.81 –3.68(m,1H),2.44–2.26(m,1H),2.20–1.90(m,2H),1.83–1.52(m,3H),0.84(ddd,J=10.3,8.3,5.0Hz,3H),0.75(t,J=6.7Hz,3H).

[0271] Preparation Example 35 Preparation of Compound B-2-2

[0272] first step

[0273] Compound B-2-2a (15 g, 0.21 mol) was dissolved in dichloromethane (250 mL), and (R)-tert-butylsulfenamide (27.5 g, 0.23 mol) and anhydrous copper sulfate (8.6 g, 0.05 mol) were added. The resulting reaction system was stirred at 25°C for 24 hours, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate B-2-2b (7 g, 39.3 mmol, yield 17.6%). MS-ESI theoretical value [M+H] + : 176.1; measured value: 176.1.

[0274] Step 2

[0275] Compound 1,3-oxazole (1 g, 14.5 mmol) was dissolved in tetrahydrofuran (30 mL). After nitrogen substitution, a borane tetrahydrofuran solution (22 mL) was added. The reaction solution was cooled to -78°C and a tetrahydrofuran solution of n-butyllithium (2.4 M, 10 mL, 24 mmol) was added. The reaction was stirred for 30 minutes, and then intermediate B-2-2b (2.5 g, 14.5 mmol) was slowly added. The reaction solution was stirred at -78°C for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (100 mL × 2), saturated ammonium chloride solution (100 mL × 2), and saturated brine (100 mL × 2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain intermediate B-2-2c (1 g, 4.1 mmol, yield 28.7%). MS-ESI theoretical value [M+H] + : 245.1; measured value: 245.1.

[0276] Step 3

[0277] At 0°C, a 2M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added to intermediate B-2-2c (1 g, 4.1 mmol). The reaction was stirred at 0°C for 1 hour and then concentrated to afford intermediate B-2-2d (400 mg, 2.85 mmol, yield 69.7%). MS-ESI theoretical value [M+H] + : 141.1; measured value: 141.1.

[0278] Step 4

[0279] To a solution of intermediate A-2-6b (2.5 g, 12.4 mmol) in dichloromethane (30 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.57 g, 18.6 mmol), 1-hydroxybenzotriazole (2.51 g, 18.6 mmol), and N-methylmorpholine (11.29 g, 111.6 mmol). The mixture was stirred at -15°C for 10 minutes, followed by the addition of intermediate B-2-2d (1.91 g, 13.64 mmol). The reaction mixture was stirred at -15°C for 4 hours. After completion of the reaction, the reaction mixture was washed with saturated citric acid solution (50 mL × 2) and saturated sodium carbonate solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain intermediate B-2-2e (2.5 g, 7.7 mmol, yield 56.7%). MS-ESI theoretical value [M+H]+ : 324.2; measured value: 324.2.

[0280] Step 5

[0281] Intermediate B-2-2e (2.5 g, 6.4 mmol) was dissolved in a solution of trifluoroacetic acid in dichloromethane (V / V = 1:1, 40 mL) and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated to obtain a crude intermediate B-2-2f (5.58 g). MS-ESI theoretical value [M+H] + : 224.1; measured value: 224.1.

[0282] Step 6

[0283] To a solution of the crude intermediate B-2-2f (5.58 g) in dichloromethane (40 mL) was added N,N-diisopropylethylamine (7.96 g, 61.6 mmol). The mixture was purged three times under nitrogen and stirred at 0°C for 5 minutes before the addition of deuterated acetyl chloride (0.69 g, 8.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain product B-2-2 (1.57 g, 5.85 mmol, total yield for two steps 75.6%). MS-ESI theoretical value [M+H] + : 269.2; measured value: 269.0. 1 H NMR (400MHz, d6-DMSO) δ8.64(dd,J=64.7,8.7Hz,1H),8.02(dd,J=7.4,0.6Hz,1H),7.13(d,J=7.8Hz,1H),4.92–4.61(m,2H),4.00(t,J=7 .6Hz,1H),3.71(dt,J=8.8,6.3Hz,1H),2.44–2.23(m,1H),2.23–1.85(m,2H),0.86(dd,J=11.2,6.8Hz,3H),0.77(dd,J=11.0,6.8Hz,3H).

[0284] Preparation Example 36 Preparation of Compound B-2-3

[0285] first step:

[0286] To a solution of compound A-2-7b (2 g, 9.96 mmol) in dichloromethane (50 mL) at -10°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g, 12.45 mmol), 1-hydroxybenzotriazole (1.68 g, 12.45 mmol), and N,N-diisopropylethylamine (5.36 g, 41.50 mmol) were added. After stirring for 10 minutes, intermediate B-2-2d (1.47 g, 8.30 mmol) was added, and the reaction was continued at -10°C for 2 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous citric acid (50 mL × 2) and saturated sodium carbonate solution (50 mL × 2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain intermediate B-2-3a (2 g, 6.2 mmol, 62.2%). MS-ESI theoretical value [M+H] + : 324.2; measured value: 324.0.

[0287] Step 2:

[0288] Intermediate B-2-3a (2 g, 6.2 mmol) was dissolved in trifluoroacetic acid in dichloromethane (V / V = 1:1, 20 mL) and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to obtain the crude intermediate B-2-3b (3.6 g). MS-ESI theoretical value [M+H] + : 224.1; measured value: 224.0.

[0289] Step 3:

[0290] To a solution of the crude intermediate B-2-3b (3.6 g) in dichloromethane (60 mL) at 0°C were added N,N-diisopropylethylamine (6.4 g, 49.6 mmol) and deuterated acetyl chloride (606 mg, 7.4 mmol) in sequence. The reaction was continued at 0°C for 1 hour. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain product B-2-3 (1.22 g, 4.55 mmol, total yield for two steps 73.5%). MS-ESI theoretical value [M+H] +: 269.2; found: 269.0. 1H NMR (400 MHz, Chloroform-d) δ 8.50 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.08 (s, 1H), 5.08 (dd, J = 8.5, 6.0 Hz, 1H), 4.95 (dd, J = 9.6, 6.6 Hz, 1H), 4.06 (t, J = 8.0 Hz, 2H), 2.73–2.59 (m, 1H), 2.51–2.35 (m, 1H), 2.28 (dq, J = 13.4, 6.7 Hz, 1H), 0.96 (dd, J = 13.9, 6.8 Hz, 6H).

[0291] Preparation Example 37 Preparation of Compound B-2-4

[0292] first step

[0293] Dissolve intermediate B-2-3a (6 g, 18.55 mmol) in dichloromethane (50 mL) and add 4 M hydrogen chloride in dioxane (15 mL). Allow to react at room temperature for 2 hours. TLC indicates the reaction is complete. Concentrate to afford crude intermediate B-2-4a (4.83 g, 18.6 mmol, 100% yield). MS-ESI theoretical value [M+H] + : 224.1; measured value: 224.3.

[0294] Step 2

[0295] In a dry, single-necked flask, intermediate B-2-4a (500.0 mg, 1.93 mmol) was added and dissolved in ultra-dry dichloromethane (5 mL), and the atmosphere was replaced with nitrogen. Diisopropylethylamine (0.75 g, 5.79 mmol) was then added at 0°C and stirred for 10 min. Finally, cyclopropylcarbonyl chloride (262.3 mg, 2.51 mmol) was slowly added to the reaction system. The reaction was continued at 0°C for 2 hours. TLC indicated completion of the reaction. Water (10 mL) was added, and the mixture was extracted and separated. The aqueous phase was then extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE = 10% to 50%) to obtain product B-2-4 (351.0 mg, 1.20 mmol, yield 62.40%). MS-ESI theoretical value [M+H] + : 292.2; measured value: 292.1. 1H NMR(400MHz,Chloroform-d)δ8.37(d,J=8.2Hz,1H),7.52(s,1H),6.99(s,1H),4.99(dd,J=8.5,6.3Hz,1H),4.87(dd,J=9.4,6.7Hz,1H),4.27–3.93(m ,2H),2.72–2.53(m,1H),2.48–2.36(m,1H),2.22–2.13(m,1H),1.41–1.33( m,1H),1.01–0.90(m,2H),0.86(dd,J=13.0,6.8Hz,6H),0.81–0.73(m,2H).

[0296] Preparation Example 38 Preparation of Compound B-2-5

[0297] In a dry, single-necked flask, intermediate B-2-4a (500.0 mg, 1.93 mmol) was added and dissolved in ultra-dry dichloromethane (5 mL), and the atmosphere was replaced with nitrogen. Diisopropylethylamine (0.75 g, 5.79 mmol) was then added at 0°C and stirred for 10 min. Finally, trimethylacetyl chloride (302.5 mg, 2.51 mmol) was slowly added to the reaction system. The reaction was continued at 0°C for 2 hours. TLC indicated completion of the reaction. Water (10 mL) was added, and the mixture was extracted and separated. The aqueous phase was then extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE = 10% to 50%) to obtain product B-2-5 (170.0 mg, 0.55 mmol, yield 28.7%). MS-ESI theoretical value [M+H] + : 308.2; Measured value: 308.2. 1 H NMR(400MHz,Chloroform-d)δ8.17(d,J=8.4Hz,1H),7.50(s,1H),6.98(s,1H),5.00(dd,J=8.9,6.1Hz,1H),4.90(dd,J=9.6,5.9Hz,1H ), 4.24(t,J=7.7Hz,2H),2.59(dq,J=14.1,7.2Hz,1H),2.44–232(m,1H),2.27–2.09(m,1H),1.14(s,9H),0.87(dd,J=11.6,6.8Hz,6H).

[0298] Preparation Example 39 Preparation of Compound B-2-8

[0299] first step

[0300] B-2-8a (5 g, 46.68 mmol) was dissolved in ultra-dry dichloromethane (100 ml), and cesium carbonate (18.25 g, 56.02 mmol) and (S)-tert-butylsulfenamide (5.66 g, 46.68 mmol) were added sequentially. Stirring was continued at room temperature for 2 hours. TLC indicated the reaction was complete. Water (100 ml) was added and the mixture was extracted with dichloromethane (50 ml x 2). The organic phases were combined, washed with saturated sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate B-2-8b (9.56 g, 45.52 mmol, 97.4% yield).

[0301] Step 2

[0302] Intermediate B-2-8b (9.56 g, 45.46 mmol) was dissolved in ultra-dry tetrahydrofuran (100 ml), protected by nitrogen, and cooled to -78°C. 1M isopropylmagnesium bromide (50 ml) was slowly added dropwise. After the addition was complete, the reaction was continued for 2 h. TLC showed that the reaction was complete. Water (100 ml) was added and the mixture was extracted with dichloromethane (50 ml x 2). The organic phases were combined, washed with saturated sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate B-2-8c (6.15 g, 24.21 mmol, yield 53.2%). MS-ESI theoretical value [M+H] + : 255.2; measured value: 255.3.

[0303] Step 3

[0304] Intermediate B-2-8c (6.15 g, 24.21 mmol) was dissolved in dichloromethane (100 ml), and 4M hydrogen chloride in dioxane solution (30 ml) was added and reacted at room temperature for 2 hours. TLC showed that the reaction was complete, and the mixture was concentrated to obtain the crude intermediate B-2-8d.

[0305] Step 4

[0306] Dissolve the crude intermediate B-2-8d (0.5 g, 2.48 mmol) in dichloromethane (50 ml). Add intermediate A-2-7b (0.56 g, 3.72 mmol), N,N-diisopropylethylamine (0.96 g, 7.44 mmol), and 1-hydroxybenzotriazole (0.5 g, 3.72 mmol) in an ice bath. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.71 g, 3.72 mmol) and continue the reaction in an ice bath for 30 minutes before returning to room temperature. After 3 hours of reaction, TLC indicates complete reaction of the starting material. Add water (50 ml), extract with dichloromethane (50 ml×3), wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain intermediate B-2-8e (0.60 g, 1.80 mmol, total yield of two steps 72.4%). 1 H NMR (400MHz, CDCl3) δ8.56(t,J=5.3Hz,1H),7.85(s,1H),7.63(td,J=7.7,1.6H z,1H),7.19(t,J=8.5Hz,2H),4.91(dd,J=8.9,7.0Hz,1H),4.77–4.59(m,1H),3 .92(dd,J=16.3,8.3Hz,1H),3.79(td,J=8.6,5.3Hz,1H),2.46(s,1H),2.22(dd ,J=12.7,7.1Hz,2H),1.50(s,9H),0.94(d,J=6.8Hz,3H),0.84(d,J=6.7Hz,3H).

[0307] Step 5

[0308] Intermediate B-2-8e (0.60 g, 1.8 mmol) was dissolved in dichloromethane (5 ml), and 4M hydrogen chloride in dioxane solution (8 ml) was added. The mixture was reacted at room temperature for 2 hours. TLC showed that the reaction was complete. The mixture was concentrated to give intermediate B-2-8f (0.42 g, 1.8 mmol, yield 100%). 1H NMR(400MHz,MeOD)δ8.81(d,J=5.4Hz,1H),8.65(t,J=7.5Hz,1H),8.13(d,J=8.2Hz,1H), 8.08–7.93(m,1H),5.26–5.14(m,1H),4.95(d,J=7.8Hz,1H),4.19–4.05(m,1H),3.95(td ,J=10.0,6.3Hz,1H),2.94(dtd,J=15.8,9.5,6.3Hz,1H),2.58(dq,J=12.2,7.8Hz,1H),2 .33(dd,J=13.9,6.8Hz,1H), 1.11(dd,J=11.6,4.3Hz,3H), 0.90(dd,J=12.5,6.8Hz,3H).

[0309] Step 6

[0310] Intermediate B-2-8f (0.42 g, 1.8 mmol) was dissolved in tetrahydrofuran (20 ml). N,N-diisopropylethylamine (0.70 g, 5.40 mmol) was added and acetic anhydride (0.37 g, 3.60 mmol) was slowly added dropwise under an ice bath. The reaction was continued under an ice bath for 30 minutes and then brought to room temperature. After 2 hours of reaction, TLC showed a reaction. Methanol (5 mL) was added, the mixture was concentrated, and the product B-2-8 (0.25 g, 0.91 mmol, 50.4% yield) was obtained by silica gel column chromatography. MS-ESI theoretical value [M+H] + : 276.2; measured value: 276.3. 1 H NMR (400MHz, CDCl3) δ8.49(d,J=4.5Hz,1H),8.27(d,J=8.1Hz,1H),7.68–7.51( m,1H),7.19–7.05(m,2H),4.86(dd,J=8.7,6.0Hz,1H),4.83–4.74(m,1H),4.06– 3.91(m,2H),2.58–2.44(m,1H),2.37(ddd,J=19.4,11.8,7.9Hz,1H),2.17(dd,J =13.5,6.8Hz,1H),1.91–1.83(m,3H),0.85(t,J=6.9Hz,3H),0.81–0.73(m,3H).

[0311] Preparation Example 40 Preparation of Compounds B-2-9 and B-2-10

[0312] first step

[0313] B-2-9a (2 g, 18.67 mmol) was dissolved in ultra-dry dichloromethane (100 ml), and cesium carbonate (7.30 g, 22.40 mmol) and (S)-tert-butylsulfenamide (2.26 g, 18.67 mmol) were added sequentially. Stir at room temperature for 2 hours. After TLC showed that the reaction was complete, water (100 ml) was added and extracted with dichloromethane (50 ml × 2). The organic phases were combined, washed with saturated sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate B-2-9b (3.82 g, 18.02 mmol, yield 97.38%).

[0314] Step 2

[0315] Intermediate B-2-9b (3.82 g, 18.02 mmol) was dissolved in ultra-dry tetrahydrofuran (100 ml), replaced with nitrogen, and cooled to -78°C. A 1 M tetrahydrofuran solution of isopropylmagnesium bromide (20 ml) was slowly added dropwise. After the addition was complete, the reaction was continued at -78°C for 2 hours. TLC indicated that the reaction was complete, and water (100 ml) was added. The mixture was extracted with dichloromethane (50 ml x 2). The organic phases were combined, washed with saturated sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain two components.

[0316] The component 1 with the shortest retention time is intermediate B-2-9c (1.88 g, 7.43 mmol, yield 41.26%), MS-ESI theoretical value [M+H] + : 255.2, measured value: 255.3.

[0317] The component 2 with the longest retention time is B-2-10c (1.83 g, 7.22 mmol, yield 40.10%), MS-ESI theoretical value [M+H] + : 255.2, measured value: 255.3.

[0318] Step 3 - Component 1

[0319] Intermediate B-2-9c (1 g, 3.93 mmol) was dissolved in dichloromethane (10 ml), and 4M hydrogen chloride in dioxane solution (5 ml) was added and reacted at room temperature for 3 hours. TLC showed that the reaction was complete, and the mixture was concentrated to obtain the crude intermediate B-2-9d.

[0320] Step 4 - Component 1

[0321] The crude intermediate B-2-9d was dissolved in dichloromethane (30 ml), and N,N-diisopropylethylamine (1.02 g, 7.86 mmol) was added sequentially, followed by intermediate A-2-7b (0.87 g, 4.32 mmol), 1-hydroxybenzotriazole (0.53 g, 3.93 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.75 g, 3.93 mmol). The reaction was allowed to proceed overnight at room temperature, and water (50 ml) was added. The mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain intermediate B-2-9e (0.8 g, 2.40 mmol, total yield for two steps 61.1%). 1 H NMR (400MHz, CDCl3) δ8.48(d,J=5.9Hz,2H),7.14(d,J=5.9Hz,2H),4.71(dd,J=8.4,6.3Hz,1H),4.62(d,J=7.2Hz,1H),3.88(dd,J=1 6.3, 8.1Hz, 1H), 3.76 (tt, J = 16.3, 8.2Hz, 1H), 2.39 (d, J = 51.6Hz, 2H), 2.02 (td, J = 13.2, 6.6Hz, 1H), 1.40 (s, 9H), 0.90-0.67 (m, 6H).

[0322] Step 5 - Component 1

[0323] Intermediate B-2-9e (0.8 g, 2.4 mmol) was dissolved in dichloromethane (5 ml), and 4M hydrogen chloride in dioxane solution (8 ml) was added and reacted at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain the crude intermediate B-2-9f.

[0324] Step 6 - Component 1

[0325] Dissolve the crude intermediate B-2-9f in tetrahydrofuran (20 ml) and add N,N-diisopropylethylamine (1.02 g, 7.86 mmol). Slowly add acetic anhydride (0.6 g, 5.9 mmol) dropwise in an ice bath. Continue the reaction for 30 minutes and bring to room temperature. After 2 hours of reaction, TLC shows that the reaction is complete. Add methanol (2 mL), concentrate, and separate by silica gel column chromatography to obtain product B-2-9 (0.30 g, 1.09 mmol, total yield of two steps 45.4%). 1H NMR (400MHz, CDCl3) δ8.61(d,J=8.2Hz,1H),8.48(d,J=5.8Hz,2H),7.15(d,J= 6.0Hz,2H),4.83(dd,J=9.4,6.6Hz,1H),4.66(dd,J=8.2,6.4Hz,1H),4.03(t,J =7.7Hz,2H),2.74–2.58(m,1H),2.33(ddt,J=12.1,9.5,7.4Hz,1H),1.96(dd, J=13.4, 6.7Hz, 1H), 1.91 (s, 3H), 0.81 (d, J= 2.6Hz, 3H), 0.79 (d, J= 2.7Hz, 3H).

[0326] Step 3 - Component 2

[0327] Intermediate B-2-10c (1 g, 3.93 mmol) was dissolved in dichloromethane (10 ml), and 4M hydrogen chloride in dioxane solution (5 ml) was added. The mixture was reacted at room temperature for 3 hours. TLC showed that the reaction was complete. The mixture was concentrated to obtain the crude intermediate B-2-10d.

[0328] Step 4 - Component 2

[0329] The crude intermediate B-2-10d was dissolved in dichloromethane (30 ml), and N,N-diisopropylethylamine (1.02 g, 7.86 mmol) was added sequentially, followed by intermediate A-2-7b (0.87 g, 4.32 mmol), 1-hydroxybenzotriazole (0.53 g, 3.93 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.75 g, 3.93 mmol). The reaction was allowed to proceed overnight at room temperature, and water (50 ml) was added. The mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain intermediate B-2-10e (0.8 g, 2.40 mmol, total yield for two steps: 61.1%). 1 H NMR (400MHz, CDCl3) δ8.47(d,J=5.9Hz,2H),7.09(d,J=6.0Hz,2H),4.75(dd,J=8.9,6.4Hz,1H),4.69(t,J=7.5Hz,1H),3.85(d d,J=16.4,8.3Hz,1H),3.72(dd,J=14.1,8.4Hz,1H),2.51-2.23(m,2H),2.15(s,1H),1.43(s,9H),0.84(dd,J=6.7,4.1Hz,6H).

[0330] Step 5 - Component 2

[0331] Intermediate B-2-10e (0.8 g, 2.4 mmol) was dissolved in dichloromethane (5 ml), and 4M hydrogen chloride in dioxane solution (8 ml) was added and reacted at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain a crude intermediate B-2-10f.

[0332] Step 6 - Component 2

[0333] Dissolve the crude intermediate B-2-10f in tetrahydrofuran (20 ml) and add N,N-diisopropylethylamine (1.02 g, 7.86 mmol). Slowly add acetic anhydride (0.6 g, 5.9 mmol) dropwise in an ice bath. Continue the reaction for 30 minutes and bring to room temperature. After 2 hours of reaction, TLC shows that the reaction is complete. Add methanol (2 mL), concentrate, and separate by silica gel column chromatography to obtain product B-2-10 (0.33 g, 1.2 mmol, total yield of two steps 50.0%). 1 H NMR (400MHz, CDCl3) δ8.67(d,J=8.4Hz,1H),8.47(d,J=5.8Hz,2H),7.08(d,J=6.0Hz,2H),4.91(dd,J=9.3,6.7Hz,1H),4.72(dd,J=8.6,6.4Hz,1H),4.08 –3.90(m,2H),2.61(ddt,J=12.1,9.4,6.8Hz,1H),2.33(dtd,J=12.1,9.2,5 .5Hz, 1H), 1.97 (dd, J = 13.4, 6.7Hz, 1H), 1.90 (s, 3H), 0.84 (t, J = 6.4Hz, 6H).

[0334] Preparation Example 41 Compound B-2-11

[0335] first step

[0336] Dissolve B-2-11a (1 g, 9.33 mmol) in ultra-dry dichloromethane (100 ml), and add cesium carbonate (3.65 g, 11.20 mmol) and (S)-tert-butylsulfenamide (1.13 g, 9.33 mmol) in sequence. React at room temperature for 2 hours. TLC shows the reaction is complete. Add water (100 ml) and extract with dichloromethane (50 ml × 2). Combine the organic phases, wash with saturated brine (100 ml), dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain intermediate B-2-11b (1.90 g, 9.01 mmol, yield 97.3%).

[0337] Step 2

[0338] Dissolve intermediate B-2-11b (1.90 g, 9.01 mmol) in ultra-dry tetrahydrofuran (100 ml). Under nitrogen protection, cool to -78°C and slowly add 1M isopropylmagnesium bromide (10 ml). Continue the reaction at this temperature for 2 hours. TLC shows that the reaction is complete. Add water (100 ml) and extract with dichloromethane (50 ml x 2). Combine the organic phases, wash with saturated sodium chloride solution (200 ml), dry over anhydrous sodium sulfate, and chromatograph on a silica gel column to obtain two components with a single configuration.

[0339] The first component with the shortest retention time is intermediate B-2-11c (0.94 g, 3.54 mmol, yield 41.26%). MS-ESI theoretical value [M+H] + : 255.2; measured value: 255.3.

[0340] The second component with the longest retention time is intermediate B-2-11c component 2 (0.47 g, 1.85 mmol, yield 20.10%). MS-ESI theoretical value [M+H] + : 255.2; measured value: 255.3.

[0341] Step 3

[0342] Intermediate B-2-11c (0.94 g, 3.54 mmol) was dissolved in dichloromethane (10 ml), and 4M hydrogen chloride in dioxane solution (5 ml) was added and reacted at room temperature for 3 hours. TLC showed that the reaction was complete, and the mixture was concentrated to obtain the crude intermediate B-2-11d.

[0343] Step 4

[0344] The crude intermediate B-2-11d was dissolved in dichloromethane (30 ml), and N,N-diisopropylethylamine (1.02 g, 7.86 mmol), intermediate A-2-7b (0.87 g, 4.32 mmol), 1-hydroxybenzotriazole (0.53 g, 3.93 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.75 g, 3.93 mmol) were added sequentially. After reacting at room temperature overnight, water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate B-2-11e (0.30 g, 0.9 mmol, total yield for two steps 25.4%). 1H NMR (400MHz, CDCl3) δ8.60–8.47(m,2H),7.59(dt,J=7.8,1.7Hz,1H),7.32–7.24(m,1H),4.86(dd,J=8.7,7.0Hz,1H),4.77(t,J=7.5Hz,1 H),3.93(q,J=8.2Hz,1H),3.84–3.72(m,1H),2.41(s,2H),2.14–2.02(m,1H),1.52(s,9H),0.98(d,J=6.8Hz,3H),0.93(d,J=6.7Hz,3H).

[0345] Step 5

[0346] Intermediate B-2-11e (0.30 g, 0.9 mmol) was dissolved in dichloromethane (5 ml), and 4M hydrogen chloride in dioxane solution (8 ml) was added and reacted at room temperature for 2 hours. TLC showed that the reaction was complete, and the mixture was concentrated to obtain a crude intermediate B-2-11f.

[0347] Step 6

[0348] The crude intermediate B-2-11f was dissolved in tetrahydrofuran (20 ml). N,N-diisopropylethylamine (0.21 g, 1.62 mmol) was added under ice-cooling, followed by the slow dropwise addition of acetic anhydride (0.12 g, 1.22 mmol). After the addition was complete, the reaction was continued under ice-cooling for 30 minutes. The mixture was then brought to room temperature and allowed to react for 2 hours. TLC indicated the reaction was complete. Methanol (5 mL) was added, the mixture was concentrated, and the product was purified by silica gel column chromatography to afford product B-2-11 (80 mg, 0.29 mmol, 32.2% total yield for two steps). 1 H NMR (400MHz, CDCl3) δ8.73 (d, J=8.1Hz, 1H), 8.54–8.39 (m, 2H), 7.55 (dt, J= 7.9,1.8Hz,1H),7.29–7.26(m,1H),4.96(dd,J=9.4,6.7Hz,1H),4.79(dd,J= 8.4,6.9Hz,1H),4.15–3.90(m,2H),2.69–2.60(m,1H),2.43–2.35(m,1H),2 .06–2.00(m,1H),1.94(s,3H),0.94(d,J=6.8Hz,3H),0.88(d,J=6.8Hz,3H).

[0349] Preparation Example 42 Preparation of Compound ZZL-7

[0350] first step

[0351] Add (tert-Butyloxycarbonyl)-L-alanine (4.5 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 that the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was adjusted to acidity with 2M hydrochloric acid and extracted with dichloromethane (50 mL*2). The organic phases were combined, and the organic phase was adjusted to alkalinity with saturated sodium bicarbonate and extracted with dichloromethane (50 mL*2). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the intermediate (tert-butoxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol, yield 90.39%).

[0352] LCMS (M+H + )=303.1

[0353] Step 2

[0354] To a dry, single-necked flask, add (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 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 hours. After TLC indicated completion of the reaction, the organic phase was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the intermediate L-alanyl-L-valine methyl ester (3.7 g, 18.32 mmol, 87.22% yield).

[0355] LCMS (M+H + )=203.3

[0356] 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).

[0357] Step 3

[0358] L-Alanyl-L-valine methyl ester (3.7 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 (2.8 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 completion of the reaction, 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 (PE:EA = 5:1). This afforded acetyl-L-alanyl-L-valine methyl ester (2.6 g, 10.67 mmol, 58.23% yield), namely ZZL-7.

[0359] LCMS (M+H + )=245.3

[0360] 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).

[0361] Preparation Example 43 Preparation of Compound A-2-38

[0362] first step

[0363] A-2-38a (3.00 g, 13.82 mmol) was dissolved in dichloromethane (50 mL) and stirred at 4°C for 10 min. Tetrahydro-2H-pyran-4-ol (2.11 g, 20.71 mmol), 4-dimethylaminopyridine (2.52 g, 20.71 mmol), and N,N'-dicyclohexylcarbodiimide (4.27 g, 20.71 mmol) were added in one portion. After stirring at room temperature for 12 h, TLC indicated the reaction was complete. Water (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed sequentially with saturated brine (200 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-38b (2.50 g, 8.30 mmol, 60.0% yield).

[0364] Step 2

[0365] Intermediate A-2-38b (2.50 g, 8.30 mmol) was dissolved in dichloromethane (20 ml) and a 4 M solution of hydrogen chloride in dioxane (20 ml) was added. After stirring at room temperature for 2 h, TLC indicated that the reaction was complete. The crude product of intermediate A-2-38c was obtained by concentration and used directly in the next step without purification.

[0366] Step 3

[0367] Dissolve the crude intermediate A-2-38c and intermediate A-2-7b (1.66 g, 8.30 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (3.22 g, 24.90 mmol), N-hydroxy-7-azabenzotriazole (1.13 g, 8.30 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.59 g, 8.30 mmol). After the addition is complete, react in an ice bath for 1 hour and then transfer to room temperature. After overnight reaction, TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-38d (2.00 g, 5.20 mmol, total yield of two steps 62.7%).

[0368] 1 H NMR(400MHz, CDCl3)δ5.05(dt,J=12.4,4.1Hz,1H),4.70(t,J=8.0Hz,1H),4.57(dd,J=8.7,4.6Hz,1H),4.03–3.80(m,4H),3.64–3.52(m,2H),2.46 (d,J=29.1Hz,2H),2.27(qd,J=11.7,6.9Hz,1H),2.03–1.90(m,2H),1.73 (ddd,J=13.1,8.6,4.0Hz,2H),1.49(s,9H),0.99(dd,J=24.2,6.9Hz,6H).

[0369] Step 4

[0370] Intermediate A-2-38d (1.10 g, 2.86 mmol) was dissolved in dichloromethane (5 ml) and a 4M solution of hydrogen chloride in dioxane (10 ml) was added. After stirring at room temperature for 2 h, TLC indicated the reaction was complete. The crude product of intermediate A-2-38e was obtained by concentration and used directly in the next step without purification.

[0371] Step 5

[0372] Dissolve the crude intermediate A-2-38e in tetrahydrofuran (20 ml) and add N,N-diisopropylethylamine (1.11 g, 8.58 mmol). After stirring in an ice bath for 10 minutes, slowly add acetic anhydride (0.58 g, 5.72 mmol). After reacting for 30 minutes, bring the mixture to room temperature. After continuing the reaction for 2 hours, TLC indicates the reaction is complete. Add ethanol (10 mL), concentrate, and purify by silica gel column chromatography to obtain product A-2-38 (0.60 g, 1.84 mmol, total yield for two steps 64.3%).

[0373] 1 H NMR (400MHz, CDCl3) δ8.28(d,J=8.3Hz,1H),4.95(tt,J=8.1,4.0Hz,1H),4.86(dd,J=9.5,6.5Hz,1H ),4.41(dd,J=8.5,4.7Hz,1H),4.00(t,J=7.7Hz,2H),3.88–3.74(m,2H),3.49(ddd,J=11.6,8.3,3. 2Hz,2H),2.61(ddt,J=12.0,8.0,7.2Hz,1H),2.37(ddt,J=12.0,9.5,7.2Hz,1H),2.17(dtd,J=13.8 ,6.9,4.9Hz,1H),1.88(s,3H),1.87–1.81(m,2H),1.69–1.53(m,2H),0.90(dd,J=19.1,6.9Hz,6H).

[0374] Preparation Example 44 Preparation of Compound A-2-39

[0375] first step

[0376] A-2-38a (2.00 g, 9.21 mmol) was dissolved in dichloromethane (50 ml) and, under ice-cooling, methyl 2-hydroxyacetate (1.24 g, 13.81 mmol), 4-dimethylaminopyridine (1.69 g, 13.81 mmol), and N,N'-dicyclohexylcarbodiimide (4.27 g, 20.71 mmol) were added sequentially. After the addition, the mixture was stirred at room temperature for 12 h. TLC indicated the reaction was complete. Water (50 ml) was added and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed sequentially with saturated brine (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-39a (1.50 g, 5.18 mmol, 56.2% yield).

[0377] Step 2

[0378] Intermediate A-2-39a (1.50 g, 5.18 mmol) was dissolved in dichloromethane (20 ml) and a 4 M solution of hydrogen chloride in dioxane (20 ml) was added. After stirring at room temperature for 2 h, TLC indicated that the reaction was complete. The solution was concentrated to afford the crude intermediate A-2-39b, which was used directly in the next reaction without purification.

[0379] Step 3

[0380] Dissolve the crude intermediate A-2-39b and intermediate A-2-7b (1.06 g, 5.29 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (1.92 g, 14.91 mmol), N-hydroxy-7-azabenzotriazole (0.71 g, 5.29 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.01 g, 5.29 mmol) in an ice bath. Continue the reaction in an ice bath for 1 hour and then transfer to room temperature. After overnight reaction, TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-39c (1.10 g, 2.95 mmol, total yield of two steps 55.8%).

[0381] 1 H NMR (400MHz, CDCl3) δ4.73(d,J=15.9Hz,1H),4.60(t,J=7.7Hz,2H),4.51(d,J=15.9Hz,1H),3.87(d,J=8.2Hz,1H),3.77(dd,J=14 .1,8.4Hz,1H),3.70(s,3H),2.38(d,J=15.2Hz,1H),2.35–2.19(m,2H),1.39(s,9H),0.97(d,J=6.9Hz,3H),0.93(d,J=6.9Hz,3H).

[0382] Step 4

[0383] Intermediate A-2-39c (1.10 g, 2.95 mmol) was dissolved in dichloromethane (5 ml) and a 4M solution of hydrogen chloride in dioxane (10 ml) was added. After stirring at room temperature for 2 h, TLC indicated the reaction was complete. The crude product of intermediate A-2-39d was obtained by concentration and used directly in the next step without purification.

[0384] Step 5

[0385] The crude intermediate A-2-39d was dissolved in tetrahydrofuran (20 ml) and N,N-diisopropylethylamine (1.14 g, 8.85 mmol) was added. After stirring in an ice bath for 10 min, acetic anhydride (0.60 g, 5.90 mmol) was slowly added dropwise and the reaction continued for 30 min. After the mixture was brought to room temperature and allowed to react for 2 h, TLC indicated the reaction was complete. Ethanol (10 mL) was added, the mixture was concentrated, and purified by silica gel column chromatography to afford product A-2-39 (0.24 g, 0.76 mmol, 25.8% total yield for two steps).

[0386] 1 H NMR (400MHz, CDCl3) δ8.30 (d, J=8.0Hz, 1H), 4.85 (dd, J=9.5, 6.6Hz, 1H), 4. 73(d,J=15.9Hz,1H),4.55–4.50(m,1H),4.50–4.44(m,1H),4.08–3.93(m,2 H),3.69(s,3H),2.60(ddt,J=12.0,9.0,6.8Hz,1H),2.37(dtd,J=11.9,8.9 ,6.0Hz,1H),2.31–2.21(m,1H),1.87(s,3H),0.96(dd,J=12.9,6.9Hz,6H).

[0387] Preparation Example 45 Preparation of Compound A-2-40

[0388] first step

[0389] A-2-38a (5.00 g, 23.04 mmol) was dissolved in dichloromethane (50 ml), and 1-methylpiperidin-4-ol (3.97 g, 34.56 mmol), 4-dimethylaminopyridine (4.21 g, 34.56 mmol), and N,N'-dicyclohexylcarbodiimide (7.12 g, 34.56 mmol) were added sequentially under ice-cooling. After addition, the mixture was brought to room temperature and allowed to react for 12 h. TLC indicated the reaction was complete. Water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-40a (4.00 g, 12.72 mmol, 55.2% yield).

[0390] Step 2

[0391] Intermediate A-2-40a (4.00 g, 12.72 mmol) was dissolved in dichloromethane (20 ml) and a 4M solution of hydrogen chloride in dioxane (20 ml) was added. After 2 h at room temperature, TLC indicated the reaction was complete. The crude intermediate A-2-40b was concentrated and used directly in the next reaction without purification.

[0392] Step 3

[0393] Dissolve the crude intermediate A-2-40b and A-2-7b (2.67 g, 13.36 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (3.16 g, 24.48 mmol), N-hydroxy-7-azabenzotriazole (1.8 g, 13.22 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.55 g, 13.36 mmol) under ice-cooling. After the addition is complete, react for 1 hour and then transfer to room temperature. Allow to react overnight. TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-40c (2.50 g, 6.29 mmol, total yield for two steps 47.1%). 1 H NMR (400MHz, CDCl3) δ4.88–4.74(m,1H),4.66–4.53(m,1H),4.47(dd,J=8.8,4.6Hz ,1H),3.87(q,J=8.3Hz,1H),3.76(td,J=8.5,5.4Hz,1H),2.54(s,2H),2.47–2.27(m ,2H),2.22(s,3H),2.17(ddd,J=18.4,9.2,4.5Hz,2H),2.04(s,1H),1.91–1.78(m, 2H), 1.68 (dqd, J=16.6, 8.3, 3.7Hz, 2H), 1.40 (s, 9H), 0.89 (dd, J=24.2, 6.9Hz, 6H).

[0394] Step 4

[0395] Intermediate A-2-40c (2.50 g, 6.29 mmol) was dissolved in dichloromethane (5 ml) and a 4M solution of hydrogen chloride in dioxane (10 ml) was added. After stirring at room temperature for 2 h, TLC indicated the reaction was complete. The product was concentrated to afford the crude intermediate A-2-40d, which was used directly in the next reaction without purification.

[0396] Step 5

[0397] The crude intermediate A-2-40d was dissolved in tetrahydrofuran (20 ml) and N,N-diisopropylethylamine (2.44 g, 18.87 mmol) was added. After stirring in an ice bath for 10 min, acetic anhydride (1.28 g, 12.58 mmol) was slowly added dropwise. The reaction was continued for 30 min and then the mixture was brought to room temperature. After another 2 h of reaction, TLC indicated that the reaction was complete. Ethanol (10 mL) was added, the mixture was concentrated, and the mixture was purified by silica gel column chromatography to obtain the product A-2-40 (1.00 g, 2.95 mmol, 46.8% total yield for two steps). MS-ESI theoretical value [M+H] + : 340.2; measured value: 340.3. 1 H NMR (400MHz, CDCl3) δ8.35(d,J=7.4Hz,1H),5.06(s,1H),4.84(dd,J=9.3,6.6Hz,1H),4.29(dd,J=7.5,5.5Hz,1H),4.02(t,J=7.9Hz,2 H),3.12(s,4H),2.73(s,3H),2.64–2.54(m,1H),2.45–2.31(m,2H),2.11(dt,J=13.5,7.0Hz,4H),1.88(s,3H),0.92(t,J=7.0Hz,6H).

[0398] Preparation Example 46 Preparation of Compound A-2-41

[0399] first step

[0400] A-2-41a (3.00 g, 13.82 mmol) was dissolved in dichloromethane (50 ml), and 2-methoxyethane-1-ol (1.57 g, 20.73 mmol), 4-dimethylaminopyridine (2.52 g, 20.73 mmol), and N,N'-dicyclohexylcarbodiimide (4.27 g, 20.73 mmol) were added sequentially under ice-cooling. After addition, the mixture was brought to room temperature and allowed to react for 12 h. TLC indicated the reaction was complete. Water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-41a (1.50 g, 5.45 mmol, 39.4% yield).

[0401] Step 2

[0402] Intermediate A-2-41a (1.50 g, 5.45 mmol) was dissolved in dichloromethane (20 ml) and a 4 M solution of hydrogen chloride in dioxane (20 ml) was added. After 2 h at room temperature, TLC indicated the reaction was complete. The crude intermediate A-2-41b was concentrated and used directly in the next reaction without purification.

[0403] Step 3

[0404] Dissolve the crude intermediate A-2-41b and A-2-7b (1.21 g, 6.91 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (2.11 g, 16.35 mmol), N-hydroxy-7-azabenzotriazole (1.1 g, 8.18 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.57 g, 8.18 mmol) under ice-cooling. After addition, react for 1 hour and then transfer to room temperature. Allow to react overnight. TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-41c (1.00 g, 2.79 mmol, total yield for two steps 51.2%). 1 H NMR (400MHz, CDCl3) δ4.72–4.64 (m, 1H), 4.60 (dd, J = 8.9, 4.6Hz, 1H), 4.40–4 .32(m,1H),4.31–4.23(m,1H),3.94(q,J=8.2Hz,1H),3.84(td,J=8.5,5.4Hz, 1H),3.64–3.55(m,2H),3.38(s,3H),2.42(d,J=39.7Hz,2H),2.25(dtd,J=13. 7, 6.9, 4.9Hz, 1H), 1.47 (s, 9H), 0.99 (d, J = 6.9Hz, 3H), 0.93 (d, J = 6.9Hz, 3H).

[0405] Step 4

[0406] Intermediate A-2-41c (1.00 g, 2.79 mmol) was dissolved in dichloromethane (5 ml) and a 4M solution of hydrogen chloride in dioxane (10 ml) was added. After stirring at room temperature for 2 h, TLC indicated the reaction was complete. The crude product of intermediate A-2-41d was obtained by concentration and used directly in the next reaction without purification.

[0407] Step 5

[0408] The crude intermediate A-2-41d was dissolved in tetrahydrofuran (20 ml) and N,N-diisopropylethylamine (1.08 g, 8.37 mmol) was added. After stirring in an ice bath for 10 min, acetic anhydride (0.57 g, 5.58 mmol) was slowly added dropwise. The reaction was continued for 30 min and then brought to room temperature. After another 2 h of reaction, TLC indicated that the reaction was complete. Ethanol (10 mL) was added, the mixture was concentrated, and the mixture was purified by silica gel column chromatography to obtain the product A-2-41 (0.30 g, 1.00 mmol, 35.8% total yield for two steps). MS-ESI theoretical value [M+H] + : 301.2; measured value: 301.4. 1 H NMR (400MHz, CDCl3) δ8.29 (d, J=8.1Hz, 1H), 4.91 (dd, J=9.4, 6.6Hz, 1H), 4.52 (d d,J=8.4,4.7Hz,1H),4.40–4.29(m,1H),4.27–4.18(m,1H),4.11–4.02(m,2H),3. 65–3.55(m,2H),3.37(s,3H),2.74–2.59(m,1H),2.44(dtd,J=11.9,8.8,6.3Hz,1 H), 2.34–2.18 (m, 1H), 1.95 (s, 3H), 0.99 (d, J = 6.9Hz, 3H), 0.95 (d, J = 6.9Hz, 3H).

[0409] Preparation Example 47 Preparation of Compound A-2-42

[0410] first step

[0411] A-2-38a (3.00 g, 13.82 mmol) was dissolved in dichloromethane (50 ml) and n-butanol (1.54 g, 20.73 mmol), 4-dimethylaminopyridine (2.52 g, 20.73 mmol), and N,N'-dicyclohexylcarbodiimide (4.27 g, 20.73 mmol) were added sequentially under an ice bath. After addition, the mixture was brought to room temperature and allowed to react for 12 h. TLC indicated the reaction was complete. Water (50 ml) was added and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-42a (2.50 g, 9.15 mmol, 66.2% yield).

[0412] Step 2

[0413] Intermediate A-2-42a (2.50 g, 9.15 mmol) was dissolved in dichloromethane (20 ml) and a 4 M solution of hydrogen chloride in dioxane (20 ml) was added. After 2 h at room temperature, TLC indicated the reaction was complete. The crude product of intermediate A-2-42b was obtained by concentration and used directly in the next step without purification.

[0414] Step 3

[0415] Dissolve the crude intermediate A-2-42b and A-2-7b (2.21 g, 10.98 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (3.55 g, 27.45 mmol), N-hydroxy-7-azabenzotriazole (1.48 g, 10.98 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.10 g, 10.98 mmol) under ice-cooling. After the addition is complete, react for 1 hour and then transfer to room temperature. Allow to react overnight. TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-42c (2.00 g, 5.61 mmol, total yield for two steps 61.3%). 1 H NMR (400MHz, CDCl3) δ4.71–4.59(m,1H),4.53(dd,J=9.0,4.7Hz,1H),4.18–4.08(m,2H),3.92(dd,J=16.4,8.3Hz,1H),3.81(td,J=8.5,5.4Hz,1H), 2.40(d,J=40.5Hz,2H),2.26–2.14(m,1H),1.65–1.57(m,2H),1.45(s,9H) ), 1.38 (dd, J = 15.2, 7.4Hz, 2H), 0.96 (d, J = 6.9Hz, 3H), 0.94–0.89 (m, 6H).

[0416] Step 4

[0417] Intermediate A-2-42c (2.00 g, 5.61 mmol) was dissolved in dichloromethane (5 ml) and a 4M solution of hydrogen chloride in dioxane (10 ml) was added. After stirring at room temperature for 2 h, TLC indicated the reaction was complete. Concentration afforded the crude intermediate A-2-42d, which was used directly in the next reaction without purification.

[0418] Step 5

[0419] The crude intermediate A-2-42d was dissolved in tetrahydrofuran (20 ml) and N,N-diisopropylethylamine (2.18 g, 16.83 mmol) was added. After stirring in an ice bath for 10 min, acetic anhydride (1.15 g, 11.22 mmol) was slowly added dropwise. The reaction was continued for 30 min and then the mixture was brought to room temperature. After another 2 h of reaction, TLC indicated that the reaction was complete. Ethanol (10 mL) was added, the mixture was concentrated, and the mixture was purified by silica gel column chromatography to obtain the product A-2-42 (0.60 g, 2.01 mmol, 35.8% total yield for two steps). MS-ESI theoretical value [M+H] + : 299.2; measured value: 299.4. 1 H NMR (400MHz, CDCl3) δ8.27(d,J=8.3Hz,1H),4.92(dd,J=9.5,6.5Hz,1H),4.48(dd,J=8.6,4.7Hz,1H),4.21–4.09(m,2H),4.07(t,J=6.0Hz,2H),2.73–2. 59(m,1H),2.51–2.38(m,1H),2.31–2.16(m,1H),1.95(s,3H),1.68–1.58(m, 2H), 1.40 (dt, J=15.1, 7.4Hz, 2H), 0.99 (d, J=6.9Hz, 3H), 0.96–0.91 (m, 6H).

[0420] Preparation Example 48 Preparation of Compound A-2-43

[0421] first step

[0422] A-2-38a (5.00 g, 23.04 mmol) was dissolved in dichloromethane (50 ml) and cyclopentanol (2.97 g, 34.56 mmol), 4-dimethylaminopyridine (4.21 g, 34.56 mmol), and N,N'-dicyclohexylcarbodiimide (7.12 g, 34.56 mmol) were added sequentially under an ice bath. After addition, the mixture was brought to room temperature and allowed to react for 12 h. TLC indicated the reaction was complete. Water (50 ml) was added and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-43a (3.50 g, 12.28 mmol, 53.3% yield).

[0423] Step 2

[0424] Intermediate A-2-43a (3.50 g, 12.28 mmol) was dissolved in dichloromethane (20 ml) and a 4 M solution of hydrogen chloride in dioxane (ml) was added. After 2 h at room temperature, TLC indicated the reaction was complete. The crude intermediate A-2-43b was concentrated and used directly in the next reaction without purification.

[0425] Step 3

[0426] Dissolve the crude intermediate A-2-43b and A-2-7b (2.45 g, 12.28 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (3.16 g, 24.48 mmol), N-hydroxy-7-azabenzotriazole (1.65 g, 12.28 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.34 g, 12.28 mmol) under ice-cooling. After the addition is complete, react for 1 hour and then transfer to room temperature. Allow to react overnight. TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-43c (2.00 g, 5.43 mmol, total yield of two steps 44.2%). 1 H NMR(400MHz, CDCl3)δ5.16(ddd,J=8.1,5.8,2.2Hz,1H),4.67–4.52(m,1H),4.44(dd, J=9.0,4.6Hz,1H),3.87(dd,J=16.4,8.2Hz,1H),3.76(td,J=8.5,5.4Hz,1H),2.35(d ,J=43.0Hz,2H),2.14(qd,J=6.8,2.0Hz,1H),1.84–1.75(m,2H),1.72–1.59(m,4H),1 .55(dd,J=7.8,3.3Hz,2H),1.40(s,9H),0.90(d,J=6.9Hz,3H),0.84(d,J=6.9Hz,3H).

[0427] Step 4

[0428] Intermediate A-2-43c (2.00 g, 5.43 mmol) was dissolved in dichloromethane (5 ml) and a 4M solution of hydrogen chloride in dioxane (10 ml) was added. After stirring at room temperature for 2 h, TLC indicated the reaction was complete. The product was concentrated to afford the crude intermediate A-2-43d, which was used directly in the next reaction without purification.

[0429] Step 5

[0430] Dissolve the crude intermediate A-2-43d in tetrahydrofuran (20 ml) and add N,N-diisopropylethylamine (2.11 g, 16.29 mmol). After stirring in an ice bath for 10 minutes, slowly add acetic anhydride (1.11 g, 10.86 mmol) dropwise. Continue the reaction for 30 minutes and then bring the mixture to room temperature. After another 2 hours of reaction, TLC indicates the reaction is complete. Add ethanol (10 mL), concentrate, and purify by silica gel column chromatography to obtain product A-2-43 (0.80 g, 2.58 mmol, 47.5% total yield for two steps). 1 H NMR (400MHz, CDCl3) δ8.24 (d, J=8.4Hz, 1H), 5.21 (td, J=5.7, 2.9Hz, 1H), 4.92 (dd, J=9.5, 6.5Hz,1H),4.45(dd,J=8.7,4.6Hz,1H),4.06(d,J=7.2Hz,2H),2.73–2.60(m,1H),2.50–2 .38(m,1H),2.31–2.15(m,1H),1.95(s,3H),1.83(ddd,J=10.9,7.3,5.5Hz,2H),1.78–1.6 5 (m, 4H), 1.61 (dd, J = 7.7, 2.5 Hz, 2H), 0.98 ( d, J = 6.9 Hz, 3H), 0.92 ( dd, J = 9.9, 4.8 Hz, 3H).

[0431] Preparation Example 49 Preparation of Compound A-2-44

[0432] first step

[0433] A-2-38a (3.00 g, 13.82 mmol) was dissolved in dichloromethane (50 ml) and cyclopropanol (1.20 g, 20.71 mmol), 4-dimethylaminopyridine (2.52 g, 20.71 mmol), and N,N'-dicyclohexylcarbodiimide (4.27 g, 20.71 mmol) were added sequentially under an ice bath. After addition, the mixture was brought to room temperature and the reaction was continued for 12 h. TLC indicated the reaction was complete. Water (50 ml) was added and the mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-44a (2.10 g, 8.17 mmol, 59.1% yield).

[0434] Step 2

[0435] Intermediate A-2-44a (2.10 g, 8.17 mmol) was dissolved in dichloromethane (20 ml) and a 4M solution of hydrogen chloride in dioxane (20 ml) was added. After 2 h at room temperature, TLC indicated the reaction was complete. The crude intermediate A-2-44b was concentrated and used directly in the next reaction without purification.

[0436] Step 3

[0437] Dissolve the crude intermediate A-2-44b and A-2-7b (1.63 g, 8.16 mmol) in dichloromethane (40 ml). Add N,N-diisopropylethylamine (3.16 g, 24.48 mmol), N-hydroxy-7-azabenzotriazole (1.10 g, 8.16 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.56 g, 8.16 mmol) under ice-cooling. After the addition is complete, react for 1 hour and then transfer to room temperature. Allow to react overnight. TLC indicates the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-44c (1.50 g, 4.41 mmol, total yield of two steps 54.0%).

[0438] 1 H NMR (400MHz, CDCl3) δ4.59(t,J=8.0Hz,1H),4.44(dd,J=8.9,4.8Hz,1H),4.16–4.08(m,1H),3.87(dd,J=16.4,8.1Hz,1H),3.77(dd,J=14 .1,8.4Hz,1H),2.35(d,J=34.0Hz,2H),2.16–2.05(m,1H),1.40(s,9H),0.90(d,J=6.8Hz,3H),0.84(d,J=6.9Hz,3H),0.70–0.61(m,4H).

[0439] Step 4

[0440] Intermediate A-2-44c (1.50 g, 4.41 mmol) was dissolved in dichloromethane (5 ml) and a 4M solution of hydrogen chloride in dioxane (10 ml) was added. After stirring at room temperature for 2 h, TLC indicated the reaction was complete. Concentration afforded the crude intermediate A-2-44d, which was used directly in the next reaction without purification.

[0441] Step 5

[0442] The crude intermediate A-2-44d was dissolved in tetrahydrofuran (20 ml) and N,N-diisopropylethylamine (1.71 g, 13.23 mmol) was added. After stirring in an ice bath for 10 min, acetic anhydride (0.90 g, 8.82 mmol) was slowly added dropwise. The reaction was continued for 30 min and then the mixture was brought to room temperature. After another 2 h of reaction, TLC indicated that the reaction was complete. Ethanol (10 mL) was added, the mixture was concentrated, and the mixture was purified by silica gel column chromatography to obtain the product A-2-44 (0.60 g, 2.12 mmol, 48.2% total yield for two steps). MS-ESI theoretical value [M+H] + : 283.2; measured value: 283.2. 1 H NMR (400MHz, CDCl3) δ8.21 (d, J=8.3Hz, 1H), 4.84 (dd, J=9.5, 6.5Hz, 1H), 4.3 6(dd,J=8.5,4.8Hz,1H),4.16–4.06(m,1H),4.04–3.92(m,2H),2.60(ddt,J=1 2.0,8.8,6.9Hz,1H),2.37(tdd,J=12.0,8.8,6.2Hz,1H),2.20–2.06(m,1H), 1.88(s,3H),0.90(d,J=6.9Hz,3H),0.86(d,J=6.9Hz,3H),0.73–0.58(m,4H).

[0443] Preparation Example 50 Preparation of Compounds B-2-12 and B-2-13

[0444] first step

[0445] Dissolve B-2-12a (4.00 g, 37.69 mmol) in dichloromethane (50 mL), and add (R)-tert-butylsulfenamide (4.57 g, 37.69 mmol) and cesium carbonate (12.28 g, 37.69 mmol) in sequence. Allow the reaction to proceed overnight. TLC indicates completion of the reaction. Filter the resulting filtrate, wash with saturated brine (100 × 2 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain intermediate B-2-12b (7.00 g, 33.4 mmol, yield 88.7%). MS-ESI theoretical value [M+H] + : 210.1; measured value: 210.1.

[0446] Step 2

[0447] Intermediate B-2-12b (4.50 g, 21.50 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (40.00 mL, 40.00 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0448] The component 1 with the shorter retention time is intermediate B-2-12c (1.00 g, 3.94 mmol, yield 18.4%). MS-ESI theoretical value [M+H] + : 254.2; measured value: 254.1. 1 H NMR (400MHz, Chloroform-d) δ7.29–7.23(m,2H),7.22–7.14(m,3H),3.38(d,J=5.3Hz,1H),2.35–1.95(m,1H),1.18(s,9H),0.80(dd,J=49.9,6.8Hz,6H).

[0449] The component 2 with a longer retention time is intermediate B-2-13c (0.24 g, 0.95 mmol, yield: 4.4%). MS-ESI theoretical value [M+H] + : 254.2; measured value: 254.1. 1 H NMR (400MHz, Chloroform-d) δ7.28–7.22(m,2H),7.22–7.15(m,3H),4.09(dd,J=6.7,2. 2Hz, 1H), 3.42 (s, 1H), 1.90 (h, J = 6.8Hz, 1H), 1.12 (s, 9H), 0.83 (dd, J = 72.1, 6.8Hz, 6H).

[0450] Step 3 - Component 1

[0451] Intermediate B-2-12c (1.00 g, 3.95 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to obtain the crude intermediate B-2-12d, which was used directly in the next reaction without purification.

[0452] Step 4 - Component 1

[0453] The crude product B-2-12d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (1.08 g, 5.38 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.41 g, 7.33 mmol), 1-hydroxybenzotriazole (0.99 g, 7.33 mmol), and ethyldiisopropylamine (1.90 g, 14.67 mmol) were added sequentially at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-12e (0.55 g, 1.65 mmol, yield 33.8%). MS-ESI theoretical value [M-Boc+2H] + : 233.2; measured value: 233.2. 1 H NMR(400MHz,Chloroform-d)δ7.24(dd,J=8.1,6.4Hz,2H),7.17(td,J=7.5,6.7,2.0Hz,3H),4.74(dd,J=9.4,7.0Hz,1H),4.66(s,1 H), 4.05 (q, J = 7.1Hz, 1H), 3.76 (dq, J = 55.3, 8.2Hz, 2H), 2.32 (s, 2H), 1.97–1.92 (m, 1H), 1.42 (s, 9H), 0.83 (dd, J = 27.0, 6.7Hz, 6H).

[0454] Step 5 - Component 1

[0455] Intermediate B-2-12e (0.55 g, 1.65 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-12f, which was used directly in the next reaction without purification.

[0456] Step 6 - Component 1

[0457] The crude intermediate B-2-12f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.16 g, 2.08 mmol) and ethyldiisopropylamine (0.73 g, 5.67 mmol) were added. After reacting at -10°C for 1 h, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-12 (86.2 mg, 0.31 mmol, total yield for two steps 19.0%). MS-ESI theoretical value [M+H]+ : 275.2; measured value: 275.1. 1 H NMR(400MHz,Chloroform-d)δ8.51(d,J=9.1Hz,1H),7.28–7.21(m,2H),7.18–7.06(m,3H),4.90(dd,J=9.5,6.5Hz,1H),4.71(dd,J=9.1,6.9Hz,1H) ,4.02–3.81(m,2H),2.59(ddt,J=12.0,9.4,6.7Hz,1H),2.42–2.18(m,1H) ,1.94(dt,J=13.6,6.7Hz,1H),1.86(s,3H),0.83(dd,J=33.1,6.8Hz,6H).

[0458] Step 3 - Component 2

[0459] Intermediate B-2-13c (0.24 g, 0.95 mmol) was dissolved in dichloromethane (2 mL) and a 4 M solution of hydrogen chloride in dioxane (4 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-13d, which was used directly in the next reaction without purification.

[0460] Step 4 - Component 2

[0461] The crude product B-2-13d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.27 g, 1.33 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.35 g, 1.81 mmol), 1-hydroxybenzotriazole (0.25 g, 1.81 mmol), and ethyldiisopropylamine (0.47 g, 3.63 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-13e (0.32 g, 0.96 mmol, total yield for two steps 100%). MS-ESI theoretical value [M-Boc+2H] + : 233.2; measured value: 233.2.

[0462] Step 5 - Component 2

[0463] Intermediate B-2-13e (0.32 g, 0.96 mmol) was dissolved in dichloromethane (3 mL). 4 M hydrogen chloride solution in dioxane (6 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-13f, which was used directly in the next reaction without purification.

[0464] Step 6 - Component 2

[0465] The crude intermediate B-2-13f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (97.0 mg, 1.23 mmol) and ethyldiisopropylamine (0.43 g, 3.36 mmol) were added. After reacting at -10°C for 1 hour, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-13 (118.2 mg, 0.43 mmol, total yield for two steps 44.8%). MS-ESI theoretical value [M+H] + : 275.2; measured value: 275.1. 1 HNMR(400MHz,Chloroform-d)δ8.45(d,J=8.8Hz,1H),7.23(d,J=7.2Hz,2H),7.20–7.12(m,3H),4.79(dd,J=9.5,6.5Hz,1H),4.66(dd,J=8.8,7.0Hz,1 H),4.01(ddd,J=9.0,6.5,3.8Hz,2H),2.78–2.49(m,1H),2.42–2.22(m,1H ), 1.95 (dd, J = 13.4, 6.6 Hz, 1H), 1.89 ( s, 3H), 0.79 ( dd, J = 25.4, 6.7 Hz, 6H).

[0466] Preparation Example 51 Preparation of Compounds B-2-14 and B-2-15

[0467] first step

[0468] B-2-14a (4.00 g, 28.46 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (3.45 g, 28.46 mmol) and cesium carbonate (13.91 g, 42.69 mmol) were added sequentially. The reaction was allowed to proceed overnight. TLC indicated the reaction was complete, and the product was filtered. The filtrate was washed with saturated brine (100 × 2 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford intermediate B-2-14b (6.00 g, 24.6 mmol, 86.5% yield).

[0469] Step 2

[0470] Intermediate B-2-14b (5.00 g, 20.51 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (41.0 mL, 41.00 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0471] The component 1 with a shorter retention time is intermediate B-2-14c (0.70 g, 2.43 mmol, yield 11.9%).

[0472] The component 2 with a longer retention time is intermediate B-2-15c (2.00 g, 6.94 mmol, yield 33.9%).

[0473] Step 3 - Component 1

[0474] Intermediate B-2-14c (0.70 g, 2.43 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-14d, which was used directly in the next reaction without purification.

[0475] Step 4 - Component 1

[0476] The crude product B-2-14d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.65 g, 3.32 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.85 g, 4.41 mmol), 1-hydroxybenzotriazole (0.60 g, 4.41 mmol), and ethyldiisopropylamine (1.14 g, 8.82 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by the addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-14e (0.45 g, 1.23 mmol, total yield for two steps 50.5%). MS-ESI theoretical value [M-Boc+2H] + : 267.1; measured value: 267.1.

[0477] Step 5 - Component 1

[0478] Intermediate B-2-14e (0.45 g, 1.23 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-14f, which was used directly in the next reaction without purification.

[0479] Step 6 - Component 1

[0480] The crude intermediate B-2-14f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.12 g, 1.53 mmol) and ethyldiisopropylamine (0.54 g, 4.17 mmol) were added. After reacting at -10°C for 1 h, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-14 (155.0 mg, 0.50 mmol, total yield for two steps 40.8%). MS-ESI theoretical value [M+H] + : 309.1; measured value: 309.1. 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J=8.9Hz,1H),7.21(d,J=2.0Hz,1H),7.19(s,1H),7.09–7.03(m,2H),4.89(dd,J=9.5,6.5Hz,1H),4.65(dd ,J=8.8,6.9Hz,1H),4.08–3.82(m,2H),2.45(ddtd,J=116.3,12.0,9.3,6 .1Hz,2H),1.95–1.88(m,1H),1.86(s,3H),0.82(dd,J=35.7,6.7Hz,6H).

[0481] Step 3 - Component 2

[0482] Intermediate B-2-15c (2.00 g, 6.95 mmol) was dissolved in dichloromethane (20 mL) and a 4M solution of hydrogen chloride in dioxane (40 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-15d, which was used directly in the next reaction without purification.

[0483] Step 4 - Component 2

[0484] The crude product B-2-15d was dissolved in dichloromethane (20 mL) and intermediate A-2-7b (1.81 g, 8.99 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.35 g, 12.25 mmol), 1-hydroxybenzotriazole (1.66 g, 12.25 mmol), and ethyldiisopropylamine (3.17 g, 24.51 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-15e (0.70 g, 1.91 mmol, total yield for two steps 27.5%). MS-ESI theoretical value [M-Boc+2H] + : 267.1; measured value: 267.1.

[0485] Step 5 - Component 2

[0486] Intermediate B-2-15e (0.70 g, 1.91 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-15f, which was used directly in the next reaction without purification.

[0487] Step 6 - Component 2

[0488] The crude intermediate B-2-15f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.16 g, 2.10 mmol) and ethyldiisopropylamine (0.74 g, 5.73 mmol) were added. After reacting at -10°C for 1 h, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-15 (74.0 mg, 0.24 mmol, total yield for two steps 12.5%). MS-ESI theoretical value [M+H] + : 309.1; measured value: 309.1. 1H NMR(400MHz,Chloroform-d)δ8.48(d,J=8.5Hz,1H),7.33–7.17(m,2H),7.16–7.00(m,2H),4.79(dd,J=9.5,6.5Hz,1H),4.60(dd,J=8.5,7.0Hz,1H ), 4.01 (dd, J=9.0, 6.5Hz, 2H), 2.66 (dtd, J=12.0, 8.7, 6.8Hz, 1H), 2.31 (ddt, J=12.3, 5.9, 4.7Hz, 1H), 1.89 (s, 4H), 0.78 (dd, J=25.4, 6.7Hz, 6H).

[0489] Preparation Example 52 Preparation of Compounds B-2-16 and B-2-17

[0490] first step

[0491] B-2-16a (4.00 g, 33.29 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (4.03 g, 33.29 mmol) and cesium carbonate (16.27 g, 49.94 mmol) were added sequentially. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete, and the product was filtered. The filtrate was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-16b (6.50 g, 29.1 mmol, yield 87.4%).

[0492] Step 2

[0493] Intermediate B-2-16b (5.00 g, 22.39 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (44.5 mL, 40.50 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0494] The component 1 with the shorter retention time is intermediate B-2-16c (1.86 g, 6.96 mmol, yield 31.1%). MS-ESI theoretical value [M+H] + : 268.2; measured value: 268.1. 1H NMR(400MHz,Chloroform-d)δ7.19–7.03(m,4H),4.24(dd,J=7.7,6.2Hz,1H),3.32(d,J =6.2Hz,1H),2.33(s,3H),2.15–1.91(m,1H),1.14(s,9H),0.85(dd,J=90.1,6.7Hz,6H).

[0495] The component 2 with a longer retention time is intermediate B-2-17c (0.50 g, 1.87 mmol, yield 8.4%). MS-ESI theoretical value [M+H] + : 268.2; measured value: 268.1. 1 H NMR(400MHz,Chloroform-d)δ7.19–7.04(m,4H),4.33(dd,J=7.6,2.6Hz,1H),3.62–3. 27(m,1H),2.32(s,3H),2.04–1.82(m,1H),1.09(s,9H),0.87(dd,J=88.1,6.7Hz,6H).

[0496] Step 3 - Component 1

[0497] Intermediate B-2-16c (1.86 g, 6.96 mmol) was dissolved in dichloromethane (15 mL) and a 4 M solution of hydrogen chloride in dioxane (30 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-16d, which was used directly in the next reaction without purification.

[0498] Step 4 - Component 1

[0499] The crude product B-2-16d was dissolved in dichloromethane (20 mL) and intermediate A-2-7b (1.36 g, 6.74 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.76 g, 9.20 mmol), 1-hydroxybenzotriazole (1.24 g, 9.20 mmol), and ethyldiisopropylamine (2.38 g, 18.39 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by the addition of water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-16e (1.30 g, 3.75 mmol, total yield for two steps 53.9%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.3.

[0500] Step 5 - Component 1

[0501] Intermediate B-2-16e (1.00 g, 2.89 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-16f, which was used directly in the next reaction without purification.

[0502] Step 6 - Component 1

[0503] The crude intermediate B-2-16f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.25 g, 3.12 mmol) and ethyldiisopropylamine (1.10 g, 8.52 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-16 (331.5 mg, 1.15 mmol, total yield for two steps 39.8%). MS-ESI theoretical value [M+H] + : 289.2; measured value: 289.4. 1 H NMR(400MHz,Chloroform-d)δ8.40(d,J=8.9Hz,1H),7.13(t,J=7.8Hz,1H),7.05–6.90(m,3H),4.79(dd,J=9.5,6.4Hz,1H),4.61(dd,J=8.9,7.1Hz, 1H),4.10–3.91(m,2H),2.78–2.60(m,1H),2.30(dq,J=9.0,3.0Hz,1H),2 .26(s,3H),1.99–1.90(m,1H),1.89(s,3H),0.79(dd,J=27.0,6.8Hz,6H).

[0504] Step 3 - Component 2

[0505] Intermediate B-2-17c (0.50 g, 1.87 mmol) was dissolved in dichloromethane (5 mL) and a 4 M solution of hydrogen chloride in dioxane (10 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to obtain the crude intermediate B-2-17d, which was used directly in the next reaction without purification.

[0506] Step 4 - Component 2

[0507] The crude product B-2-17d was dissolved in dichloromethane (20 mL) and intermediate A-2-7b (0.62 g, 3.10 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.81 g, 4.23 mmol), 1-hydroxybenzotriazole (0.57 g, 4.23 mmol), and ethyldiisopropylamine (1.09 g, 8.46 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-17e (0.50 g, 1.44 mmol, total yield for two steps 77.0%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.4.

[0508] Step 5 - Component 2

[0509] Intermediate B-2-17e (0.50 g, 1.44 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-17f, which was used directly in the next reaction without purification.

[0510] Step 6 - Component 2

[0511] The crude intermediate B-2-17f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.13 g, 1.61 mmol) and ethyldiisopropylamine (0.57 g, 4.38 mmol) were added. After reacting at -10°C for 1 hour, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-17 (130.4 mg, 0.45 mmol, total yield of two steps 31.4%). MS-ESI theoretical value [M+H] + : 289.2; measured value: 289.2. 1H NMR(400MHz,Chloroform-d)δ8.41(d,J=8.9Hz,1H),7.18–6.97(m,4H),4.88(t,J=8.3Hz,1H),4.75(dd,J=9.5,6.4Hz,1H),4.11–3.87(m,2 H), 2.66(ddt,J=12.0,9.2,6.7Hz,1H),2.36(s,3H),2.35–2.19(m,1H),1.95(d,J=23.8Hz,1H),1.89(s,3H),0.82(dd,J=49.2,6.7Hz,6H).

[0512] Preparation Example 53 Preparation of Compounds B-2-18 and B-2-19

[0513] first step

[0514] B-2-18a (4.00 g, 33.29 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (4.03 g, 33.29 mmol) and cesium carbonate (16.27 g, 49.94 mmol) were added in sequence. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete, and the product was filtered. The filtrate was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-18b (7.20 g, 32.24 mmol, yield 96.8%).

[0515] Step 2

[0516] Intermediate B-2-18b (5.00 g, 22.39 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (44.5 mL, 44.50 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0517] The component 1 with the shorter retention time is intermediate B-2-18c (0.95 g, 3.55 mmol, yield 15.9%). MS-ESI theoretical value [M+H] + : 268.2; measured value: 268.2.

[0518] The component 2 with a longer retention time is intermediate B-2-19c (0.50 g, 1.87 mmol, yield 8.4%). MS-ESI theoretical value [M+H] + : 268.2; measured value: 268.2.

[0519] Step 3 - Component 1

[0520] Intermediate B-2-18c (0.95 g, 3.55 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-18d, which was used directly in the next reaction without purification.

[0521] Step 4 - Component 1

[0522] The crude product B-2-18d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (1.22 g, 6.06 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.58 g, 8.27 mmol), 1-hydroxybenzotriazole (1.12 g, 8.27 mmol), and ethyldiisopropylamine (2.14 g, 16.53 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-18e (1.30 g, 3.75 mmol, total yield of the two-step reaction was 100%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.4.

[0523] Step 5 - Component 1

[0524] Intermediate B-2-18e (1.30 g, 3.75 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-18f, which was used directly in the next reaction without purification.

[0525] Step 6 - Component 1

[0526] The crude intermediate B-2-18f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.35 g, 4.47 mmol) and ethyldiisopropylamine (1.57 g, 12.18 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-18 (192.1 mg, 0.67 mmol, total yield for two steps 17.8%). MS-ESI theoretical value [M+H] + : 289.2; measured value: 289.2. 1 H NMR(400MHz,Chloroform-d)δ8.40(d,J=8.9Hz,1H),7.13(t,J=7.8Hz,1H),7.04–6.86(m,3H),4.79(dd,J=9.5,6.4Hz,1H),4.61(dd,J=8.9,7.1Hz,1H),4 .14–3.83(m,2H),2.68(ddt,J=12.0,9.1,6.7Hz,1H),2.34–2.27(m,1H),2.2 6(s,3H),1.95(d,J=19.6Hz,1H),1.89(s,3H),0.79(dd,J=27.0,6.8Hz,6H).

[0527] Step 3 - Component 2

[0528] Intermediate B-2-19c (0.50 g, 1.87 mmol) was dissolved in dichloromethane (5 mL) and a 4 M solution of hydrogen chloride in dioxane (10 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-19d, which was used directly in the next reaction without purification.

[0529] Step 4 - Component 2

[0530] The crude product B-2-19d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.64 g, 3.17 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.83 g, 4.32 mmol), 1-hydroxybenzotriazole (0.58 g, 4.32 mmol), and ethyldiisopropylamine (1.12 g, 8.64 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-19e (0.55 g, 1.59 mmol, total yield for two steps 84.9%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.3.

[0531] Step 5 - Component 2

[0532] Intermediate B-2-19e (0.55 g, 1.59 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-19f, which was used directly in the next reaction without purification.

[0533] Step 6 - Component 2

[0534] The crude intermediate B-2-19f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.14 g, 1.78 mmol) and ethyldiisopropylamine (0.63 g, 4.63 mmol) were added. After reacting at -10°C for 1 hour, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-19 (99.9 mg, 0.35 mmol, total yield for two steps 21.8%). MS-ESI theoretical value [M+H] + : 289.2; measured value: 289.4. 1H NMR(400MHz,Chloroform-d)δ8.47(d,J=9.2Hz,1H),7.12(t,J=7.5Hz,1H),7.04–6.88(m,3H),4.89(dd,J=9.6,6.5Hz,1H),4.68(dd,J=9.2,6. 9Hz,1H),4.06–3.70(m,2H),2.67–2.49(m,1H),2.38–2.28(m,1H),2.2 6(s,3H),2.06–1.88(m,1H),1.86(s,3H),0.83(dd,J=33.3,6.8Hz,6H).

[0535] Preparation Example 54 Preparation of Compounds B-2-20 and B-2-21

[0536] first step

[0537] B-2-20a (4.00 g, 33.29 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (4.03 g, 33.29 mmol) and cesium carbonate (16.27 g, 49.94 mmol) were added sequentially. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete, and the product was filtered. The filtrate was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-20b (7.00 g, 30.79 mmol, yield 92.5%).

[0538] Step 2

[0539] Intermediate B-2-20b (5.00 g, 22.00 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen protection, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (40.00 mL, 40.00 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0540] The component 1 with a shorter retention time is intermediate B-2-20c (1.12 g, 4.12 mmol, yield 18.8%).

[0541] The component 2 with a longer retention time is intermediate B-2-21c (1.12 g, 4.12 mmol, yield 18.8%).

[0542] Step 3 - Component 1

[0543] Intermediate B-2-20c (1.12 g, 4.12 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to obtain the crude intermediate B-2-20d, which was used directly in the next reaction without purification.

[0544] Step 4 - Component 1

[0545] The crude product B-2-20d was dissolved in dichloromethane (20 mL) and intermediate A-2-7b (1.39 g, 6.91 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.81 g, 9.42 mmol), 1-hydroxybenzotriazole (1.27 g, 9.42 mmol), and ethyldiisopropylamine (2.43 g, 18.84 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-20e (0.55 g, 1.57 mmol, total yield for the two-step reaction was 38.1%). MS-ESI theoretical value [M-Boc+2H] + : 251.2; measured value: 251.2.

[0546] Step 5 - Component 1

[0547] Intermediate B-2-20e (0.55 g, 1.57 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-20f, which was used directly in the next reaction without purification.

[0548] Step 6 - Component 1

[0549] The crude intermediate B-2-20f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.14 g, 1.80 mmol) and ethyldiisopropylamine (0.64 g, 4.92 mmol) were added. After reacting at -10°C for 1 hour, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-20 (76.7 mg, 0.26 mmol, total yield for two steps 16.7%). MS-ESI theoretical value [M+H] +: 293.2; measured value: 293.2. 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J=8.6Hz,1H),7.19–7.11(m,2H),6.93(t,J=8.7Hz,2H),4.79(dd,J=9.5,6.5Hz,1H),4.61(dd,J=8.6,7.1Hz,1 H),4.06–3.88(m,2H),2.76–2.49(m,1H),2.31(dddd,J=12.0,9.5,8.3,6. 3Hz, 1H), 1.92 (d, J = 7.0Hz, 1H), 1.89 (s, 3H), 0.78 (dd, J = 29.5, 6.7Hz, 6H).

[0550] Step 3 - Component 2

[0551] Intermediate B-2-21c (1.12 g, 4.19 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-21d, which was used directly in the next reaction without purification.

[0552] Step 4 - Component 2

[0553] The crude product B-2-21d was dissolved in dichloromethane (20 mL) and intermediate A-2-7b (1.39 g, 6.91 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.81 g, 9.42 mmol), 1-hydroxybenzotriazole (1.27 g, 9.42 mmol), and ethyldiisopropylamine (2.43 g, 18.84 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-21e (1.50 g, 4.28 mmol, total yield for two steps 100%). MS-ESI theoretical value [M-Boc+2H] + : 251.1; measured value: 251.3.

[0554] Step 5 - Component 2

[0555] Intermediate B-2-21e (1.00 g, 2.85 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-21f, which was used directly in the next reaction without purification.

[0556] Step 6 - Component 2

[0557] The crude intermediate B-2-21f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.28 g, 3.52 mmol) and ethyldiisopropylamine (1.24 g, 9.60 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-21 (0.49 g, 1.68 mmol, total yield for two steps 58.8%). MS-ESI theoretical value [M+H] + : 293.2; measured value: 293.2. 1 H NMR(400MHz,Chloroform-d)δ8.65–8.34(m,1H),7.12–7.02(m,2H),7.00–6.79(m,2H),4.89(dd,J=9.5,6.5Hz,1H),4.67(dd,J=8.9,7.0Hz,1H),4.1 3–3.79(m,2H),2.60(ddt,J=12.0,9.4,6.7Hz,1H),2.31(dtd,J=12.0,9.3 ,5.5Hz,1H),1.95–1.87(m,1H),1.86(s,3H),0.82(dd,J=38.1,6.7Hz,6H).

[0558] Preparation Example 55 Preparation of Compounds B-2-22 and B-2-23

[0559] first step

[0560] B-2-22a (4.00 g, 22.79 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (2.78 g, 22.97 mmol) and cesium carbonate (11.23 g, 34.45 mmol) were added sequentially. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete, and the product was filtered. The filtrate was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-22b (6.00 g, 21.6 mmol, yield 94.9%).

[0561] Step 2

[0562] Intermediate B-2-22b (5.00 g, 18.03 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (36.0 mL, 36.0 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0563] The component 1 with the shorter retention time is intermediate B-2-22c (1.00 g, 3.11 mmol, yield 17.3%). MS-ESI theoretical value [M+H] + : 322.1; measured value: 322.4. 1 H NMR(400MHz,Chloroform-d)δ7.67–7.48(m,2H),7.38–7.28(m,2H),4.12(t,J=6.3Hz,1 H), 3.41 (d, J = 6.4Hz, 1H), 2.42–1.95 (m, 1H), 1.18 (s, 9H), 0.81 (dd, J = 52.3, 6.7Hz, 6H).

[0564] The component 2 with a longer retention time is intermediate B-2-23c (1.00 g, 3.11 mmol, yield 17.3%). MS-ESI theoretical value [M+H] + : 322.1; measured value: 322.4. 1 H NMR(400MHz,Chloroform-d)δ7.51(d,J=8.1Hz,2H),7.31(d,J=8.0Hz,2H),4.17(dd,J=6.6,2. 0Hz, 1H), 3.46 (d, J = 2.0Hz, 1H), 1.95–1.87 (m, 1H), 1.13 (s, 9H), 0.83 (dd, J = 69.5, 6.8Hz, 6H).

[0565] Step 3 - Component 1

[0566] Intermediate B-2-22c (1.00 g, 3.11 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-22d, which was used directly in the next reaction without purification.

[0567] Step 4 - Component 1

[0568] The crude product B-2-22d was dissolved in dichloromethane (20 mL) and intermediate A-2-7b (1.02 g, 5.06 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.32 g, 6.90 mmol), 1-hydroxybenzotriazole (0.93 g, 6.90 mmol), and ethyldiisopropylamine (1.78 g, 13.80 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-22e (1.10 g, 2.75 mmol, total yield for the two-step reaction was 88.3%).

[0569] Step 5 - Component 1

[0570] Intermediate B-2-22e (1.10 g, 2.75 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-22f, which was used directly in the next reaction without purification.

[0571] Step 6 - Component 1

[0572] The crude intermediate B-2-22f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.23 g, 2.93 mmol) and ethyldiisopropylamine (1.03 g, 7.98 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-22 (152.1 mg, 0.44 mmol, total yield for two steps 16.2%). MS-ESI theoretical value [M+H] + : 343.2; measured value: 343.2. 1H NMR (400MHz, Chloroform-d) δ8.58(d,J=8.3Hz,1H),7.50(d,J=8.1Hz,2H),7.32(d,J=8.1Hz,2H),4.80(dd,J=9.5,6.5Hz,1H),4.67(dd,J=8.4,6. 9Hz,1H),4.06–3.95(m,2H),2.73–2.58(m,1H),2.31(ddt,J=12.1,9.5,6 .9Hz,1H),2.00–1.92(m,1H),1.90(s,3H),0.80(dd,J=22.1,6.8Hz,6H).

[0573] Step 3 - Component 2

[0574] Intermediate B-2-23c (1.00 g, 3.11 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-23d, which was used directly in the next reaction without purification.

[0575] Step 4 - Component 2

[0576] The crude product B-2-23d was dissolved in dichloromethane (20 mL) and intermediate A-2-7b (1.07 g, 5.31 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.39 g, 7.25 mmol), 1-hydroxybenzotriazole (0.98 g, 7.25 mmol), and ethyldiisopropylamine (1.87 g, 14.49 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-23e (1.00 g, 2.50 mmol, total yield for two steps 80.3%).

[0577] Step 5 - Component 2

[0578] Intermediate B-2-23e (1.00 g, 2.50 mmol) was dissolved in dichloromethane (10 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (20 mL) was added and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-23f, which was used directly in the next reaction without purification.

[0579] Step 6 - Component 2

[0580] The crude intermediate B-2-23f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.20 g, 2.56 mmol) and ethyldiisopropylamine (0.90 g, 6.99 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-23 (284.6 mg, 0.83 mmol, total yield for two steps 33.2%). MS-ESI theoretical value [M+H] + : 343.2; measured value: 343.2. 1 H NMR (400MHz, Chloroform-d) δ8.64(d,J=8.8Hz,1H),7.49(d,J=8.0Hz,2H),7.24(d,J=8.1Hz,2H),4.90(dd,J=9.5,6.5Hz,1H),4.74(dd,J=8.8,6. 8Hz,1H),4.08–3.78(m,2H),2.68–2.52(m,1H),2.31(dtd,J=12.0,9.3,5 .5Hz,1H),2.01–1.91(m,1H),1.88(s,3H),0.84(dd,J=30.1,6.8Hz,6H).

[0581] Preparation Example 56 Preparation of Compound B-2-24

[0582] first step

[0583] B-2-24a (4.00 g, 29.38 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (4.57 g, 29.38 mmol) and anhydrous copper sulfate (4.69 g, 29.38 mmol) were added sequentially. The reaction was allowed to proceed overnight. TLC indicated that the reaction was complete. The product was filtered and the filtrate was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-24b (4.00 g, 16.7 mmol, yield 56.9%). MS-ESI theoretical value [M+H] + : 240.1; measured value: 240.1.

[0584] Step 2

[0585] Intermediate B-2-24b (2.00 g, 8.36 mmol) was dissolved in tetrahydrofuran (20 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (16.72 mL, 16.72 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC indicated the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed sequentially with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a mixture of two components, designated as intermediate B-2-24c (1.00 g, 3.53 mmol, yield 42.2%). MS-ESI theoretical value [M+H] + : 284.2; measured value: 284.1.

[0586] Step 3

[0587] Intermediate B-2-24c component 1 (1.00 g, 3.53 mmol) was dissolved in dichloromethane (10 mL) and a 4M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to obtain the crude intermediate B-2-24d, which was used directly in the next reaction without purification.

[0588] Step 4

[0589] The crude product B-2-24d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (1.11 g, 5.02 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.44 g, 7.53 mmol), 1-hydroxybenzotriazole (1.02 g, 7.53 mmol), and ethyldiisopropylamine (1.95 g, 15.06 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-24e (1.20 g, 3.31 mmol, total yield for the two-step reaction was 93.8%). MS-ESI theoretical value [M-Boc+2H] + : 263.2; measured value: 263.2.

[0590] Step 5

[0591] Intermediate B-2-24e (1.20 g, 3.31 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-24f, which was used directly in the next reaction without purification.

[0592] Step 6 - Component 1

[0593] The crude intermediate B-2-24f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.28 g, 3.61 mmol) and ethyldiisopropylamine (1.27 g, 9.84 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-24 (332.9 mg, 1.09 mmol, total yield for two steps 33.0%). MS-ESI theoretical value [M+H] + : 305.2; measured value: 305.2. 1 H NMR(400MHz,Chloroform-d)δ8.40(dd,J=25.0,8.9Hz,1H),7.14–7.00(m,2H),6.81–6.72(m,2H),4.83(ddd,J=41.8,9.5,6.5Hz,1H),4.62(ddd,J=21.1,8. 9,7.1Hz,1H),4.16–3.86(m,2H),3.71(d,J=2.8Hz,3H),2.79–2.47(m,1H),2. 43–2.17(m,1H),1.99–1.90(m,1H),1.87(d,J=15.0Hz,3H),0.89–0.64(m,6H).

[0594] Preparation Example 57 Preparation of Compound B-2-25

[0595] first step

[0596] B-2-25a (5.00 g, 36.72 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (4.90 g, 40.39 mmol) and anhydrous copper sulfate (5.86 g, 36.72 mmol) were added sequentially. The reaction was allowed to proceed overnight. TLC indicated that the reaction was complete. The product was filtered and the filtrate was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-25b (8.00 g, 27.28 mmol, yield 74.3%). MS-ESI theoretical value [M+H] + : 240.1; measured value: 240.1.

[0597] Step 2

[0598] Intermediate B-2-25b (5.00 g, 17.05 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N solution of isopropylmagnesium bromide in tetrahydrofuran (41.78 mL, 41.78 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC indicated the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a mixture of two components, designated as intermediate B-2-25c (2.30 g, 8.12 mmol, yield 47.6%). MS-ESI theoretical value [M+H] + : 284.2; measured value: 284.2.

[0599] Step 3

[0600] Dissolve intermediate B-2-25c component 1 (1.30 g, 4.59 mmol) in dichloromethane (10 mL) and add 4M hydrogen chloride in dioxane (20 mL) under ice-cooling. Continue the reaction under ice-cooling for 1 hour, then concentrate to obtain the crude intermediate B-2-25d, which is used directly in the next reaction without purification.

[0601] Step 4

[0602] The crude product B-2-25d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (1.45 g, 7.36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.92 g, 10.04 mmol), 1-hydroxybenzotriazole (1.36 g, 10.04 mmol), and ethyldiisopropylamine (2.59 g, 20.07 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-25e (1.50 g, 4.14 mmol, total yield for the two-step reaction was 90.2%). MS-ESI theoretical value [M-Boc+2H] + : 263.2; measured value: 263.4.

[0603] Step 5

[0604] Intermediate B-2-25e (1.50 g, 4.14 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-25f, which was used directly in the next reaction without purification.

[0605] Step 6

[0606] The crude intermediate B-2-25f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.33 g, 4.19 mmol) and ethyldiisopropylamine (1.48 g, 11.43 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-25 (431.5 g, 1.44 mmol, total yield for two steps 34.9%). MS-ESI theoretical value [M+H] + : 305.2; measured value: 305.2. 1H NMR(400MHz,Chloroform-d)δ8.36(t,J=12.2Hz,1H),7.17–6.99(m,2H),6.86–6.78(m,2H),4.91–4.81(m,1H),4.77–4.57(m,1H),4.05–3.90(m,2H) ,3.78(d,J=13.5Hz,3H),2.70–2.48(m,1H),2.32(ddtd,J=15.1,11.9,9.3 ,5.7Hz,1H),2.13–2.01(m,1H),1.86(d,J=18.2Hz,3H),0.90–0.69(m,6H).

[0607] Preparation Example 58 Preparation of Compound B-2-26

[0608] first step

[0609] Dissolve B-2-26a (5.00 g, 36.72 mmol) in dichloromethane (50 mL), and add (R)-tert-butylsulfenamide (4.90 g, 40.39 mmol) and anhydrous copper sulfate (5.86 g, 36.72 mmol) in sequence. Allow the reaction to proceed overnight. TLC indicates completion of the reaction. Filter the resulting filtrate, wash with saturated brine (100 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain intermediate B-2-26b (6.00 g, 25.07 mmol, yield 68.3%). MS-ESI theoretical value [M+H] + : 240.1; measured value: 240.1.

[0610] Step 2

[0611] Intermediate B-2-26b (5.00 g, 20.89 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (41.78 mL, 41.78 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC indicated the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a mixture of two components, designated as intermediate B-2-26c (2.30 g, 8.12 mmol, yield 38.8%). MS-ESI theoretical value [M+H] + : 284.2; measured value: 284.1.

[0612] Step 3

[0613] Intermediate B-2-26c (1.50 g, 5.29 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-26d, which was used directly in the next reaction without purification.

[0614] Step 4

[0615] The crude product B-2-26d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (1.73 g, 8.59 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.25 g, 11.71 mmol), 1-hydroxybenzotriazole (1.58 g, 11.71 mmol), and ethyldiisopropylamine (3.03 g, 23.43 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-26e (1.70 g, 4.69 mmol, total yield for the two-step reaction was 88.7%). MS-ESI theoretical value [M-Boc+2H] + : 263.2; measured value: 263.2.

[0616] Step 5

[0617] Intermediate B-2-26e (1.00 g, 2.76 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-26f, which was used directly in the next reaction without purification.

[0618] Step 6

[0619] The crude intermediate B-2-26f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.24 g, 3.01 mmol) and ethyldiisopropylamine (1.06 g, 8.22 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-26 (199.8 mg, 0.66 mmol, total yield for two steps 23.8%). MS-ESI theoretical value [M+H] + : 305.2; measured value: 305.2. 1H NMR(400MHz,Chloroform-d)δ8.40(dd,J=25.0,8.9Hz,1H),7.14–7.00(m,2H),6.81–6.72(m,2H),4.83(ddd,J=41.8,9.5,6.5Hz,1H),4.62(ddd,J=21.1,8. 9,7.1Hz,1H),4.16–3.86(m,2H),3.71(d,J=2.8Hz,3H),2.79–2.47(m,1H),2. 43–2.17(m,1H),1.99–1.90(m,1H),1.87(d,J=15.0Hz,3H),0.89–0.64(m,6H).

[0620] Preparation Example 59 Preparation of Compounds B-2-27 and B-2-28

[0621] first step

[0622] B-2-27a (5.00 g, 34.21 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (4.56 g, 37.63 mmol) and cesium carbonate (22.29 g, 68.42 mmol) were added in sequence. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete. The product was filtered and the filtrate was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-27b (4.00 g, 16.04 mmol, yield 46.9%). MS-ESI theoretical value [M+H] + : 250.1; measured value: 250.1.

[0623] Step 2

[0624] Intermediate B-2-27b (4.00 g, 16.04 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (32.00 mL, 32.00 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0625] The component 1 with the shorter retention time is intermediate B-2-27c (1.30 g, 4.43 mmol, yield 27.6%). MS-ESI theoretical value [M+H] +: 294.1; measured value: 294.1. 1 H NMR(400MHz,Chloroform-d)δ7.53–7.28(m,2H),7.18–7.04(m,2H),6.64(d,J=0.8Hz,1H),4.18(ddd,J=8.8,6.2,0 .7Hz, 1H), 3.54 (d, J = 8.7Hz, 1H), 2.26 (dq, J = 13.4, 6.7Hz, 1H), 1.19 (d, J = 5.3Hz, 9H), 0.90 (dd, J = 12.3, 6.8Hz, 6H).

[0626] The component 2 with a longer retention time is intermediate B-2-28c (1.00 g, 3.41 mmol, yield 21.2%). MS-ESI theoretical value [M+H] + : 294.1; measured value: 294.1. 1 HNMR(400MHz,Chloroform-d)δ7.58–7.30(m,2H),7.22–7.12(m,2H),6.52(t,J=0.7Hz,1H),4.30(dd,J =6.4, 4.7Hz, 1H), 3.46 (d, J = 4.7Hz, 1H), 2.29–2.06 (m, 1H), 1.13 (s, 9H), 0.94 (dd, J = 29.7, 6.8Hz, 6H).

[0627] Step 3 - Component 1

[0628] Intermediate B-2-27c (1.00 g, 3.41 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (10 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-27d, which was used directly in the next reaction without purification.

[0629] Step 4 - Component 1

[0630] The crude product B-2-27d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.94 g, 4.65 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.22 g, 6.35 mmol), 1-hydroxybenzotriazole (0.86 g, 6.35 mmol), and ethyldiisopropylamine (1.64 g, 12.69 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-27e (0.80 g, 2.15 mmol, total yield for the two-step reaction was 63.0%). MS-ESI theoretical value [M-Boc+2H] + : 273.2; measured value: 273.2.

[0631] Step 5 - Component 1

[0632] Intermediate B-2-27e (0.50 g, 1.34 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (5 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-27f, which was used directly in the next reaction without purification.

[0633] Step 6 - Component 1

[0634] The crude intermediate B-2-27f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.12 g, 1.50 mmol) and ethyldiisopropylamine (0.53 g, 4.08 mmol) were added. After reacting at -10°C for 1 h, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-27 (75.0 mg, 0.24 mmol, total yield for two steps 17.8%). MS-ESI theoretical value [M+H] + : 315.2; measured value: 315.2. 1H NMR(400MHz,Chloroform-d)δ8.44(d,J=9.0Hz,1H),7.53–7.41(m,2H),7.20(dtd,J=18.6,7.3,1.3Hz,2H),6.59(d,J=0.9Hz,1H),4.97(ddd,J=53.4,9 .2,6.4Hz,2H),4.27–3.94(m,2H),2.76(ddt,J=12.0,9.0,6.7Hz,1H),2.45 –2.35(m,1H),2.34–2.22(m,1H),1.96(s,3H),0.94(dd,J=6.8,1.2Hz,6H).

[0635] Step 3 - Component 2

[0636] Intermediate B-2-28c (1.00 g, 3.41 mmol) was dissolved in dichloromethane (2 mL) and a 4 M solution of hydrogen chloride in dioxane (4 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-28d, which was used directly in the next reaction without purification.

[0637] Step 4 - Component 2

[0638] The crude product B-2-28d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.82 g, 4.07 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.06 g, 5.55 mmol), 1-hydroxybenzotriazole (0.75 g, 5.55 mmol), and ethyldiisopropylamine (1.43 g, 11.10 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-28e (0.80 g, 2.15 mmol, total yield for two steps 63.0%).

[0639] Step 5 - Component 2

[0640] Intermediate B-2-28e (0.80 g, 2.15 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-28f, which was used directly in the next reaction without purification.

[0641] Step 6 - Component 2

[0642] The crude intermediate B-2-28f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.18 g, 2.34 mmol) and ethyldiisopropylamine (0.83 g, 6.39 mmol) were added. After reacting at -10°C for 1 hour, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-28 (189.0 g, 0.60 mmol, total yield for two steps 28.0%). MS-ESI theoretical value [M+H] + : 315.2; measured value: 315.4. 1 HNMR(400MHz,Chloroform-d)δ8.46(d,J=9.1Hz,1H),7.60–7.38(m,2H),7.26–7.17(m,2H),6.51(d,J=0.9Hz,1H),5.24–4.87(m,2H), 4.12–3.82(m,2H),2.68(ddt,J=12.0,9.2,6.9Hz,1H),2.49–2.36(m,1H),2.35–2.15(m,1H),1.94(s,3H),0.98(dd,J=9.6,6.8Hz,6H).

[0643] Preparation Example 60 Preparation of Compounds B-2-29 and B-2-30

[0644] first step

[0645] B-2-29a (5.00 g, 27.44 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (3.66 g, 30.18 mmol) and cesium carbonate (17.88 g, 54.88 mmol) were added in sequence. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete. The product was filtered and the filtrate was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-29b (7.00 g, 24.53 mmol, yield 89.4%). MS-ESI theoretical value [M+H] + : 286.1; measured value: 286.2.

[0646] Step 2

[0647] Intermediate B-2-29b (5.00 g, 17.52 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, 1N tetrahydrofuran solution of isopropylmagnesium bromide (35.00 mL, 35.00 mmol) was slowly added dropwise. After the addition, the reaction was continued at -78 ° C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0648] The component 1 with the shorter retention time is intermediate B-2-29c (1.20 g, 3.64 mmol, yield 20.8%). MS-ESI theoretical value [M+H] + : 330.2; measured value: 330.2.

[0649] The component 2 with a longer retention time is intermediate B-2-30c (1.40 g, 4.25 mmol, yield 24.3%). MS-ESI theoretical value [M+H] + : 330.2; measured value: 330.2.

[0650] Step 3 - Component 1

[0651] Intermediate B-2-29c (1.20 g, 3.64 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (10 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-29d, which was used directly in the next reaction without purification.

[0652] Step 4 - Component 1

[0653] The crude product B-2-29d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.79 g, 3.91 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.02 g, 5.32 mmol), 1-hydroxybenzotriazole (0.72 g, 5.32 mmol), and ethyldiisopropylamine (1.38 g, 10.65 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-29e (0.98 g, 2.40 mmol, total yield for the two-step reaction was 65.9%). MS-ESI theoretical value [M-Boc+2H] +: 309.2; measured value: 309.1.

[0654] Step 5 - Component 1

[0655] Intermediate B-2-29e (0.98 g, 2.40 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-29f, which was used directly in the next reaction without purification.

[0656] Step 6 - Component 1

[0657] The crude intermediate B-2-29f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.21 g, 2.64 mmol) and ethyldiisopropylamine (0.93 g, 7.20 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-29 (0.45 g, 1.28 mmol, total yield for two steps 53.5%). MS-ESI theoretical value [M+H] + : 351.2; measured value: 351.3. 1 H NMR(400MHz,Chloroform-d)δ8.57(d,J=8.7Hz,1H),7.60–7.52(m,4H),7.46–7.30(m,5H),4.88(dd,J=9.5,6.4Hz,1H),4.77(dd,J=8.8,6.9Hz ,1H),4.19–3.95(m,2H),2.75(ddt,J=12.0,9.0,6.8Hz,1H),2.43–2.28(m,1H),2.10–2.00(m,1H),1.97(s,3H),0.90(dd,J=23.2,6.7Hz,6H).

[0658] Step 3 - Component 2

[0659] Intermediate B-2-30c (1.40 g, 4.25 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (10 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-30d, which was used directly in the next reaction without purification.

[0660] Step 4 - Component 2

[0661] The crude product B-2-30d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.88 g, 4.39 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.15 g, 5.99 mmol), 1-hydroxybenzotriazole (0.81 g, 5.99 mmol), and ethyldiisopropylamine (1.55 g, 11.97 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-30e (0.80 g, 1.96 mmol, total yield for two steps 46.1%). MS-ESI theoretical value [M-Boc+2H] + : 309.2; measured value: 308.9.

[0662] Step 5 - Component 2

[0663] Intermediate B-2-30e (0.80 g, 1.96 mmol) was dissolved in dichloromethane (3 mL). 4 M hydrogen chloride solution in dioxane (6 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-30f, which was used directly in the next reaction without purification.

[0664] Step 6 - Component 2

[0665] The crude intermediate B-2-30f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (0.17 g, 2.15 mmol) and ethyldiisopropylamine (0.76 g, 5.85 mmol) were added. After reacting at -10°C for 1 hour, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-30 (0.49 g, 1.40 mmol, total yield for two steps 71.3%). MS-ESI theoretical value [M+H] + : 351.2; measured value: 351.3. 1H NMR(400MHz,Chloroform-d)δ8.63(d,J=9.0Hz,1H),7.63–7.48(m,4H),7.43(dd,J= 8.4,6.9Hz,2H),7.35–7.30(m,1H),7.28(s,1H),7.26(s,1H),4.90(ddd,J=61.6,9. 3,6.6Hz,2H),4.10–3.92(m,2H),2.68(ddt,J=12.0,9.4,6.7Hz,1H),2.39(dtd,J=1 2.0, 9.3, 5.5Hz, 1H), 2.08–2.00 (m, 1H), 1.94 (s, 3H), 0.94 (dd, J = 30.7, 6.7Hz, 6H).

[0666] Preparation Example 61 Preparation of Compounds B-2-31 and B-2-32

[0667] first step

[0668] B-2-31a (4.00 g, 24.51 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (2.97 g, 24.51 mmol) and cesium carbonate (15.97 g, 49.02 mmol) were added in sequence. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete. The product was filtered and the filtrate was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-31b (6.53 g, 24.5 mmol, 100% yield). MS-ESI theoretical value [M+H] + : 267.1; measured value: 267.2.

[0669] Step 2

[0670] Intermediate B-2-31b (5.00 g, 18.77 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N tetrahydrofuran solution of isopropylmagnesium bromide (37.5 mL, 37.5 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0671] The component 1 with the shorter retention time is intermediate B-2-31c (1.12 g, 3.62 mmol, yield 19.2%). MS-ESI theoretical value [M+H]+ : 311.1; measured value: 311.2.

[0672] The component 2 with a longer retention time is intermediate B-2-32c (0.45 g, 1.45 mmol, yield 7.7%). MS-ESI theoretical value [M+H] + : 311.1; measured value: 311.2.

[0673] Step 3 - Component 1

[0674] Intermediate B-2-31c (1.12 g, 3.62 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (10 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-31d, which was used directly in the next reaction without purification.

[0675] Step 4 - Component 1

[0676] The crude product B-2-31d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (0.75 g, 3.73 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.97 g, 5.08 mmol), 1-hydroxybenzotriazole (0.69 g, 5.08 mmol), and ethyldiisopropylamine (1.31 g, 10.17 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-31e (0.90 g, 2.31 mmol, total yield for the two-step reaction was 63.8%).

[0677] Step 5 - Component 1

[0678] Intermediate B-2-31e (0.90 g, 2.31 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-31f, which was used directly in the next reaction without purification.

[0679] Step 6 - Component 1

[0680] The crude intermediate B-2-31f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.20 g, 2.55 mmol) and ethyldiisopropylamine (0.90 g, 6.96 mmol) were added. After reacting at -10°C for 1 h, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-31 (0.40 g, 1.21 mmol, total yield for two steps 52.3%). MS-ESI theoretical value [M+H] + : 332.1; measured value: 332.2. 1 HNMR(400MHz,Chloroform-d)δ8.73(d,J=8.4Hz,1H),8.07–7.74(m,2H),7.53–7.29(m,2H),5.28(dd,J=8.4,5.3Hz,1H),4.9 9(dd,J=9.4,6.4Hz,1H),4.21–3.95(m,2H),2.87–2.75(m,1H),2.60–2.34(m,2H),1.97(s,3H),0.99(dd,J=22.7,6.8Hz,6H).

[0681] Step 3 - Component 2

[0682] Intermediate B-2-32c (0.45 g, 1.45 mmol) was dissolved in dichloromethane (5 mL) and a 4 M solution of hydrogen chloride in dioxane (5 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-32d, which was used directly in the next reaction without purification.

[0683] Step 4 - Component 2

[0684] The crude product B-2-32d was dissolved in dichloromethane (5 mL) and intermediate A-2-7b (0.32 g, 1.59 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42 g, 2.17 mmol), 1-hydroxybenzotriazole (0.29 g, 2.17 mmol), and ethyldiisopropylamine (0.56 g, 4.35 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (5 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-32e (0.38 g, 0.98 mmol, total yield for two steps 67.6%).

[0685] Step 5 - Component 2

[0686] Intermediate B-2-32e (0.38 g, 0.98 mmol) was dissolved in dichloromethane (5 mL). 4 M hydrogen chloride solution in dioxane (5 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-32f, which was used directly in the next reaction without purification.

[0687] Step 6 - Component 2

[0688] The crude intermediate B-2-32f was dissolved in dichloromethane (5 mL), cooled to -10°C, and acetyl chloride (80.0 mg, 1.02 mmol) and ethyldiisopropylamine (0.36 g, 2.79 mmol) were added. After reacting at -10°C for 1 h, water (5 mL) was added and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-32 (71.4 mg, 0.22 mmol, total yield for two steps 22.0%). MS-ESI theoretical value [M+H] + : 332.1; measured value: 332.2. 1 HNMR(400MHz,Chloroform-d)δ8.71(d,J=8.7Hz,1H),7.92(ddt,J=60.4,8.0,0.9Hz,2H),7.46(ddd,J=8.3,7.2,1.3Hz,1H),7.36(ddd,J=8.3,7.2,1.2Hz,1H) ,5.33(dd,J=8.7,5.2Hz,1H),5.00(dd,J=9.6,6.3Hz,1H),4.14–4.06(m,2H),2 .78–2.59(m,1H),2.62–2.34(m,2H),2.01(s,3H),1.03(dd,J=25.1,6.8Hz,6H).

[0689] Preparation Example 62 Preparation of Compound B-2-33

[0690] first step

[0691] B-2-33a (4.50 g, 31.00 mmol) was dissolved in dichloromethane (50 mL), and (R)-tert-butylsulfenamide (4.13 g, 34.10 mmol) and cesium carbonate (20.20 g, 62.00 mmol) were added in sequence. The reaction was allowed to proceed overnight. TLC indicated that the reaction was complete. The product was filtered and the filtrate was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-33b (7.50 g, 30.2 mmol, yield 97.4%). MS-ESI theoretical value [M+H] + : 249.1; measured value: 249.1.

[0692] Step 2

[0693] Intermediate B-2-33b (5.00 g, 20.13 mmol) was dissolved in tetrahydrofuran (50 mL). After cooling to -78°C under nitrogen, a 1N solution of isopropylmagnesium bromide in tetrahydrofuran (40.26 mL, 40.26 mmol) was slowly added dropwise. After addition, the reaction was continued at -78°C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a mixture of two components, designated as intermediate B-2-33c (3.70 g, 12.7 mmol, yield 62.8%).

[0694] Step 3

[0695] Intermediate B-2-33c (1.40 g, 4.79 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (10 mL) was added under ice-cooling. The reaction was continued under ice-cooling for 1 h, and then concentrated to afford the crude intermediate B-2-33d, which was used directly in the next reaction without purification.

[0696] Step 4

[0697] The crude product B-2-33d was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (1.06 g, 5.26 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.37 g, 7.17 mmol), 1-hydroxybenzotriazole (0.97 g, 7.17 mmol), and ethyldiisopropylamine (1.85 g, 14.37 mmol) were added sequentially at -10°C. After the addition was complete, the reaction was continued at -10°C for 2 h, followed by addition of water (10 mL) and extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-33e (0.93 g, 2.50 mmol, total yield for the two-step reaction was 52.3%). MS-ESI theoretical value [M+H] + : 372.2; measured value: 372.3.

[0698] Step 5

[0699] Intermediate B-2-33e (0.93 g, 2.50 mmol) was dissolved in dichloromethane (10 mL). 4 M hydrogen chloride solution in dioxane (20 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-33f, which was used directly in the next reaction without purification.

[0700] Step 6

[0701] The crude intermediate B-2-33f was dissolved in dichloromethane (10 mL), cooled to -10°C, and acetyl chloride (0.22 g, 2.76 mmol) and ethyldiisopropylamine (0.97 g, 7.53 mmol) were added. After reacting at -10°C for 1 h, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-33 (272.5 mg, 0.87 mmol, total yield for two steps 34.8%). MS-ESI theoretical value [M+H] + : 314.2; measured value: 314.3. 1HNMR(400MHz,Chloroform-d)δ8.91(d,J=21.2Hz,1H),8.33(dd,J=53.4,8.5Hz,1H),7.55( dt,J=7.8,1.0Hz,1H),7.33(ddq,J=7.7,5.8,1.0Hz,1H),7.19–6.99(m,2H),6.34(ddt,J=1 4.5,1.9,0.8Hz,1H),5.02–4.71(m,2H),4.10–3.97(m,2H),2.69(dddd,J=11.9,9.0,7.4,6 .3Hz, 1H), 2.47–2.25 (m, 2H), 1.92 (d, J = 14.7Hz, 3H), 1.01 (ddd, J = 23.0, 14.1, 6.8Hz, 6H).

[0702] Preparation Example 63 Preparation of Compounds B-2-34 and B-2-35

[0703] first step

[0704] B-2-34a (8.00 g, 43.24 mmol) was dissolved in dichloromethane (100 mL), and (R)-tert-butylsulfenamide (5.24 g, 43.24 mmol) and cesium carbonate (28.18 g, 86.48 mmol) were added sequentially. After the addition was complete, the reaction was allowed to proceed overnight. TLC indicated that the reaction was complete. Water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-34b (10.13 g, 35.15 mmol, 81.3% yield). 1 H NMR (400MHz, Chloroform-d) δ8.46(s,1H),7.66–7.62(m,2H),7.56–7.52(m,2H),1.19(s,9H).

[0705] Step 2

[0706] Intermediate B-2-34b (8.00 g, 27.76 mmol) was dissolved in tetrahydrofuran (100 mL). After nitrogen protection and cooling to -78 ° C, 1N tetrahydrofuran solution of isopropylmagnesium bromide (50.0 mL, 50.0 mmol) was slowly added dropwise. After the addition, the reaction was continued at -78 ° C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0707] The component 1 with the shorter retention time is intermediate B-2-34c (1.40 g, 4.21 mmol, yield 15.18%). MS-ESI theoretical value [M+H] + : 332.1; measured value: 332.2. 1 H NMR(400MHz,Chloroform-d)δ7.44–7.36(m,2H),7.14–7.02(m,2H),4.05–4.01(m,1 H), 3.35 (d, J = 5.9Hz, 1H), 1.17 (s, 9H), 0.85 (d, J = 6.7Hz, 3H), 0.72 (d, J = 6.7Hz, 3H).

[0708] The component 2 with a longer retention time is intermediate B-2-35c (1.44 g, 4.34 mmol, 15.6% yield). MS-ESI theoretical value [M+H] + : 332.1; measured value: 332.2. 1 H NMR(400MHz,Chloroform-d)δ7.42–7.33(m,2H),7.09–7.03(m,2H),4.06(dt,J=6.7,1.7 Hz, 1H), 3.41 (d, J = 1.9Hz, 1H), 1.12 (s, 9H), 0.90 (d, J = 6.7Hz, 3H), 0.72 (d, J = 6.8Hz, 3H).

[0709] Step 3 - Component 1

[0710] Intermediate B-2-34c (1.40 g, 4.21 mmol) was dissolved in methanol (10 mL) and 4 M hydrogen chloride in ethyl acetate (5 mL) was added under an ice bath. The mixture was transferred to room temperature and allowed to react for 3 h before concentration to afford the crude intermediate B-2-34d, which was used directly in the next reaction without purification.

[0711] Step 4 - Component 1

[0712] Intermediate A-2-7b (1.09 g, 5.41 mmol) was dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (1.04 g, 5.41 mmol), 1-hydroxybenzotriazole (730.7 mg, 5.41 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.61 g, 12.48 mmol) were added sequentially at -10°C. After the reaction was continued for 30 min, the crude intermediate B-2-34d was added and the reaction was continued for 2 h. TLC indicated the reaction was complete. The mixture was concentrated, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-34e (0.77 g, 1.87 mmol, 44.4% total yield for the two-step reaction). MS-ESI theoretical value [M-Boc+2H] + : 311.1; measured value: 311.2.

[0713] Step 5 - Component 1

[0714] Dissolve intermediate B-2-34e (0.77 g, 1.87 mmol) in methanol (10 mL), cool to -5°C, and add 4M hydrogen chloride in ethyl acetate (10 mL). Transfer to room temperature and continue the reaction for 2 h. Concentrate to obtain the crude intermediate B-2-34f, which is used directly in the next reaction without purification. MS-ESI theoretical value of free ammonia [M+H] + : 311.1, measured value: 311.2.

[0715] Step 6 - Component 1

[0716] The crude intermediate B-2-34f was dissolved in dichloromethane (20 mL), cooled to -10°C, and acetyl chloride (0.17 g, 2.16 mmol) and N,N-diisopropylethylamine (0.56 g, 4.32 mmol) were added. After reacting at -10°C for 2 h, TLC showed that the reaction was complete. Water (30 mL) was added and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-34 (496 mg, 1.40 mmol, total yield for two steps 74.9%). MS-ESI theoretical value [M+H] + : 353.1; measured value: 353.2. 1H NMR (400MHz, Chloroform-d) δ8.54(d,J=8.8Hz,1H),7.35(d,J=8.4Hz,2H),7.00(d,J=8.5Hz,2H),4.88(dd,J=9.5,6.5Hz,1H),4.63(dd ,J=8.8,6.9Hz,1H),4.04–3.85(m,2H),2.61–2.52(m,1H),2.37–2.26(m,1H),1.86(s,3H),0.86(d,J=6.7Hz,3H),0.77(d,J=6.7Hz,3H).

[0717] Step 3 - Component 2

[0718] Intermediate B-2-35c (1.44 g, 4.33 mmol) was dissolved in methanol (10 mL) and a 4 M solution of hydrogen chloride in ethyl acetate (5 mL) was added under an ice bath. The mixture was brought to room temperature and the reaction was continued for 3 h. TLC indicated the reaction was complete. The crude product of intermediate B-2-35d was obtained by concentration and used directly in the next reaction without purification.

[0719] Step 4 - Component 2

[0720] Intermediate A-2-7b (1.09 g, 5.41 mmol) was dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (1.04 g, 5.41 mmol), 1-hydroxybenzotriazole (730.7 mg, 5.41 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.61 g, 12.48 mmol) were added sequentially at -10°C. After the reaction was continued for 30 min, the crude intermediate B-2-35d was added and the reaction was continued for 2 h. TLC indicated the reaction was complete. The mixture was concentrated, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-35e (1.00 g, 2.43 mmol, total yield of two steps 56.4%). MS-ESI theoretical value [M-Boc+2H] + : 311.1; measured value: 311.2.

[0721] Step 5 - Component 2

[0722] Intermediate B-2-35e (1.00 g, 2.43 mmol) was dissolved in methanol (10 mL). 4 M hydrogen chloride in ethyl acetate (10 mL) was added under an ice bath and the reaction was continued for 2 h. The mixture was concentrated to afford crude intermediate B-2-35f, which was used directly in the next reaction without purification. MS-ESI calculated [M+H]+: 311.1, found: 311.2.

[0723] Step 6 - Component 2

[0724] The crude intermediate B-2-35f was dissolved in dichloromethane (20 mL), cooled to -10°C, and acetyl chloride (0.25 g, 3.24 mmol) and N,N-diisopropylethylamine (0.84 g, 6.48 mmol) were added. After reacting at -10°C for 2 h, TLC showed that the reaction was complete. Water (30 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-35 (0.74 g, 2.10 mmol, total yield for two steps 86.4%). MS-ESI theoretical value [M+H] + : 353.1; measured value: 353.2. 1 H NMR (400MHz, Chloroform-d) δ8.48(d,J=8.5Hz,1H),7.36(d,J=8.5Hz,2H),7.07(d,J=8.4Hz,2H),4.78(dd,J=9.5,6.5Hz,1H),4.58(dd,J =8.5, 6.9Hz, 1H), 4.00 (t, J = 7.8Hz, 2H), 2.67–2.58 (m, 1H), 2.34–2.24 (m, 1H), 1.88 (s, 3H), 0.81 (d, J = 6.8Hz, 3H), 0.75 (d, J = 6.7Hz, 3H).

[0725] Preparation Example 64 Preparation of Compound B-2-36

[0726] first step

[0727] B-2-36a (5.00 g, 41.61 mmol) was dissolved in dichloromethane (100 mL), and (R)-tert-butylsulfenamide (5.04 g, 41.61 mmol) and cesium carbonate (27.11 g, 83.22 mmol) were added sequentially. After the addition was complete, the reaction was allowed to proceed for 2 h. TLC indicated that the reaction was complete. Water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-36b (8.79 g, 39.36 mmol, 94.6% yield). 1 H NMR (400MHz, Chloroform-d) δ 8.47 (s, 1H), 7.70–7.63 (m, 2H), 7.19 (d, J = 7.9Hz, 2H), 2.33 (s, 3H), 1.18 (s, 9H).

[0728] Step 2

[0729] Intermediate B-2-36b (8.00 g, 35.82 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, 1N isopropylmagnesium bromide in tetrahydrofuran solution (70.0 mL, 70.0 mmol) was slowly added dropwise. After the addition, the reaction was continued at -78 ° C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0730] The fraction with the shorter retention time was intermediate B-2-36c (2.01 g, 7.52 mmol, yield 21.0%), and the other fraction was discarded.

[0731] Step 3

[0732] Intermediate B-2-36c (2.00 g, 7.48 mmol) was dissolved in methanol (10 mL) and added with a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) under an ice bath. The mixture was transferred to room temperature and allowed to react for 3 h before concentration to afford the crude intermediate B-2-36d, which was used directly in the next reaction without purification.

[0733] Step 4

[0734] Intermediate A-2-7b (2.33 g, 11.56 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (2.99 g, 23.13 mmol), 1-hydroxybenzotriazole (1.35 g, 10.02 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.92 g, 10.02 mmol) were added sequentially at -10°C. After the reaction was continued for 30 min, the crude intermediate B-2-36d was added and the reaction was continued for 2 h. TLC indicated the reaction was complete. The mixture was concentrated, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-36e (2.11 g, 6.09 mmol, total yield of two steps 81.6%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.3.

[0735] Step 5

[0736] Dissolve intermediate B-2-36e (2.11 g, 6.09 mmol) in methanol (10 mL), cool to -5°C, and add 4M hydrogen chloride in ethyl acetate (10 mL). Transfer to room temperature and continue the reaction for 2 h. Concentrate to obtain the crude intermediate B-2-36f, which is used directly in the next reaction without purification. MS-ESI theoretical value of free ammonia [M+H] + : 247.2, measured value: 247.3.

[0737] Step 6

[0738] The crude intermediate B-2-36f was dissolved in dichloromethane (20 mL), cooled to -10°C, and acetyl chloride (0.62 g, 7.95 mmol) and N,N-diisopropylethylamine (2.05 g, 15.90 mmol) were added. After reacting at -10°C for 2 h, TLC showed that the reaction was complete. Water (30 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-36 (1.43 g, 4.96 mmol, total yield for two steps 81.4%). MS-ESI theoretical value [M+H] + : 289.2; measured value: 289.2. 1H NMR(400MHz,Chloroform-d)δ8.40(d,J=8.8Hz,1H),7.08(d,J=8.2Hz,2H),7.04(d,J=8.0Hz,2H),4.77(dd,J=9.5,6.4Hz,1H),4.61(dd,J=8.8,7.1Hz, 1H),4.03–3.96(m,2H),2.66(ddt,J=11.9,9.1,6.7Hz,1H),2.33–2.26(m,1 H), 2.24 (s, 3H), 1.88 (s, 3H), 0.82 (d, J = 6.8Hz, 3H), 0.75 (d, J = 6.7Hz, 3H).

[0739] Preparation Example 65 Preparation of Compound B-2-37

[0740] first step

[0741] B-2-37a (5.00 g, 52.04 mmol) was dissolved in dichloromethane (100 mL), and (R)-tert-butylsulfenamide (6.31 g, 52.04 mmol) and cesium carbonate (33.91 g, 104.08 mmol) were added in sequence. After the addition was complete, the reaction was allowed to proceed for 2 h. TLC indicated that the reaction was complete. Water (100 mL) was added and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-37b (10.02 g, 50.28 mmol, yield 96.6%). MS-ESI theoretical value [M+H] + : 200.1, measured value: 200.2.

[0742] Step 2

[0743] Intermediate B-2-37b (10.00 g, 27.76 mmol) was dissolved in tetrahydrofuran (100 mL). After nitrogen protection and cooling to -78 ° C, 1N tetrahydrofuran solution of isopropylmagnesium bromide (50.0 mL, 50.0 mmol) was slowly added dropwise. After the addition, the reaction was continued at -78 ° C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0744] The intermediate B-2-37c (1.37 g, 7.68 mmol, yield 15.3%) had a shorter retention time. MS-ESI theoretical value [M+H] +: 244.1; Found: 244.3. Discard the other component.

[0745] Step 3

[0746] Intermediate B-2-37c (1.87 g, 7.68 mmol) was dissolved in methanol (10 mL) and 4 M hydrogen chloride in ethyl acetate (5 mL) was added under an ice bath. The mixture was transferred to room temperature and allowed to react for 3 h before concentration to afford the crude intermediate B-2-37d, which was used directly in the next reaction without purification.

[0747] Step 4

[0748] Intermediate A-2-7b (1.00 g, 4.14 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (1.61 g, 12.45 mmol), 1-hydroxybenzotriazole (0.67 g, 4.98 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.95 g, 4.98 mmol) were added sequentially at -10°C. After the reaction was continued for 30 min, the crude intermediate B-2-37d was added and the reaction was continued for 2 h. TLC indicated the reaction was complete. The mixture was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-37e (0.91 g, 2.82 mmol, total yield for the two-step reaction was 36.7%). MS-ESI theoretical value [M-Boc+2H] + : 223.1; measured value: 223.3.

[0749] Step 5

[0750] Intermediate B-2-37e (0.91 g, 2.82 mmol) was dissolved in methanol (10 mL), cooled to -5°C, and a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) was added. The mixture was brought to room temperature and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-37f, which was used directly in the next reaction without purification.

[0751] Step 6

[0752] The crude intermediate B-2-37f was dissolved in dichloromethane (20 mL), cooled to -10°C, and acetyl chloride (0.36 mmol, 4.59 mmol) and N,N-diisopropylethylamine (1.14 g, 9.18 mmol) were added. After reacting at -10°C for 2 h, TLC indicated that the reaction was complete. Water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-37 (0.57 g, 2.16 mmol, total yield for two steps 76.5%). MS-ESI theoretical value [M+H] + : 265.1; measured value: 265.4. 1 H NMR(400MHz,Chloroform-d)δ8.30(d,J=9.1Hz,1H),7.33(dd,J=1.9,0.9Hz,1H),6.28(dd,J=3.2,1.8Hz,1H),6.18(d,J=3.2Hz,1H),4 .88(td,J=9.6,6.4Hz,2H),4.11–4.04(m,2H),2.73(ddt,J=11.9,8.9,6.8Hz,1H),2.45–2.33(m,1H),1.92(s,3H),0.91–0.85(m,6H).

[0753] Preparation Example 66 Preparation of Compound B-2-38

[0754] first step

[0755] B-2-38a (5.00 g, 44.19 mmol) was dissolved in dichloromethane (100 mL), and (R)-tert-butylsulfenamide (5.36 g, 44.19 mmol) and cesium carbonate (28.80 g, 88.38 mmol) were added sequentially. After addition, the reaction was allowed to proceed for 2 h. TLC indicated the reaction was complete. Water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-38b (8.27 g, 38.23 mmol, 86.5% yield).

[0756] Step 2

[0757] Intermediate B-2-38b (5.00 g, 23.11 mmol) was dissolved in tetrahydrofuran (100 mL). After nitrogen protection and cooling to -78 ° C, 1N tetrahydrofuran solution of isopropylmagnesium bromide (50.0 mL, 50.0 mmol) was slowly added dropwise. After the addition, the reaction was continued at -78 ° C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0758] The component 1 with the shorter retention time is intermediate B-2-38c (2.51 g, 9.63 mmol, yield 41.7%). MS-ESI theoretical value [M+H] + : 261.1; measured value: 261.1. 1 H NMR (400MHz, Chloroform-d) δ7.66(d,J=3.3Hz,1H),7.21(d,J=3.2Hz,1H),4.45–4.38(m,2H),2.21–2.12(m,1H),1.21(s,9H),0.87(dd,J=6.8,3.8Hz,6H).

[0759] The other component is discarded.

[0760] Step 3

[0761] Intermediate B-2-38c (2.51 g, 9.63 mmol) was dissolved in methanol (10 mL) and 4 M hydrogen chloride in ethyl acetate (5 mL) was added under an ice bath. The mixture was transferred to room temperature and allowed to react for 3 h before concentration to afford the crude intermediate B-2-38d, which was used directly in the next reaction without purification.

[0762] Step 4

[0763] Intermediate A-2-7b (1.31 g, 6.53 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (2.11 g, 16.32 mmol), 1-hydroxybenzotriazole (0.88 g, 6.53 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.25 g, 6.53 mmol) were added sequentially at -10°C. After the reaction was continued for 30 min, the crude intermediate B-2-38d was added and the reaction was continued for 2 h. TLC indicated the reaction was complete. The mixture was concentrated, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-38e (1.38 g, 4.07 mmol, total yield of two-step reaction 42.3%).

[0764] Step 5

[0765] Intermediate B-2-38e (1.38 g, 4.07 mmol) was dissolved in methanol (10 mL), cooled to -5°C, and a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) was added. The mixture was brought to room temperature and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-38f, which was used directly in the next reaction without purification.

[0766] Step 6

[0767] The crude intermediate B-2-38f was dissolved in dichloromethane (20 mL), cooled to -10°C, and acetyl chloride (0.48 g, 6.07 mmol) and N,N-diisopropylethylamine (1.57 g, 4.32 mmol) were added. After reacting at -10°C for 2 h, TLC showed that the reaction was complete. Water (30 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-38 (496.0 mg, 1.40 mmol, total yield for two steps 34.4%). MS-ESI theoretical value [M+H] + : 282.2; measured value: 282.4. 1H NMR (400MHz, Chloroform-d) δ8.66(d,J=8.5Hz,1H),7.75(d,J=3.3Hz,1H),7.23(d,J=3.3Hz,1H),5.21(dd,J=8.6,5.4Hz,1H),4.95(dd ,J=9.5,6.4Hz,1H),4.14–4.07(m,2H),2.82–2.70(m,1H),2.46–2.38(m,2H),1.96(s,3H),0.96(d,J=6.8Hz,3H),0.91(d,J=6.9Hz,3H).

[0768] Preparation Example 67 Preparation of Compounds B-2-39 and B-2-40

[0769] first step

[0770] B-2-40a (5.00 g, 44.58 mmol) was dissolved in dichloromethane (100 mL), and (R)-tert-butylsulfenamide (5.40 g, 44.58 mmol) and cesium carbonate (29.05 g, 89.16 mmol) were added in sequence. After the addition was complete, the reaction was allowed to proceed for 2 h. TLC indicated that the reaction was complete. Water (100 mL) was added and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-40b (7.87 g, 36.55 mmol, 92.0% yield). [M+H] + : 216.0, measured value: 216.2.

[0771] Step 2

[0772] Intermediate B-2-40b (5.00 g, 23.23 mmol) was dissolved in tetrahydrofuran (100 mL). After nitrogen protection and cooling to -78 ° C, 2N isopropylmagnesium bromide in tetrahydrofuran solution (24.0 mL, 48.0 mmol) was slowly added dropwise. After the addition, the reaction was continued at -78 ° C for 2 h. TLC showed that the reaction was complete. The pH was adjusted to 6 with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0773] The component 1 with a shorter retention time is intermediate B-2-40c (2.51 g, 9.68 mmol, yield 41.7%).

[0774] The component 2 with a longer retention time is intermediate B-2-39c (0.76 g, 2.90 mmol, yield 12.6%).

[0775] Step 3 - Component 1

[0776] Intermediate B-2-40c (1.12 g, 4.30 mmol) was dissolved in methanol (10 mL) and added with a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) under an ice bath. The mixture was transferred to room temperature and allowed to react for 3 h before concentration to afford the crude intermediate B-2-40d, which was used directly in the next reaction without purification.

[0777] Step 4 - Component 1

[0778] Intermediate A-2-7b (671.1 mg, 3.36 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (1.09 g, 8.41 mmol), 1-hydroxybenzotriazole (454.0 mg, 3.36 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (644.1 mg, 3.36 mmol) were added sequentially at -10°C. After the reaction was continued for 30 min, the crude intermediate B-2-40d was added and the reaction was continued for 2 h. TLC indicated the reaction was complete. The mixture was concentrated, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-40e (742.0 mg, 2.19 mmol, total yield of two-step reaction 51.0%). MS-ESI theoretical value [M-Boc+2H] + : 239.1; measured value: 239.2.

[0779] Step 5 - Component 1

[0780] Intermediate B-2-40e (742.0 mg, 2.19 mmol) was dissolved in methanol (10 mL), cooled to -5°C, and a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) was added. The mixture was brought to room temperature and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-40f, which was used directly in the next reaction without purification.

[0781] Step 6 - Component 1

[0782] The crude intermediate B-2-40f was dissolved in dichloromethane (20 mL), cooled to -10°C, and acetyl chloride (0.26 g, 3.29 mmol) and N,N-diisopropylethylamine (0.85 g, 6.57 mmol) were added. After reacting at -10°C for 2 h, TLC showed that the reaction was complete. Water (30 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-40 (468.0 mg, 1.67 mmol, total yield for two steps 76.2%). MS-ESI theoretical value [M+H] + : 281.1; measured value: 281.2. 1 H NMR(400MHz,Chloroform-d)δ8.42(d,J=9.0Hz,1H),7.16(dd,J=4.6,1.6Hz,1H),6.96–6.91(m,2H),5.07(dd,J=8.9,6.4Hz,1H),4.87(dd,J=9.5,6. 4Hz,1H),4.10–4.03(m,2H),2.78–2.67(m,1H),2.44–2.32(m,1H),2.09(h ,J=6.7Hz,1H),1.94(s,3H),0.93(d,J=2.0Hz,3H),0.91(d,J=1.9Hz,3H).

[0783] Step 3 - Component 2

[0784] Intermediate B-2-39c (0.76 g, 2.90 mmol) was dissolved in methanol (5 mL) and 4 M hydrogen chloride in ethyl acetate (5 mL) was added under an ice bath. The mixture was transferred to room temperature and allowed to react for 3 h before concentration to afford the crude intermediate B-2-39d, which was used directly in the next reaction without purification.

[0785] Step 4 - Component 2

[0786] Intermediate A-2-7b (700 mg, 3.48 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (1.12 g, 8.70 mmol), 1-hydroxybenzotriazole (0.47 g, 3.48 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.67 g, 3.48 mmol) were added sequentially at -10°C. After the reaction was continued for 30 min, the crude intermediate B-2-39d was added and the reaction was continued for 2 h. TLC indicated the reaction was complete. The mixture was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-39e (0.74 g, 2.19 mmol, total yield for the two-step reaction was 75.5%).

[0787] Step 5 - Component 2

[0788] Intermediate B-2-39e (0.74 g, 2.19 mmol) was dissolved in methanol (10 mL), cooled to -5°C, and a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) was added. The mixture was brought to room temperature and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-39f, which was used directly in the next reaction without purification.

[0789] Step 6 - Component 2

[0790] The crude intermediate B-2-39f was dissolved in dichloromethane (20 mL), cooled to -10°C, and acetyl chloride (0.26 g, 3.29 mmol) and N,N-diisopropylethylamine (0.85 g, 6.57 mmol) were added. After reacting at -10°C for 2 h, TLC showed that the reaction was complete. Water (30 mL) was added and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-39 (0.37 g, 1.32 mmol, total yield for two steps 60.3%). MS-ESI theoretical value [M+H] + : 281.1; measured value: 282.4. 1HNMR(400MHz,Chloroform-d)δ8.40(d,J=9.2Hz,1H),7.09(dd,J=5.1,1.2Hz,1 H), 6.86 (dd, J=5.1, 3.5Hz, 1H), 6.80 (dt, J=3.5, 1.1Hz, 1H), 5.05 (dd, J=8.9, 6. 2Hz,1H),4.87(dd,J=9.6,6.4Hz,1H),4.00–3.94(m,2H),2.66–2.56(m,1H),2.3 8–2.31(m,1H),2.03(h,J=6.7Hz,1H),1.87(s,3H),0.88(dd,J=6.8,5.5Hz,6H).

[0791] Preparation Example 68 Preparation of Compound B-2-41

[0792] Intermediate B-2-3b (1.10 g, 4.93 mmol) and N,N-diisopropylethylamine (2.55 g, 19.73 mmol) were dissolved in anhydrous dichloromethane (20 mL) and cooled to -10°C. Acetyl chloride (0.77 g, 9.86 mmol) was slowly added dropwise. The reaction solution was stirred at 0°C for 2 hours. TLC showed that the reaction was complete. Water (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-41 (0.40 mg, 1.51 mmol, yield 30.6%). MS-ESI theoretical value [M+H] + : 266.1; measured value: 266.1. 1 H NMR(400MHz,DMSO-d6)δ8.76(d,J=8.6Hz,0.5H),8.54(d,J=8.9Hz,0.5H),8 .10–8.03(m,1H),7.18(s,1H),4.94–4.67(m,2H),4.03(t,J=7.7Hz,1H),3.7 5(dt,J=9.0,6.1Hz,1H),2.49–2.32(m,1H),2.25–1.95(m,2H),1.77(s,1.5H ), 1.57 (s, 1.5H), 0.89 (dd, J = 16.4, 6.7Hz, 3H), 0.80 (dd, J = 8.6, 6.7Hz, 3H).

[0793] Preparation Example 69 Preparation of Compound B-2-42

[0794] first step

[0795] Dissolve B-2-2a (10.00 g, 138.68 mmol) in dichloromethane (300 mL), add (S)-tert-butylpyridinesulfonamide (16.81 g, 138.68 mmol) and copper sulfate (5.53 g, 34.67 mmol). Allow to react for 16 h, and TLC indicates the reaction is complete. Filter, concentrate, and dissolve in ethyl acetate (150 mL). Then, slowly add petroleum ether (450 mL), stir for 12 h, filter, and concentrate the filtrate to obtain crude intermediate B-2-42a (15.00 g, 85.6 mmol, 61.7% yield).

[0796] Step 2

[0797] Under nitrogen, oxazole (17.73 g, 256.71 mmol) was added to a 1M borane solution in tetrahydrofuran (171.14 mL, 171.14 mmol) and the temperature was lowered to -78°C. 2.5M n-butyllithium was slowly added to obtain a tetrahydrofuran solution (171.14 mmol, 68.46 mmol). After the reaction was continued for 30 minutes, crude intermediate B-2-42a (15.00 g, 85.6 mmol) was slowly added. After 4 hours of reaction, TLC indicated completion of the reaction. The reaction mixture was poured into saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-42b (10.0 g, 40.9 mmol, 47.8% yield).

[0798] Step 3

[0799] Intermediate B-2-42b (10.0 g, 40.9 mmol) was dissolved in methanol (200 mL) and a 4 M solution of hydrogen chloride in dioxane (200 mL) was added at 0°C. The reaction was continued for 2 h, and TLC showed that the reaction was complete. The pH was adjusted to 7 with aqueous ammonia and concentrated. The resulting residue was dissolved in methanol (50 mL), heated to 60°C and stirred for 1 h, acetonitrile (500 mL) was added and continued to stir for 1 h, and then slowly cooled to room temperature to precipitate a solid. Filter and dry to obtain intermediate B-2-42c (5.00 g, 35.7 mmol, yield 87.2%). 1 H NMR (400MHz, MeOD) δ 8.01 (s, 1H), 7.26 (s, 1H), 4.42 (d, J = 6.4Hz, 1H), 2.45–2.22 (m, 1H), 1.09 (d, J = 6.8Hz, 3H), 0.96 (d, J = 6.8Hz, 3H).

[0800] Step 4

[0801] Intermediate A-2-6b (1.43 g, 7.11 mmol) was dissolved in dichloromethane (40 mL), cooled to -10°C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.05 g, 10.70 mmol) and 1-hydroxybenzotriazole (1.45 g, 10.70 mmol) were added. After the reaction was continued for 10 minutes, Intermediate B-2-42c (1.00 g, 7.14 mmol) and N,N-diisopropylethylamine (2.76 g, 21.39 mmol) were added. The reaction was continued for 3 hours, and TLC indicated the reaction was complete. Dichloromethane (50 mL) was added and the mixture was washed with water (100 mL). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain Intermediate B-2-42d (0.60 g, 1.86 mmol, 26.1% yield).

[0802] Step 5

[0803] Intermediate B-2-42d (0.60 g, 1.86 mmol) was dissolved in dichloromethane (25 mL) and a 4 M solution of hydrogen chloride in dioxane (5 mL) was added. After 1 h of reaction, TLC indicated that the reaction was complete. The product was concentrated to afford the crude intermediate B-2-42e, which was used directly in the next reaction without purification.

[0804] Step 6

[0805] Deuterated acetic acid (0.57 g, 8.96 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.41 g, 8.96 mmol) was added. After 30 minutes of reaction, the crude intermediate B-2-42e and N,N-diisopropylethylamine (1.29 g, 10 mmol) were added sequentially. The reaction was continued for 16 hours, and TLC showed that the reaction was complete. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-42 (45.1 mg, 0.17 mmol, 9.0% total yield for the two-step reaction). MS-ESI theoretical value [M+H] + : 269.2; measured value: 269.4. 1H NMR (400MHz, CDCl3) δ8.37(d,J=8.2Hz,1H),7.53(s,1H),7.00(s,1H),4.99(dt,J=19.6,9.8Hz,1H),4.87(dd,J=9.4,6.6Hz,1H ),4.09–3.93(m,1H),3.72–3.54(m,1H),2.63–2.50(m,1H),2.45–2.30(m,1H),2.19(td,J=13.4,6.8Hz,1H),0.93–0.81(m,6H).

[0806] Preparation Example 70 Preparation of Compound B-2-43

[0807] first step

[0808] Intermediate A-2-7b (1.43 g, 7.13 mmol) was dissolved in dichloromethane (40 mL), cooled to -10°C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.05 g, 10.70 mmol) and 1-hydroxybenzotriazole (1.45 g, 10.70 mmol) were added. After the reaction was continued for 10 minutes, Intermediate B-2-42c (1.00 g, 7.14 mmol) and N,N-diisopropylethylamine (2.76 g, 21.39 mmol) were added. The reaction was continued for 3 hours, and TLC indicated that the reaction was complete. Dichloromethane (50 mL) was added and the mixture was washed with water (100 mL). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain Intermediate B-2-43a (0.40 g, 1.24 mmol, 17.3% yield).

[0809] Step 2

[0810] Intermediate B-2-43a (0.40 g, 1.24 mmol) was dissolved in dichloromethane (25 mL) and a 4 M solution of hydrogen chloride in dioxane (5 mL) was added. After 1 h of reaction, TLC indicated that the reaction was complete. The product was concentrated to afford the crude intermediate B-2-43b, which was used directly in the next reaction without purification.

[0811] Step 3

[0812] Deuterated acetic acid (0.20 g, 3.14 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.19 g, 3.14 mmol) was added. After 30 minutes of reaction, the crude intermediate B-2-43b and N,N-diisopropylethylamine (0.61 g, 4.71 mmol) were added sequentially. The reaction was continued for 16 hours, and TLC showed that the reaction was complete. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain product B-2-43 (78.2 mg, 0.29 mmol, total yield for the two-step reaction was 23.4%). MS-ESI theoretical value [M+H] + : 269.2; measured value: 269.4. 1 H NMR (400MHz, CDCl3) δ8.50(d,J=7.7Hz,1H),7.54(d,J=8.6Hz,1H),7.01(s,1H),4.98(dd,J=8.4,5.9Hz,1H),4.87(dd,J=9 .3,6.4Hz,1H),4.10–3.93(m,2H),2.79–2.58(m,1H),2.43–2.29(m,1H),2.18(tt,J=11.6,5.8Hz,1H),0.92–0.69(m,6H).

[0813] Preparation Example 71 Preparation of Compound B-2-44

[0814] first step

[0815] Dissolve A-2-38a (3.00 g, 13.81 mmol) in methanol, and add 2-bromoethylamine hydrobromide (2.83 g, 13.81 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride (3.82 g, 13.81 mmol), and 4-methylmorpholine (1.40 g, 13.81 mmol) in sequence. After addition, react at room temperature for 1 hour. Add a methanol solution of sodium hydroxide (2.71 g, 48.24 mmol, dissolved in 125 mL of methanol), reflux for 2.5 hours, and then concentrate. Add water (100 mL) to the residue, and extract with dichloromethane (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-44a (1.80 g, 7.43 mmol, yield 53.8%). MS-ESI theoretical value [M+H] +: 243.2; measured value: 243.2.

[0816] Step 2

[0817] Intermediate B-2-44a (1.80 g, 7.43 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (20 mL) was added under ice-cooling. After the addition was complete, the reaction was allowed to proceed for 2 h, and the mixture was concentrated to afford the crude intermediate B-2-44b, which was used directly in the next step without purification. MS-ESI theoretical value [M+H] + : 179.1; measured value: 179.1.

[0818] Step 3

[0819] Intermediate B-2-44b was dissolved in dichloromethane (10 mL) and intermediate A-2-7b (1.13 g, 5.60 mmol) was added. After cooling to -10°C, N,N-diisopropylethylamine (2.17 g, 16.80 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.40 g, 7.28 mmol), and 1-hydroxybenzotriazole (0.98 g, 7.28 mmol) were added and the reaction continued for 3 h. The mixture was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-44c (1.80 g, 5.24 mmol, total yield for the two steps was 70.5%). MS-ESI theoretical value [M+H] + : 362.2; measured value: 362.4.

[0820] Step 4

[0821] Under ice bath, intermediate B-2-44c (1.20 g, 3.32 mmol) was dissolved in dichloromethane (10 mL), and 4 M hydrogen chloride in dioxane solution (20 mL) was added. After reacting for 2 h, the mixture was concentrated to obtain the crude intermediate B-2-44d, which was used directly in the next reaction without purification. MS-ESI theoretical value [M+H] + : 262.1; measured value: 262.1.

[0822] Step 5

[0823] Dissolve the crude intermediate B-2-44d in dichloromethane (10 mL), cool to -10°C, and add N,N-diisopropylethylamine (1.48 g, 11.46 mmol). Slowly add acetyl chloride (0.36 g, 4.58 mmol). Continue the reaction for 4 h, add water (20 mL), and extract with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain intermediate B-2-44e (0.80 g, 2.63 mmol, total yield of the two-step reaction is 79.3%). MS-ESI theoretical value [M+H] + : 304.1; measured value: 304.1.

[0824] Step 6

[0825] Intermediate B-2-44e (0.46 g, 1.5 mmol) was dissolved in methanol (10 mL), potassium hydroxide (0.35 g, 6.30 mmol) was added, and the mixture was heated under reflux for 2.5 h. After the reaction, the solvent was dried, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate B-2-44 (0.20 g, 0.75 mmol, yield 49.8%). MS-ESI theoretical value [M+H] + : 268.2; measured value: 268.2. 1 H NMR(400MHz,Chloroform-d)δ8.13(dd,J=47.5,8.8Hz,1H),4.84(dt,J=9.6,6.6Hz,1H),4.58–4.46(m,1H),4.27–4.13(m,2H),4.04–3.9 1(m,2H),3.84–3.69(m,2H),2.73–2.48(m,1H),2.43–2.23(m,1H),2.09(qd,J=6.9,5.3Hz,1H),1.86(d,J=4.0Hz,3H),0.98–0.68(m,6H).

[0826] Comparative Example 1: Compound D4-pEL

[0827] first step

[0828] To a 100 mL three-necked flask, D4-pEL-1 (1.00 g, 4.36 mmol), L-leucine tert-butyl ester hydrochloride (0.98 g, 5.23 mmol), triethylamine (1.32 g, 13.08 mmol), N,N-dimethylformamide (20 mL), 1-hydroxybenzotriazole (1.18 g, 8.72 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.25 g, 6.54 mmol) were added sequentially. The mixture was allowed to react at room temperature for 5 hours. After completion of the reaction as monitored by LCMS and TLC, the reaction solution was diluted with saturated brine (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to obtain D4-pEL-3 (1.3 g, 3.26 mmol, 74.8% yield). ESI-LCMS: m / z 243.2[M- t Bu-Boc+H] + .

[0829] Step 2

[0830] To a 100 mL three-necked flask, D4-pEL-3 (1.3 g, 3.26 mmol) and a 1,4-dioxane solution of hydrochloric acid (4.0 M, 20 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as monitored by LCMS and TLC, the reaction mixture was concentrated and diluted with dichloromethane (50 mL). Subsequently, the mixture was concentrated under reduced pressure to remove the residual hydrochloric acid-dioxane solution. The residue was purified by multiple reverse-phase column chromatography and lyophilized to obtain D4-pEL (200 mg, 0.83 mmol, 25.5% yield). ESI-LCMS: m / z 243.3 [M+H] + .

[0831] 1 H NMR(400MHz, DMSO-d6)δ7.90(s,1H),7.69(d,J=8.0Hz,1H),4.08–3.91(m,2H),2.29–1.97(m,3H), 1.94–1.83(m,1H),1.69–1.55(m,1H),1.55–1.46(m,1H),1.46–1.35(m,1H),0.84(t,J=6.4Hz,6H).

[0832] Comparative Example 2: Compound D5-PA

[0833] D5-PA was purchased from Shanghai Bidex Pharmaceutical Technology Co., Ltd., product number BD133842, batch DSY151, with a purity of 97%.

[0834] Experimental Example 1 Plasma stability determination

[0835] 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 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:

[0836] Table 1 Plasma stability data of some compounds Note: If the remaining percentage of the compound is still greater than 75% after 120 minutes, then T 1 / 2 Recorded as >289.1min.

[0837] 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 and D5-PA.

[0838] Experimental Example 2 Compound Permeability Detection

[0839] MDR1-MDCKⅡ cells (from the Netherlands Cancer Institute) were seeded in 96-well cell plates at a density of 3.33×10 5Cells were cultured in a CO2 incubator for 4-7 days to form a monolayer. Hank's balanced salt buffer (HBSS, pH 7.40 ± 0.05) containing 10.0 mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) was used as the transport buffer. Compound DMSO stock solutions were diluted to 2 μM (DMSO <1.0%) in transport buffer and added to the basolateral (B) and apical (A) sites (N = 2). The P-gp substrate digoxin was incubated at a concentration of 10 μM in both directions (AB and BA), while the hypotonic control nadolol and the hypertonic control metoprolol were incubated at a concentration of 2 μM in the unidirectional (AB) directions. The cell plates were incubated for 2.5 hours in a cell culture incubator at 37°C, 5% CO2, and saturated humidity. Final samples from the receiving and dosing sites were collected, and appropriate proportions of transport buffer and precipitant were added. LC-MS / MS analysis was performed to calculate the apparent permeability coefficient, efflux rate, and solution recovery rate.

[0840] After the transport experiment, the integrity of the MDR1-MDCKⅡ cell layer was assessed using a Lucifer Yellow assay. The remaining solution in the apical and basolateral wells was removed, and 75 μL of transport buffer containing 100 μM Lucifer Yellow was added to the apical well and 250 μL of transport buffer was added to the basolateral well. The cell plate was incubated in a cell culture incubator at 37°C, 5% CO2, and saturated humidity for 30 minutes. A 20 μL sample was taken from the apical well and mixed with 60 μL of transport buffer. An 80 μL sample was taken from the basolateral well and the relative fluorescence intensity was measured at 425 / 528 nm (excitation / emission) using a microplate reader. The Lucifer Yellow transmittance was calculated.

[0841] The apparent permeability coefficient (P app ), efflux ratio (ER), and solution recovery (%Solution Recovery) were calculated using the following formulas:

[0842] V R is the volume of the solution in the receiving end (the volumes on the top and base sides are 0.075 and 0.25 mL, respectively), V D is the volume of the solution in the dosing end (the volumes of the apical and basal ends are 0.075 and 0.25 mL, respectively), C R is the peak area ratio of the receiving end compound, C D is the peak area ratio of the compound at the administration end, C0 is the initial peak area ratio of the compound at the administration end, and Area is the surface area of ​​the cell monolayer (0.143 cm 2 ), Time is the incubation time 9000s (150min). app (BA) and Papp (AB) are the apparent permeability coefficients from the base end to the apex end and from the apex end to the base end, respectively.

[0843] The transmittance of fluorescent yellow (%Lucifer Yellow) is calculated using the following formula:

[0844] RFU Apical and RFU Basolateral are the relative fluorescence intensities of fluorescein at the top and bottom, respectively. Apical With V Basolateral These are the apical and basolateral loading volumes (0.075 and 0.25 mL, respectively).

[0845] Table 2 Permeability data of some compounds

[0846] The compound of this patent has moderate permeability and is superior to the control compounds D4-pEL and D5-PA.

[0847] Experimental Example 3 Pharmacokinetics in mice

[0848] The test was performed 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.

[0849] Table 3 Oral pharmacokinetic data of some compounds in mice Note: The dosage of ZZL-7 is 100 mg / kg, PO.

[0850] Experimental Example 4 Pharmacokinetics in rats

[0851] The test was performed in 6-8 week old male SD rats (purchased from: Sibeifu (Beijing) Biotechnology Co., Ltd.). The test compound was dissolved in 10% DMSO + 15% Solutol HS + 75% (10% hydroxypropyl-β-cyclodextrin aqueous solution) and administered by intravenous injection (10 mg / kg) or oral gavage (15 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). 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.

[0852] Table 4 Oral pharmacokinetic data of some compounds in rats

[0853] Tables 3 and 4 show 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, D4-pEL, and D5-PA.

[0854] Experimental Example 5 In vivo drug efficacy detection (1)

[0855] 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, 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.

[0856] The results of the tail suspension test are shown in Figures 1 and 2. The test results show that compounds B-2-3 and B-2-41 can quickly reverse the prolonged immobility time in the tail suspension test of mice in the chronic unpredictable stress model, proving that the example compounds of the present invention have a rapid antidepressant effect.

[0857] Experimental Example 6 In vivo drug efficacy detection (2)

[0858] 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, and a compound group. The test compound was administered intravenously (iv) 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.

[0859] The results of the forced swimming test are shown in Figure 3, and the results of the tail suspension test are shown in Figure 4. The test results show that compounds A-1-7, A-1-1 and A-2-1 can quickly reverse the prolonged immobility time in the forced swimming and tail suspension tests in mice with chronic unpredictable stress models, demonstrating that the embodiments of the present invention have a rapid antidepressant effect.

[0860] References:

[0861] [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.

[0862] [2]Chen Z,Gu J,Lin S,et al.Saffron essential oil ameliorates CUMS-induced depression-like behavior in mice viathe MAPK-CREB1-BDNF signalingpathway[J].Journal ofEthnopharmacology,2023,300:115719.

[0863] [3]Pentkowski,Nathan S.,et al."Anxiety andAlzheimer’s disease:Behavioral analysis and neural basis in rodent models ofAlzheimer’s-related neuropathology."Neuroscience & Biobehavioral Reviews 127(2021):647-658.

[0864] [4]Can,Adem,et al."The mouse forced swim test."JoVE(Journal of Visualized Experiments)59(2012):e3638.

[0865] [5]Can,Adem,et al."The tail suspension test."JoVE(Journal of Visualized Experiments)59(2012):e3769.

Claims

1. A compound represented by the general formula (IA) or (IB) or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof: in: X is a bond or CHR5; Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time; Z3 is CHR6 or carbonyl; Z4, Z5 and Z6 are independently selected from CR6, N; n is an integer from 0 to 4; R1 is hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7-N(CO)-, or a C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C4-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 Heteroaryl; R2 is selected from carboxyl, C1-C 15 Chain alkoxycarbonyl, C1-C 15 Heterochain alkoxycarbonyl, C3-C 15 Cycloalkoxycarbonyl, C4-C 15 Heterocycloalkoxycarbonyl, C5-C 15 Aryl, C5-C 15 heteroaryl; R3 and R4 are independently selected from hydrogen or 0 to 8 C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C4-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; R5 is optionally selected from hydrogen, C1-C5 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl; R6 is optionally selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -COR7, -SOR7, -SO2R7, -NR7COR8, -CONR7R8, -OCOR7, -COOR7, -OCOOR7, -OCONR7R8, -NR7CONR8R9, -NR7COOR8, -NR7SO2R8, -SO2NR7R8, -OSO2R7, -SO3R7, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of 0 to 8 R 10 replace; R7, R8, R9 are independently selected from hydrogen, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each 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; R 10 Selected from hydrogen, halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each linear alkyl, heterolinear 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; Wherein, the general formula (IA) does not contain compounds The general formula (IB) does not include compounds 2. A compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof: in: X is a bond or CHR5; Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time; Z3 is CHR6 or carbonyl; Z4, Z5 and Z6 are independently selected from CR6 or N; n is an integer from 0 to 4; R1 is selected from hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7N(CO)-, 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 to 8 R6; or, R1 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 is optionally substituted by 0 to 8 R6; R2 is selected from -(CO)O-(CH2) m R6, wherein m is an integer from 0 to 4, or, R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 Aryl or 5-15 membered heteroaryl is optionally substituted by 0 to 8 R6; R3 and R4 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 is optionally substituted by 0-8 R6, R3 and R4 are not hydrogen at the same time; or, R3, R4 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 is optionally substituted by 0 to 8 R6; R5 is selected from hydrogen, C1-C5 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocycloalkyl; R6 is selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -(CO)-R7, -(SO)-R7, -(SO2)-R7, -NR7-(CO)-R8, -(CO)-NR7R8, -O(CO)-R7, -(CO)OR 7. -O(CO)OR7, -O(CO)-NR7R8, -NR7-(CO)-NR8R9, -NR7-(CO)OR8, -NR7-(SO2)-R8, -(SO2)-NR7R8, -O(SO2)-R7, -(SO2)OR7, 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 10 Substituted; or, R6 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 10 replace; R7, R8, and R9 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 is optionally substituted by 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl; or, R7, R8, R9 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 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups; R 10 is selected from hydrogen, halogen, 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 or 5-15 membered heteroaryl is optionally substituted with 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl; Wherein, formula (Ia) does not include the following compounds: Formula (Ib) does not include the following compounds:

3. A compound represented by formula (Ia) or (Ib) according to claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in: X is a bond; Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time; Z3 is CHR6 or carbonyl; Z4, Z5 and Z6 are independently selected from CR6 or N; n is an integer from 0 to 4; R1 is selected from hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7N(CO)-, 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 to 8 R6; R2 is selected from -(CO)O-(CH2) m R6, wherein m is an integer from 0 to 4, or, R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 Aryl or 5-15 membered heteroaryl is optionally substituted by 0 to 8 R6; R3 and R4 are independently selected from hydrogen or C1-C 15 Alkyl, where C1-C 15 The alkyl group is optionally substituted by 0 to 8 R6; R3 and R4 are not hydrogen at the same time; R6 is selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -(CO)-R7, -(SO)-R7, -(SO2)-R7, -NR7-(CO)-R8, -(CO)-NR7R8, -O(CO)-R7, -(CO)OR 7. -O(CO)OR7, -O(CO)-NR7R8, -NR7-(CO)-NR8R9, -NR7-(CO)OR8, -NR7-(SO2)-R8, -(SO2)-NR7R8, -O(SO2)-R7, -(SO2)OR7, 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 10 replace; R7, R8, and R9 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 is optionally substituted with 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl; R 10 is selected from hydrogen, halogen, 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 or 5-15 membered heteroaryl is optionally substituted with 0-8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl.

4. The compound of formula (Ia) or (Ib) according to claim 3, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (Ia) is the compound represented by the following formula (Ia-1), and the compound represented by formula (Ib) is the compound represented by the following formula (Ib-1) wherein R1, R2, Z1, Z2, Z3, Z4, Z5, Z6 and n are as defined in claim 3.

5. The compound of formula (Ia) or (Ib) according to claim 3, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (Ia) is a compound represented by the following formula (Ia-1'), Wherein R1, R2, R3, and R4 are as defined in claim 3.

6. The compound of formula (Ia) or (Ib) according to claim 5, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (Ia) is a compound represented by the following formula (Ia-2), Wherein R1 and R2 are as defined in claim 5.

7. The compound of formula (Ia) or (Ib) 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 (Ia) is a compound represented by the following formula (Ia-3), wherein R2 is as defined in claim 6.

8. A compound of formula (Ia) or (Ib) according to any one of claims 3 to 7, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in: R2 is selected from -(CO)O-(CH2) m R6, wherein m is an integer from 0 to 4.

9. A compound of formula (Ia) or (Ib) according to any one of claims 3 to 7, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 The aryl or 5-15 membered heteroaryl is optionally substituted with 0 to 8 R6.

10. The compound of formula (Ia) or (Ib) according to claim 9, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, R2 is selected from:

11. The compound of formula (Ia) or (Ib) according to claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof: in: X is a bond; Z1 and Z2 are independently selected from: CHR6, NR7, oxygen or carbonyl, and Z1 and Z2 are not NR7 or oxygen at the same time; Z3 is CHR6 or carbonyl; Z4, Z5 and Z6 are independently selected from CR6 or N; n is an integer from 0 to 4; R1 is selected from hydrogen, R6-(CO)-, R6-(SO)-, R6-(SO2)-, R6-O(CO)-, R6R7N(CO)-, 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 to 8 R6; R2 is selected from C6-C 15 Aryl or 5-15 membered heteroaryl, wherein C6-C 15 Aryl or 5-15 membered heteroaryl is optionally substituted by 0 to 8 R6; R3 and R4 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 R6; R3 and R4 are not hydrogen at the same time; R6 is selected from hydrogen, halogen, -CN, -NO2, -OR7, -NR7R8, -SR7, -(CO)-R7, -(SO)-R7, -(SO2)-R7, -NR7-(CO)-R8, -(CO)-NR7R8, -O(CO)-R7, -(CO)OR 7. -O(CO)OR7, -O(CO)-NR7R8, -NR7-(CO)-NR8R9, -NR7-(CO)OR8, -NR7-(SO2)-R8, -(SO2)-NR7R8, -O(SO2)-R7, -(SO2)OR7, 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 10 replace; R7, R8, and R9 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 is optionally substituted with 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl; R 10 is selected from hydrogen, halogen, 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 or 5-15 membered heteroaryl is optionally substituted with 0-8 halogen, cyano, hydroxy, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl.

12. The compound of formula (Ia) or (Ib) according to claim 11, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (Ia) is a compound represented by the following formula (Ia-4), and the compound represented by formula (Ib) is a compound represented by the following formula (Ib-2) wherein R1, R2, R3, Z1, Z2, Z3, Z4, Z5, Z6 and n are as defined in claim 11.

13. A compound of formula (Ia) or (Ib) according to claim 12, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, in, The compound represented by formula (Ia) is a compound represented by the following formula (Ia-5) wherein R1, R2, and R3 are as defined in claim 12.

14. The compound of formula (Ia) or (Ib) 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 (Ia) is a compound represented by the following formula (Ia-6) Wherein R2 and R3 are as defined in claim 13.

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

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 a therapeutically effective amount of a compound according to any one of claims 1 to 16, 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, characterized in that: The medicine is a fast-acting medicine.

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