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

Abstract

The invention provides a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt, a prodrug, a deuterated compound, a hydrate, a solvate, an enantiomer, a diastereoisomer or a racemate thereof, and a preparation method and application thereof. Application of compounds in preparation of anti-depression drug # imgabs0 # capable of taking effect quickly

Description

Technical Field

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

[0002] Depression is a common mental illness characterized by significant and persistent low mood. Clinically, it can be seen that the mood is not commensurate with the situation. The depression can range from melancholy to grief, inferiority and depression, and even pessimism and world-weariness. There may be suicidal attempts or behaviors; in severe cases, psychotic symptoms such as hallucinations and delusions may occur. More than 350 million people suffer from depression worldwide, an increase of 18% in the past decade. As of 2017, there are more than 54 million depression patients in China alone. The recurrence rate of major depressive disorder is as high as 50%-85%, and the suicide rate is 4.0%-10.6%. It has become the most common mental illness.

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

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

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

[0006] The purpose of the present invention includes providing a 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 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 substance, 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 includes providing a method for preparing the compound of the above general formula.

[0010] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes:

[0011] The present invention provides 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:

[0012]

[0013] in:

[0014] X is a bond or CHR5;

[0015] 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;

[0016] Z3 is CHR6 or carbonyl;

[0017] Z4, Z5 and Z6 are independently selected from CR6, N;

[0018] 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;

[0019] 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;

[0020] R5 is optionally selected from hydrogen, C1-C5 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl;

[0021] 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;

[0022] 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;

[0023] 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;

[0024] Wherein, the general formula (IA) does not contain compounds The general formula (IB) does not include compounds

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

[0026]

[0027] in:

[0028] X is a bond or CHR5;

[0029] 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;

[0030] Z3 is CHR6 or carbonyl;

[0031] Z4, Z5 and Z6 are independently selected from CR6 or N;

[0032] n is an integer from 0 to 4;

[0033] 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;

[0034] 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;

[0035] 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 15The chain alkyl is optionally substituted by 0 to 8 R6;

[0036] R5 is selected from hydrogen, C1-C5 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocycloalkyl;

[0037] 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;

[0038] 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 15A 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;

[0039] 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;

[0040] Wherein, formula (Ia) does not include the following compounds:

[0041]

[0042]

[0043]

[0044] Formula (Ib) does not include the following compounds:

[0045]

[0046] In some embodiments, wherein,

[0047] X is a bond;

[0048] 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;

[0049] Z4, Z5 and Z6 are independently selected from CR6 or N;

[0050] n is an integer from 0 to 4;

[0051] 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;

[0052] 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;

[0053] 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;

[0054] 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;

[0055] 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;

[0056] 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.

[0057] In some embodiments, wherein,

[0058] 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)

[0059]

[0060] wherein R1, R2, Z1, Z2, Z3, Z4, Z5, Z6 and n 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-1'),

[0063]

[0064] wherein R1, R2, R3, and R4 are as defined above.

[0065] In some embodiments, wherein,

[0066] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-2),

[0067]

[0068] wherein R1 and R2 are as defined above.

[0069] In some embodiments, wherein,

[0070] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-3),

[0071]

[0072] wherein R2 is as defined above.

[0073] In some embodiments, wherein,

[0074] R2 is selected from -(CO)O-(CH2) m R6, wherein m is an integer from 0 to 4.

[0075] In some embodiments, wherein,

[0076] 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 by 0 to 8 R6.

[0077] In some embodiments, wherein,

[0078] R2 is selected from:

[0079]

[0080] In some embodiments, wherein,

[0081] X is a bond;

[0082] 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;

[0083] Z3 is CHR6 or carbonyl;

[0084] Z4, Z5 and Z6 are independently selected from CR6 or N;

[0085] n is an integer from 0 to 4;

[0086] 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;

[0087] 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;

[0088] 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;

[0089] 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 15Aryl or 5-15 membered heteroaryl, wherein C1-C 15 Alkyl, C1-C 15 Alkoxy, C3-C 15 Cycloalkyl, 3-15 membered heterocycloalkyl, C6-C 15 The aryl or 5-15 membered heteroaryl group is optionally substituted with 0 to 8 R 10 replace;

[0090] 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;

[0091] 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.

[0092] In some embodiments, wherein,

[0093] 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)

[0094]

[0095] wherein R1, R2, R3, Z1, Z2, Z3, Z4, Z5, Z6 and n are as defined above.

[0096] In some embodiments, wherein,

[0097] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-5)

[0098]

[0099] wherein R1, R2, and R3 are as defined above.

[0100] In some embodiments, wherein,

[0101] The compound represented by formula (Ia) is a compound represented by the following formula (Ia-6)

[0102] wherein R2 and R3 are as defined above.

[0103] In some embodiments, wherein,

[0104] The compound is selected from any of the following compounds:

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113] In some embodiments, the compound is selected from any of the following compounds:

[0114]

[0115]

[0116]

[0117]

[0118] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound described herein, its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate, and a pharmaceutically acceptable excipient or auxiliary ingredient.

[0119] The present invention also provides use of the compound described herein or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate, or the pharmaceutical composition in the preparation of a medicament for preventing and / or treating depression.

[0120] In some embodiments, the drug in the above use is a fast-acting drug.

[0121] The hydrogen described herein may be in any isotopic form, including 1 H (hydrogen), 2 H (D or deuterium) and 3 H (T or tritium).

[0122] definition

[0123] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0124] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0125] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 15 carbon atoms, more preferably an alkyl group of 1 to 8 carbon atoms, and further preferably an alkyl group of 1, 2, 3, 4, 5, or 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof. The alkyl group may be optionally further substituted by one or more substituents.

[0126] "Alkoxy" refers to a group formed by linking an alkyl group to an oxygen atom. The definition of the alkyl group is the same as the definition of "alkyl" described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, cyclobutyloxy, etc. The alkoxy group may optionally be further substituted with one or more substituents.

[0127] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic substituent, and the cycloalkyl contains 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, 8 carbon atoms). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed rings, and bridged rings. The cycloalkyl may optionally be further substituted by one or more substituents.

[0128] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 6-12 membered (e.g., 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3-8 membered heterocyclic ring. 1, 2 or 3 N, S optionally substituted in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; "heterocycloalkyl" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl" include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, etc. The heterocycloalkyl may be optionally further substituted with one or more substituents.

[0129] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5-8 membered monocyclic ring (e.g., 5, 6, 7, 8 members), a 6-12 membered bicyclic ring (e.g., 6, 7, 8, 9, 10, 11, 12 members), or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be a bridged ring or a spiro ring, non-limiting examples include phenyl, naphthyl, etc. The aryl group may be optionally further substituted with one or more substituents.

[0130] "Heteroaryl" refers to an aromatic ring group having a conjugated planar ring system and containing heteroatoms, which can be a 5-8 membered (e.g., 5, 6, 7, 8 membered) monocyclic ring, an 8-12 membered (e.g., 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S. Non-limiting examples of heteroaryl include oxazolyl, triazolyl, pyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, etc. The heteroaryl group may be optionally further substituted with one or more substituents.

[0131] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0132] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0133] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.

[0134] 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.

[0135] Beneficial technical effects achieved:

[0136] (1) The compounds of the present invention have good rapid antidepressant activity in vivo.

[0137] (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

[0138] Figure 1 , Figure 2 The results of the tail suspension experiment in Experimental Example 5 are shown.

[0139] Figure 3 The results of the forced swimming test in Experimental Example 6 are shown.

[0140] Figure 4 The results of the tail suspension experiment in Experimental Example 6 are shown. DETAILED DESCRIPTION

[0141] Unless otherwise specified, all raw materials, reagents, and instruments used in the examples of the present invention are conventional commercially available products.

[0142] Among them, the present invention 1The instrument for HNMR detection is Bruker Advance 400 MHz spectrometer; the instrument for MS-ESI detection of the present invention is Agilent LCMS1260-6120.

[0143] Preparation Example 1 Preparation of Compound A-1-7

[0144]

[0145] first step

[0146] Dissolve L-valine methyl ester hydrochloride (779 mg, 4.65 mmol) and 4-dimethylaminopyridine (1.3 g, 10.80 mmol) in N,N-dimethylformamide (10 mL), cool to 0°C, add compound A-1-7a (600 mg, 5.40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 g, 5.94 mmol). React at room temperature for 16 hours, and TLC shows that the reaction is complete. Dilute with water (50 mL) and extract with ethyl acetate 3 times (50 mL×3). Combine the organic phases, wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, and concentrate to obtain a crude product, which is 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.

[0147] Preparation Example 2 Preparation of Compound A-1-1

[0148]

[0149] first step

[0150] Dissolve L-valine methyl ester hydrochloride (686 mg, 4.09 mmol) and 4-dimethylaminopyridine (1.2 g, 9.52 mmol) in N,N-dimethylformamide (10 mL), cool to 0°C, add compound A-1-1a (600 mg, 4.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.32 mmol), react at room temperature for 16 hours, and TLC shows that the reaction is complete. Dilute with water (50 mL) and extract with ethyl acetate 3 times (50 mL × 3). Combine the organic phases, wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, and concentrate to obtain a crude product, which is 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.

[0151] Preparation Example 3 Preparation of Compound A-2-1

[0152]

[0153] first step

[0154] 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 sufficient 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 the reaction was complete as monitored by LCMS, water (60 mL) was added to dilute the mixture and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give intermediate A-2-1b (8.60 g, 42.74 mmol, yield 86%).

[0155] Step 2

[0156] Add L-valine methyl ester hydrochloride (7.52g, 44.86mmol), 4-dimethylaminopyridine (10.45g, 85.45mmol) and N,N-dimethylformamide (80mL) into a 200mL dry three-necked flask, cool to 0℃, add compound A-2-1b (8.60g, 42.74mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.83g, 51.29mmol), react at room temperature for 16 hours, monitor the reaction by LCMS, dilute with water (100mL), extract with ethyl acetate (200mL×3). Combine the organic phases, wash with water (500mL) and saturated brine (500mL) in turn, dry over anhydrous sodium sulfate, and concentrate to obtain intermediate A-2-1c (13.80g, 43.90mmol).

[0157] Step 3

[0158] 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), reacted at room temperature for 2 hours, and after the reaction was completed under LCMS monitoring, it was concentrated and purified by medium pressure preparation to obtain intermediate A-2-1d (7.56 g, 35.28 mmol, yield 80%).

[0159] Step 4

[0160] Dissolve the intermediate A-2-1d (1.0 g, 4.67 mmol) in dichloromethane (10 ml). Add acetic anhydride (6.7 g, 65.41 mmol) and react at room temperature for 16 hours. TLC shows that the reaction is complete. Cool to 0 ° C and adjust the pH to 2 with 1M hydrochloric acid. Extract with ethyl acetate 3 times (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. Purify by reverse phase preparation 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.

[0161] Preparation Example 4 Preparation of Compound A-2-2

[0162]

[0163] Dissolve the intermediate A-2-1d (1.00 g, 4.67 mmol) in dry dichloromethane (20 mL), add cyclopropylcarbonyl chloride (0.54 g, 5.14 mmol), and then drop triethylamine (1.18 g, 11.68 mmol). After the addition is complete, react at room temperature for 1 hour. After the reaction is completed by LCMS monitoring, dilute with water (50 mL) and extract with ethyl acetate (100 mL×3). Combine the organic phases, wash with saturated brine in turn, dry with anhydrous sodium sulfate, concentrate, and purify by medium pressure preparation to obtain compound A-2-2 (0.49 g, 1.74 mmol, yield 37%). 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).

[0164] Preparation Example 5 Preparation of Compound A-2-4

[0165]

[0166] first step

[0167] Compound A-2-1 (0.92 g, 3.59 mmol) and THF (10 mL) were added to a 50 mL dry three-necked flask, and then sodium hydroxide aqueous solution (2 M, 3 mL) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, 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 obtain a crude intermediate A-2-4a (0.80 g, 3.31 mmol, yield 92%).

[0168] Step 2

[0169] 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, and then concentrated sulfuric acid (0.36 g, 3.64 mmol) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, 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, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure preparation to obtain the product A-2-4 (0.25 g, 0.98 mmol, yield 30%). 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).

[0170] Preparation Example 6 Preparation of Compound A-2-5

[0171]

[0172] 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. Then 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 added in sequence. After nitrogen replacement three times, the temperature was raised to 110 degrees and the reaction was carried out for 6 hours. After the reaction was completed by LCMS monitoring, water (20 mL) was added for dilution and dichloromethane (50 mL×3) was extracted. The organic phases were combined, washed with water (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure preparation to obtain product A-2-5 (0.27 g, 0.93 mmol, yield 20%). MS-ESI calculated value [M+H] + : 292.2; measured value: 292.2. 1 H 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).

[0173] Preparation Example 7 Preparation of Compound A-2-6

[0174]

[0175] first step

[0176] 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 sufficient 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 the reaction was completed by monitoring by LCMS, water (60 mL) was added for dilution and the pH was adjusted to 3 with 1.0 M dilute hydrochloric acid, and then extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate A-2-6b (8.60 g, 42.74 mmol, yield 86%).

[0177] Step 2

[0178] Add L-valine methyl ester hydrochloride (7.52g, 44.86mmol), 4-dimethylaminopyridine (10.45g, 85.45mmol) and N,N-dimethylformamide (80mL) to a 200mL dry three-necked flask. After cooling to 0℃, add intermediate A-2-6b (8.60g, 42.74mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.83g, 51.29mmol), react at room temperature for 16 hours, and after LCMS monitoring, dilute with water (100mL) and extract with ethyl acetate (200mL×3). Combine the organic phases, wash with water (500mL) and saturated brine (500mL) in turn, dry over anhydrous sodium sulfate, and concentrate to obtain the crude intermediate A-2-6c (13.80g, 43.90mmol).

[0179] Step 3

[0180] The crude intermediate A-2-6c (13.80 g, 43.90 mmol) was dissolved in a 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-2-6d (7.56 g, 35.28 mmol, yield 80%).

[0181] Step 4

[0182] Add intermediate A-2-6d (1.00 g, 4.67 mmol) and dichloromethane (15 mL) to a 50 mL dry three-necked flask, then slowly add acetic anhydride (4.76 g, 46.70 mmol), and react overnight at room temperature. After the reaction is completed, LCMS monitoring is performed. Add saturated sodium bicarbonate aqueous solution (50 mL) to the reaction solution, stir for 0.5 hours, and then extract with dichloromethane (50 mL × 3). Combine the organic phases, then wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by medium pressure preparation to obtain product A-2-6 (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) δ8.31 (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).

[0183] Preparation Example 8 Preparation of Compound A-2-7

[0184]

[0185] first step

[0186] 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 sufficient 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 the reaction was complete as monitored by LCMS, water (60 mL) was added for dilution and the pH was adjusted to 3 with 1.0 M dilute hydrochloric acid, and ethyl acetate (150 mL × 3) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate A-2-7b (8.60 g, 42.74 mmol, yield 86%).

[0187] Step 2

[0188] Add L-valine methyl ester hydrochloride (7.52g, 44.86mmol), 4-dimethylaminopyridine (10.45g, 85.45mmol) and N,N-dimethylformamide (80mL) into a 200mL dry three-necked flask, cool to 0℃, add intermediate A-2-7b (8.60g, 42.74mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.83g, 51.29mmol), react at room temperature for 16 hours, monitor the reaction by LCMS, dilute with water (100mL), extract with ethyl acetate (200mL×3). Combine the organic phases, wash with water (500mL) and saturated brine (500mL) in turn, dry over anhydrous sodium sulfate, and concentrate to obtain the crude intermediate A-2-7c (13.80g, 43.90mmol).

[0189] Step 3

[0190] The crude intermediate A-2-7c (13.80 g, 43.90 mmol) was dissolved in a 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 the intermediate A-2-7d (7.56 g, 35.28 mmol, yield 80%).

[0191] Step 4

[0192] Add intermediate A-2-7d (1.00 g, 4.67 mmol) and dichloromethane (15 mL) to a 50 mL dry three-necked flask, then slowly add acetic anhydride (4.76 g, 46.70 mmol), react overnight at room temperature, monitor the reaction by LCMS, add saturated sodium bicarbonate aqueous solution (50 mL) to the reaction solution, stir for 0.5 hours, and then extract with dichloromethane (50 mL × 3). Combine the organic phases, wash with water (500 mL) and saturated brine (500 mL) in turn, dry with anhydrous sodium sulfate, concentrate, and purify by medium pressure preparation 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. 1H 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).

[0193] Preparation Example 9 Preparation of Compound A-2-8

[0194]

[0195] Dissolve the intermediate A-2-6d (1.4 g, 6.5 mmol) in dichloromethane (10 mL), add N,N-diisopropylethylamine (3.38 g, 26.2 mmol), replace nitrogen three times, reduce the reaction temperature to 0 ° C, and then start to add deuterated acetyl chloride (0.58 g, 7.19 mmol). After stirring the reaction solution at 20 ° C for 1 hour, add saturated sodium bicarbonate solution (20 mL), and extract with dichloromethane 3 times (50 mL × 3). Combine the organic phases, wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to obtain the product A-2-8 (1.31 g, 5.05 mmol, yield 77.3%). MS-ESI calculated value [M+H] + : 260.2; measured value: 260. 1 H 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).

[0196] Preparation Example 10 Preparation of Compound A-2-9

[0197]

[0198] The 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 ventilated three times under nitrogen protection. After the reaction temperature was lowered to 0 °C, deuterated acetyl chloride (630 mg, 7.7 mmol) was added dropwise. After the reaction solution was stirred at room temperature for 1 hour, a saturated aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was 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 the 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).

[0199] Preparation Example 11 Preparation of Compound A-2-10

[0200]

[0201] Compound A-2-10 is intermediate A-2-1d, and its preparation is shown in Preparation Example 3.

[0202] Preparation Example 12 Preparation of Compound A-2-11

[0203]

[0204] Compound A-2-11 is intermediate A-2-6d, and its preparation is shown in Preparation Example 7.

[0205] Preparation Example 13 Preparation of Compound A-2-12

[0206]

[0207] Compound A-2-12 is intermediate A-2-7d, and its preparation is shown in Preparation Example 8.

[0208] Preparation Example 14 Preparation of Compound A-2-15

[0209]

[0210] first step

[0211] 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), and 4-dimethylaminopyridine (900 mg, 7.38 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (780 mg, 4.06 mmol) were added at 0°C in sequence. After stirring at 0°C for 1 hour, the mixture was warmed to room temperature and reacted overnight. A small amount of water was added to quench the mixture, and after concentrating to remove N, N-dimethylformamide, the mixture was dissolved in water and acetonitrile, and compound A-2-15 (347 mg, 1.43 mmol, yield 38.6%) was prepared by medium pressure. MS-ESI calculated value [M+H] + : 244.1; measured value 244.1.

[0212] Preparation Example 15 Preparation of Compound A-2-16

[0213]

[0214] first step

[0215] 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), and 4-dimethylaminopyridine (750 mg, 6.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (650 mg, 3.38 mmol) were added at 0°C in sequence. After stirring at 0°C for 1 hour, the mixture was warmed to room temperature and reacted overnight. A small amount of water was added to quench the mixture, and after concentrating to remove N, N-dimethylformamide, the mixture was dissolved in water and acetonitrile, and compound A-2-16 (465 mg, 1.81 mmol, yield 59.0%) was prepared by medium pressure. MS-ESI calculated value [M+H] + : 257.2; measured value 257.0.

[0216] Preparation Example 16 Preparation of Compound A-2-17

[0217]

[0218] first step

[0219] 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 phase was combined and washed with brine (100 mL×3), dried over anhydrous sodium sulfate and concentrated. The obtained 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.

[0220] Step 2

[0221] 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 for 12 hours under a hydrogen atmosphere. 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 carried out at room temperature for 2 hours. After the reaction was completed, it was concentrated, and the obtained residue was separated and purified by a 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.

[0222] Step 3

[0223] 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 thereto. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was then freeze-dried and recrystallized with 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.

[0224] Step 4:

[0225] 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 thereto. 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 phase was combined and 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, giving compounds A-2-17e1 (300 mg) and A-2-17e2 (200 mg). MS-ESI calculated value [M+H] + : 358.20; measured value: 358.02.

[0226] Step 5:

[0227] 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 compound A-2-17A (155 mg) was obtained by freeze drying. 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).

[0228] 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).

[0229] Preparation Example 17 Preparation of Compound A-2-20

[0230]

[0231] first step

[0232] Compound A-2-7a (10.00 g, 98.91 mmol) was dissolved in ethanol (100 mL), then di-tert-butyl dicarbonate (43.17 g, 197.82 mmol) was added, stirred at room temperature and 4-dimethylaminopyridine (1.74 g, 14.27 mmol) was slowly added in batches. Sodium hydroxide (3.96 g, 98.91 mmol) was dissolved in water (100 mL) and added to the above reaction system, stirred at room temperature. After 4 hours, TLC monitoring showed that the reaction was complete. Water (100 mL) was added to the above reaction system for dilution, and the pH was adjusted to 3 with 1 M hydrochloric acid. 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.

[0233] Step 2

[0234] At room temperature, add intermediate A-2-7b (10.00 g, 49.70 mmol) and L-valine methyl ester hydrochloride (10.00 g, 59.64 mmol) to a single-mouth bottle, and add dichloromethane (150 mL) to dissolve. Then, add O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (22.68 g, 59.64 mmol) and triethylamine (10.06 g, 99.40 mmol) in sequence. After stirring at room temperature for 16 hours, TLC showed that the reaction was complete. Add water (200 mL) to dilute the reaction solution and extract with ethyl acetate (200 mL×3). The organic phases were combined, washed with water (500 mL × 3) and saturated brine (500 mL) in sequence, 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%).

[0235] Step 3

[0236] Add intermediate A-2-7c (3.00 g, 9.54 mmol) to a single-mouth bottle, then add hydrochloric acid ethyl acetate solution (3.0 M, 5 mL). Stir at room temperature for 4 hours. After TCL shows that the reaction is complete, concentrate to obtain intermediate A-2-20a (2.02 g, 8.07 mmol, yield 84.4%). MS-ESI theoretical value [M+H] + : 215.1; measured value: 215.3.

[0237] Step 4

[0238] In a dry three-necked bottle, add cyclopropylcarboxylic acid (0.12g, 1.44mmol), N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (0.67g, 2.40mmol), N-methylimidazole (0.20g, 2.40mmol) and triethylamine (0.20g, 1.98mmol). Add dichloromethane (5mL), stir and react for 0.5 hours, then add intermediate intermediate A-2-20a (0.30g, 1.20mmol) and react at room temperature for 2 hours. After the reaction is completed, spin dry the solvent, add water (10mL), and extract with ethyl acetate (10mL×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-2-20 (135.3 mg, 0.48 mmol, yield: 40.1%). MS-ESI theoretical value [M+H] + : 283.2; measured value: 283.3. 1H 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).

[0239] Preparation Example 18 Preparation of Compound A-2-21

[0240]

[0241] first step

[0242] In a dry three-necked flask, compound A-2-6a (5.20 g, 51.43 mmol) was added to a sodium hydroxide aqueous solution (1M, 50 mL) at 0°C, and ethanol (50 mL) was added after dissolution. 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 the reaction was completed, the pH was adjusted to 4-5 with a saturated citric acid solution, extracted with dichloromethane (100 mL×3), the combined organic phases were washed with a 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).

[0243] Step 2

[0244] In a dry three-necked bottle, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (22.68g, 59.64mmol) and triethylamine (10.00g, 99.40mmol) were dissolved in dichloromethane (100mL) at 0°C and cooled to 0°C. Intermediate A-2-6b (9.59g, 47.66mmol) was added, and after stirring for half an hour, L-valine methyl ester hydrochloride (7.82g, 59.64mmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (100mL) was added, and the mixture was extracted with ethyl acetate (100mL×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 (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. 1 H 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).

[0245] Step 3

[0246] In a dry three-necked flask, dissolve the intermediate A-2-6c (2.50 g, 7.95 mmol) in 5 mL of dichloromethane solution at 0°C, and dropwise add a solution of hydrogen chloride in dioxane (4M, 20 mL). After the addition, move to room temperature and continue stirring. After the reaction is completed, concentrate to obtain the intermediate A-2-21a (2.00 g, 7.95 mmol, 100%). MS-ESI theoretical value [M+H] + : 215.1; measured value: 215.3.

[0247] Step 4

[0248] In a dry three-necked flask, add cyclopropylcarboxylic acid (0.15g, 1.20mmol), 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.23g, 1.20mmol), 1-hydroxybenzotriazole (0.16g, 1.20mmol) and triethylamine (0.20g, 1.60mmol). Add dichloromethane (5mL), stir and react for 0.5 hours, add intermediate A-2-21a (0.25g, 1.00mmol), and react at room temperature for 2 hours. After the reaction is completed, concentrate, add water (10mL), and extract with ethyl acetate (10mL×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. 1 H 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).

[0249] Preparation Example 19 Preparation of Compound A-2-22

[0250]

[0251] In a single-mouth bottle, add benzoic acid (146.5 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (299.0 mg, 1.56 mmol), 1-hydroxybenzotriazole (210.8 mg, 1.56 mmol), and add dichloromethane (5 mL) to dissolve, and stir at 0 ° C for 0.5 hours. Then, add intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (465.3 mg, 3.60 mmol) in sequence, stir at room temperature overnight, and monitor the reaction progress by TLC. After TLC shows that the reaction is complete, add water (10 mL) to quench the reaction, extract and separate, then, the aqueous phase is continuously extracted with dichloromethane (10 mL × 2), collect the organic phase, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to obtain 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. 1 H 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).

[0252] Preparation Example 20 Preparation of Compound A-2-23

[0253]

[0254] In a dry three-necked bottle, add 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). Add dichloromethane (5 mL), stir and react for 0.5 hours, then add intermediate A-2-21a (0.32 g, 1.28 mmol) and react at room temperature for 2 hours. After the reaction is completed, concentrate, add water (10 mL), and extract with ethyl acetate (10 mL×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).

[0255] Preparation Example 21 Preparation of Compound A-2-24

[0256]

[0257] In a single-mouth bottle, add 4-trifluoromethylbenzoic acid (228.1 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.30 g, 1.56 mmol), 1-hydroxybenzotriazole (0.21 g, 1.56 mmol), and add dichloromethane (5 mL) to dissolve, and stir at 0 ° C for 0.5 hours. Then, add intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (0.47 g, 3.60 mmol) in sequence, stir at room temperature overnight, and monitor the reaction progress by TLC. After TLC shows that the reaction is complete, add water (10 mL) to quench the reaction, extract and separate, then, the aqueous phase is continuously extracted with dichloromethane (10 mL × 2), collect the organic phase, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to obtain 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).

[0258] Preparation Example 22 Preparation of Compound A-2-25

[0259]

[0260] In a dry three-necked bottle, add 4-trifluoromethylbenzoic acid (0.18 g, 0.96 mmol) and 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 to react 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×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).

[0261] Preparation Example 23 Preparation of Compound A-2-26

[0262]

[0263] In a single-mouth bottle, add p-fluorobenzoic acid (168.1 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (300 mg, 1.56 mmol), 1-hydroxybenzotriazole (0.21 g, 1.56 mmol), and add dichloromethane (5 mL) to dissolve, and stir at 0 ° C for 0.5 hours. Then, add intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (0.47 g, 3.60 mmol) in sequence, stir at room temperature overnight, and monitor the reaction progress by TLC. After TLC shows that the reaction is complete, add water (10 mL) to quench the reaction, extract and separate, then, the aqueous phase is continuously extracted with dichloromethane (10 mL × 2), collect the organic phase, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product was purified by silica gel column chromatography (=10% to 60%) to obtain 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).

[0264] Preparation Example 24 Preparation of Compound A-2-27

[0265]

[0266] 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 reaction was stirred for 0.5 hours. Intermediate A-2-21a (0.20 g, 0.80 mmol) was added. The reaction was carried out at room temperature for 2 hours, concentrated, water (10 mL) was added, and extracted with ethyl acetate (10 mL×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).

[0267] Preparation Example 25 Preparation of Compound A-2-28

[0268]

[0269] In a single-mouth bottle, add p-chlorobenzoic acid (187.9 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.30 g, 1.56 mmol), 1-hydroxybenzotriazole (0.21 g, 1.56 mmol), and add dichloromethane (5 mL) to dissolve, and stir at 0 ° C for 0.5 hours. Then, add intermediate A-2-20a (300.0 mg, 1.20 mmol) and diisopropylethylamine (0.47 g, 3.60 mmol) in sequence, stir at room temperature overnight, and monitor the reaction progress by TLC. After TLC shows that the reaction is complete, add water (10 mL) to quench the reaction, extract and separate, then, the aqueous phase is continuously extracted with dichloromethane (10 mL × 2), collect the organic phase, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to obtain 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).

[0270] Preparation Example 26 Preparation of Compound A-2-29

[0271]

[0272] In 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, 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).

[0273] Preparation Example 27 Preparation of Compound A-2-30

[0274]

[0275] In a single-mouth bottle, furan-2-carboxylic acid (165.9 mg, 1.48 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.37 g, 1.92 mmol), 1-hydroxybenzotriazole (0.26 g, 1.92 mmol) were added, and dichloromethane (5 mL) was added to dissolve, and stirred at 0°C for 0.5 hours. Then, compound intermediate A-2-20a (370.0 mg, 1.48 mmol) and diisopropylethylamine (0.57 g, 4.44 mmol) were added in sequence, stirred at room temperature overnight, and the reaction progress was monitored by TLC. After TLC showed that the reaction was complete, water (10 mL) was added to quench the reaction, extract and separate the liquids, and then the aqueous phase was continuously extracted with dichloromethane (10 mL × 2), and the organic phase was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to obtain 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).

[0276] Preparation Example 28 Preparation of Compound A-2-31

[0277]

[0278] In a dry three-necked bottle, add 2-furancarboxylic acid (0.13g, 1.20mmol) and 3-(ethylcarbamoylamino)-N,N-dimethylpropane-1-amine hydrochloride (0.23g, 1.20mmol), 1-hydroxybenzotriazole (0.16g, 1.20mmol) and triethylamine (0.20g, 1.60mmol). Add dichloromethane (5mL), stir and react for 0.5 hours, add intermediate A-2-21a (0.25g, 1.00mmol). After reacting at room temperature for 2 hours, concentrate, add water (10mL), and extract with ethyl acetate (10mL×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).

[0279] Preparation Example 29 Preparation of Compound A-2-32

[0280]

[0281] In a single-mouth bottle, add thiophene-2-carboxylic acid (306.0 mg, 2.39 mmol), and add dichloromethane (10 mL) to dissolve. Then, add compound 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) in sequence, stir at room temperature overnight, and monitor the reaction progress by TLC. After TLC shows that the reaction is complete, add water (10 mL) to quench the reaction, extract and separate, then, the aqueous phase continues to be extracted with dichloromethane (10 mL×2), collect the organic phase, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10% to 60%) to obtain 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).

[0282] Preparation Example 30 Synthesis of Compound A-2-33

[0283]

[0284] In a dry three-necked flask, add 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). Add dichloromethane (5 mL), stir and react for 0.5 hours, 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×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-2-33 (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).

[0285] Preparation Example 31 Preparation of Compound A-2-34

[0286]

[0287] first step

[0288] Add compound A-2-34a (3g, 13.81mmol) and dichloromethane (50ml) to a dry single-mouth bottle and stir under ice bath for 10 minutes. Then add cyclopentylmethanol (2.07g, 20.71mmol), 4-dimethylaminopyridine (1.69g, 13.81mmol) and N,N'-dicyclohexylcarbodiimide (4.27g, 20.71mmol) in sequence. React at room temperature for 12 hours, TLC shows that the reaction is complete. Add water (50ml) and extract with dichloromethane (50ml×3). Combine the organic phases, wash with saturated brine (20ml), dry with anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain intermediate A-2-34b (3.2g, 10.68mmol, yield 77.4%). 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).

[0289] Step 2

[0290] Add intermediate A-2-34b (3.2 g, 10.68 mmol) and dichloromethane (20 ml) to a dry single-mouth bottle. Then add 4M hydrogen chloride dioxane solution (20 mL) and stir at room temperature for 2 hours. After TLC shows that the reaction is complete, directly concentrate the reaction solution to obtain the crude intermediate A-2-34c, which is directly used in the next step.

[0291] Step 3

[0292] 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), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.91 g, 9.94 mmol) under ice bath. Continue stirring under ice bath for 1 hour and move to room temperature overnight. TLC detection reaction is complete, add water (50 ml), and extract with dichloromethane (50 ml × 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).

[0293] Step 4

[0294] Add intermediate A-2-34d (1.2 g, 3.13 mmol), dichloromethane (5 ml), and 4M hydrogen chloride in dioxane solution (10 ml) into a dry single-necked bottle and react at room temperature for 2 hours. After TLC shows that the reaction is complete, concentrate to obtain a crude intermediate A-2-34e.

[0295] Step 5

[0296] The crude intermediate A-2-34e was dissolved in tetrahydrofuran (20 ml), and N,N-diisopropylethylamine (1.22 g, 9.42 mmol) was added. In an ice bath, acetic anhydride (0.64 g, 6.28 mmol) was slowly added dropwise, and the reaction was continued for 30 minutes, then the mixture was moved to room temperature and the reaction was continued for 2 hours. After the reaction was completed by TLC, ethanol (5 mL) was added, concentrated, and purified by silica gel column chromatography to obtain the product A-2-34 (0.7 g, 2.16 mmol, yield 68.8%). 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).

[0297] Preparation Example 32 Preparation of Compound A-2-35

[0298]

[0299] first step

[0300] Add compound A-2-34a (3g, 13.81mmol) and dichloromethane (50ml) to a dry single-mouth bottle and stir under ice bath for 10 minutes. Then add cyclohexanol (2.07g, 20.71mmol), 4-dimethylaminopyridine (1.69g, 13.81mmol) and N,N'-dicyclohexylcarbodiimide (4.27g, 20.71mmol) in sequence. Continue the reaction at room temperature for 12 hours. After TLC shows that the reaction is complete. Add water (50ml) and extract with dichloromethane (50ml×3). Combine the organic phases, wash the organic phases with saturated sodium chloride solution (100ml), dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain intermediate A-2-35a (3.5g, 11.68mmol, yield 84.66%). 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).

[0301] Step 2

[0302] Add intermediate A-2-35a (3.5 g, 11.68 mmol), dichloromethane (20 ml) and 4M hydrogen chloride in dioxane solution (20 ml) into a dry single-necked bottle and react at room temperature for 2 hours. After TLC shows the reaction is complete, concentrate to obtain a crude intermediate A-2-35b.

[0303] Step 3

[0304] The crude intermediate A-2-35b and intermediate A-2-7b (1.98 g, 9.94 mmol) were dissolved in dichloromethane (40 ml), and N,N-diisopropylethylamine (3.85 g, 29.82 mmol), N-hydroxy-7-azabenzotriazole (1.35 g, 9.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.91 g, 9.94 mmol) were added under ice bath. After 1 hour of reaction, the mixture was moved to room temperature overnight. After TLC detection, the reaction was complete, water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml×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-2-35c (2.4 g, 6.27 mmol, total yield of two steps 53.7%). 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).

[0305] Step 4

[0306] Add intermediate A-2-35c (1.2 g, 3.13 mmol), dichloromethane (5 ml) and 4M hydrogen chloride in dioxane solution (10 ml) into a dry single-necked bottle, react at room temperature for 2 hours, TLC shows the reaction is complete, concentrate to obtain a crude intermediate A-2-35d.

[0307] Step 5

[0308] Dissolve the crude intermediate A-2-35d in tetrahydrofuran (20 ml), add N,N-diisopropylethylamine (1.22 g, 9.42 mmol) under ice bath, and slowly drop acetic anhydride (0.64 g, 6.28 mmol). Continue to react for 30 minutes, and then react for 2 hours at room temperature. After TLC detection, the reaction is complete, 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).

[0309] Preparation Example 33 Preparation of Compound A-2-37

[0310]

[0311] 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 bottle. Dichloromethane (5 mL) was added, the reaction was stirred for 0.5 hours, and intermediate A-2-21a (0.20 g, 0.80 mmol) was 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×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 (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).

[0312] Preparation Example 34 Preparation of Compound B-2-1

[0313]

[0314] first step

[0315] 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 for dilution (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.

[0316] Step 2

[0317] The 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 thereto. The reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the intermediate B-2-1c (8.76 g, 37.25 mmol, yield 85%) was obtained by silica gel column. MS-ESI theoretical value [M+H] + : 236.1; measured value 236.1.

[0318] Step 3

[0319] The 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), and aqueous ammonia (18.9 mL, 148.95 mmol) was slowly added thereto, and the temperature was maintained 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 the intermediate B-1-2d (6.3 g, 23.05 mmol, yield 77%). MS-ESI theoretical value [M+H] + : 274.1; measured value: 274.1.

[0320] Step 4

[0321] The intermediate B-2-1d (3.00 g, 10.98 mmol) was dissolved in methanol (75 mL), and then palladium carbon (0.3 g, 10 wt.%) was added. The mixture was ventilated with hydrogen three times, and the reaction solution was reacted at 25 ° C for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain the intermediate B-2-1e crude product (1.2 g, 8.62 mmol, yield 78%). MS-ESI theoretical value [M+H] + : 140.0; measured value: 140.1.

[0322] Step 5

[0323] The 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), and 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. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and washed with water and saturated brine. The organic phase was dried with anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by silica gel column (dichloromethane / methanol = 15 / 1) and then purified by reverse preparation to obtain the intermediate B-2-1f (0.90 g, 2.80 mmol, yield 32%). MS-ESI theoretical value [M+H] + : 323.2; measured value: 323.1.

[0324] Step 6

[0325] Dissolve the intermediate B-2-1f (0.90 g, 2.80 mmol) in ethyl acetate (20 mL), slowly add a solution of hydrogen chloride in dioxane (4.0 M, 3 ml) under stirring at room temperature, continue stirring at room temperature for 12 hours, monitor the reaction to completion, and concentrate 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.

[0326] Step 7

[0327] Dissolve the 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, concentrate to dryness, separate and purify the obtained residue with silica gel column (dichloromethane / methanol=15 / 1), and then purify by reverse preparation 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).

[0328] Preparation Example 35 Preparation of Compound B-2-2

[0329]

[0330] first step

[0331] 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.

[0332] Step 2

[0333] Compound 1,3-oxazole (1g, 14.5mmol) was dissolved in tetrahydrofuran (30mL), replaced with nitrogen, and then borane tetrahydrofuran solution (22mL) was added. The reaction solution was cooled to -78°C and then n-butyl lithium tetrahydrofuran solution (2.4M, 10mL, 24mmol) was added. After stirring for 30 minutes, intermediate B-2-2b (2.5g, 14.5mmol) was slowly added, and the reaction solution was stirred at -78°C for 3 hours. After the reaction was quenched with saturated ammonium chloride aqueous solution, it was extracted three times with ethyl acetate (50mL×3), the organic phases were combined, and washed with saturated sodium bicarbonate solution (100mL×2), saturated ammonium chloride solution (100mL×2) and saturated brine (100mL×2) in sequence. The obtained 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.

[0334] Step 3

[0335] At 0°C, add 2M hydrogen chloride in 1,4-dioxane solution (10 mL) to intermediate B-2-2c (1 g, 4.1 mmol), stir the reaction at 0°C for 1 hour, and concentrate to obtain intermediate B-2-2d (400 mg, 2.85 mmol, yield 69.7%). MS-ESI theoretical value [M+H] + : 141.1; measured value: 141.1.

[0336] Step 4

[0337] To a solution of intermediate A-2-6b (2.5 g, 12.4 mmol) in dichloromethane (30 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.57 g, 18.6 mmol), 1-hydroxybenzotriazole (2.51 g, 18.6 mmol), N-methylmorpholine (11.29 g, 111.6 mmol) were added, and after stirring at -15 ° C for 10 minutes, intermediate B-2-2d (1.91 g, 13.64 mmol) was added, and the reaction solution was stirred at -15 ° C for 4 hours. After the reaction was completed, the reaction was washed with saturated citric acid solution (50 mL × 2), saturated sodium carbonate solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained 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.

[0338] Step 5

[0339] The intermediate B-2-2e (2.5 g, 6.4 mmol) was dissolved in a dichloromethane solution of trifluoroacetic acid (V / V=1:1, 40 mL), and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed, it 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.

[0340] Step 6

[0341] Add N,N-diisopropylethylamine (7.96 g, 61.6 mmol) to a solution of the crude intermediate B-2-2f (5.58 g) in dichloromethane (40 mL), purify the mixture three times under nitrogen protection, add deuterated acetyl chloride (0.69 g, 8.4 mmol) after stirring at 0°C for 5 minutes, and stir the reaction solution at room temperature for 2 hours. The reaction solution 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 the product B-2-2 (1.57 g, 5.85 mmol, total yield of two steps 75.6%). MS-ESI theoretical value [M+H] + : 269.2; measured value: 269.0. 1H 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).

[0342] Preparation Example 36 Preparation of Compound B-2-3

[0343]

[0344] first step:

[0345] At -10°C, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g, 12.45 mmol), 1-hydroxybenzotriazole (1.68 g, 12.45 mmol), N,N-diisopropylethylamine (5.36 g, 41.50 mmol) to a solution of compound A-2-7b (2 g, 9.96 mmol) in dichloromethane (50 mL). After stirring for 10 minutes, add intermediate B-2-2d (1.47 g, 8.30 mmol) and continue to react at -10°C for 2 hours. After the reaction is completed, the reaction solution is washed with saturated citric acid aqueous solution (50 mL × 2) and saturated sodium carbonate solution (50 mL × 2) in turn. The obtained 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.

[0346] Step 2:

[0347] The intermediate B-2-3a (2 g, 6.2 mmol) was dissolved in a dichloromethane solution of trifluoroacetic acid (V / V=1:1, 20 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to obtain a crude intermediate B-2-3b (3.6 g). MS-ESI theoretical value [M+H] + : 224.1; measured value: 224.0.

[0348] Step 3:

[0349] At 0°C, N,N-diisopropylethylamine (6.4 g, 49.6 mmol) and deuterated acetyl chloride (606 mg, 7.4 mmol) were added to a solution of the crude intermediate B-2-3b (3.6 g) in dichloromethane (60 mL) in sequence. After the addition, the reaction was continued at 0°C for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain the product B-2-3 (1.22 g, 4.55 mmol, total yield of two steps 73.5%). MS-ESI theoretical value [M+H] + :269.2; found value: 269.0. 1HNMR (400MHz, Chloroform-d) δ8.50 (d, J=8.5Hz, 1H), 7.60 (s, 1H), 7.08 (s, 1H), 5.08 (dd, J=8.5, 6.0Hz, 1H), 4.95 (dd, J=9.6, 6.6Hz, 1H), 4.06 (t, J=8.0Hz, 2H), 2.73–2.59 (m, 1H), 2.51–2.35 (m, 1H), 2.28 (dq, J=13.4, 6.7Hz, 1H), 0.96 (dd, J=13.9, 6.8Hz, 6H).

[0350] Preparation Example 37 Preparation of Compound B-2-4

[0351]

[0352] first step

[0353] Dissolve intermediate B-2-3a (6 g, 18.55 mmol) in dichloromethane (50 mL) and add 4 M hydrogen chloride in dioxane solution (15 mL). React at room temperature for 2 hours. TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate B-2-4a (4.83 g, 18.6 mmol, yield 100%). MS-ESI theoretical value [M+H] + : 224.1; measured value: 224.3.

[0354] Step 2

[0355] In a dry single-mouth bottle, add intermediate B-2-4a (500.0 mg, 1.93 mmol), dissolve with ultra-dry dichloromethane (5 mL), and replace nitrogen. Then, add diisopropylethylamine (0.75 g, 5.79 mmol) at 0°C, stir for 10 min, and finally, slowly add cyclopropylcarbonyl chloride (262.3 mg, 2.51 mmol) to the above reaction system. Continue to react at 0°C for 2 hours. TLC shows that the reaction is complete. Add water (10 mL), extract and separate the liquids. Then, the aqueous phase is further extracted with dichloromethane (10 mL×2). Combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (EA:PE=10%~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. 1 H 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).

[0356] Preparation Example 38 Preparation of Compound B-2-5

[0357]

[0358] In a dry single-mouth bottle, add intermediate B-2-4a (500.0 mg, 1.93 mmol), dissolve with ultra-dry dichloromethane (5 mL), and replace nitrogen. Then, add diisopropylethylamine (0.75 g, 5.79 mmol) at 0°C, stir for 10 min, and finally, slowly add trimethylacetyl chloride (302.5 mg, 2.51 mmol) to the above reaction system. Continue to react at 0°C for 2 hours. TLC shows that the reaction is complete. Add water (10 mL), extract and separate. Then, the aqueous phase is further extracted with dichloromethane (10 mL×2). Combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (EA:PE=10%~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).

[0359] Preparation Example 39 Preparation of Compound B-2-8

[0360]

[0361] first step

[0362] 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 in sequence. Stir at room temperature for 2 hours. 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 (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate B-2-8b (9.56 g, 45.52 mmol, yield 97.4%).

[0363] Step 2

[0364] Dissolve the intermediate B-2-8b (9.56g, 45.46mmol) in ultra-dry tetrahydrofuran (100ml), protect with nitrogen and cool to -78℃. Slowly add 1M isopropylmagnesium bromide (50ml). After the addition is complete, continue the reaction for 2h. TLC shows that the reaction is complete, add water (100ml), and extract with dichloromethane (50ml×2). Combine the organic phases, wash with saturated sodium chloride solution (200ml), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain intermediate B-2-8c (6.15g, 24.21mmol, yield 53.2%). MS-ESI theoretical value [M+H] + : 255.2; measured value: 255.3.

[0365] Step 3

[0366] Dissolve intermediate B-2-8c (6.15 g, 24.21 mmol) in dichloromethane (100 ml), add 4M hydrogen chloride in dioxane solution (30 ml), react at room temperature for 2 hours, TLC shows the reaction is complete, concentrate to obtain crude intermediate B-2-8d.

[0367] Step 4

[0368] Dissolve the crude intermediate B-2-8d (0.5 g, 2.48 mmol) in dichloromethane (50 ml), and 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), continue to react in an ice bath for 30 minutes, and move to room temperature. After 3 hours of reaction, TLC shows that the raw material is completely reacted. 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%). 1H 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).

[0369] Step 5

[0370] 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, and the mixture was reacted at room temperature for 2 hours. TLC showed that the reaction was complete, and the mixture was concentrated to obtain intermediate B-2-8f (0.42 g, 1.8 mmol, yield 100%). 1 H 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).

[0371] Step 6

[0372] Dissolve the intermediate B-2-8f (0.42 g, 1.8 mmol) in tetrahydrofuran (20 ml). Add N,N-diisopropylethylamine (0.70 g, 5.40 mmol) and slowly drip acetic anhydride (0.37 g, 3.60 mmol) in an ice bath. Continue the reaction for 30 minutes in an ice bath and move to room temperature. React for 2 hours, TLC shows reaction. Add methanol (5 mL), concentrate, and separate by silica gel column chromatography to obtain product B-2-8 (0.25 g, 0.91 mmol, yield 50.4%). MS-ESI theoretical value [M+H]+ : 276.2; measured value: 276.3. 1 HNMR(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).

[0373] Preparation Example 40 Preparation of Compounds B-2-9 and B-2-10

[0374]

[0375] first step

[0376] Dissolve B-2-9a (2g, 18.67mmol) in ultra-dry dichloromethane (100ml), and add cesium carbonate (7.30g, 22.40mmol) and (S)-tert-butylsulfenamide (2.26g, 18.67mmol) in sequence. Stir at room temperature for 2 hours. After TLC shows that the reaction is complete, add water (100ml) and extract with dichloromethane (50ml×2). Combine the organic phases, wash with saturated sodium chloride solution (200ml), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain intermediate B-2-9b (3.82g, 18.02mmol, yield 97.38%).

[0377] Step 2

[0378] Dissolve the intermediate B-2-9b (3.82 g, 18.02 mmol) in ultra-dry tetrahydrofuran (100 ml), replace with nitrogen and cool to -78 ° C, slowly add 1M isopropylmagnesium bromide tetrahydrofuran solution (20 ml). After the addition is complete, continue to react at -78 ° C for 2 hours. TLC shows that the reaction is complete, add water (100 ml), and extract with dichloromethane (50 ml × 2). Combine the organic phases, wash with saturated sodium chloride solution (200 ml), dry over anhydrous sodium sulfate, and obtain two components by silica gel column chromatography.

[0379] The component 1 with a short 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.

[0380] The component 2 with a long 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.

[0381] Step 3 - Component 1

[0382] Dissolve intermediate B-2-9c (1 g, 3.93 mmol) in dichloromethane (10 ml), add 4M hydrogen chloride in dioxane solution (5 ml), react at room temperature for 3 hours, TLC detection shows the reaction is complete, concentrate to obtain crude intermediate B-2-9d.

[0383] Step 4 - Component 1

[0384] The crude intermediate B-2-9d was dissolved in dichloromethane (30 ml), and N,N-diisopropylethylamine (1.02 g, 7.86 mmol) was added in sequence, 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 mixture was reacted overnight at room temperature, and water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml × 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 of two steps 61.1%). 1 HNMR (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).

[0385] Step 5 - Component 1

[0386] Dissolve intermediate B-2-9e (0.8 g, 2.4 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (8 ml), react at room temperature for 2 hours, and concentrate to obtain crude intermediate B-2-9f.

[0387] Step 6 - Component 1

[0388] Dissolve the crude intermediate B-2-9f in tetrahydrofuran (20 ml) and add N,N-diisopropylethylamine (1.02 g, 7.86 mmol). Slowly drop acetic anhydride (0.6 g, 5.9 mmol) in an ice bath. Continue the reaction for 30 minutes and move 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%). 1 H 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).

[0389] Step 3 - Component 2

[0390] Dissolve intermediate B-2-10c (1 g, 3.93 mmol) in dichloromethane (10 ml), add 4M hydrogen chloride in dioxane solution (5 ml), react at room temperature for 3 hours, TLC detection shows the reaction is complete, concentrate to obtain crude intermediate B-2-10d.

[0391] Step 4 - Component 2

[0392] The crude intermediate B-2-10d was dissolved in dichloromethane (30 ml), and N,N-diisopropylethylamine (1.02 g, 7.86 mmol) was added in sequence, 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 mixture was reacted overnight at room temperature, and water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml × 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 of two steps 61.1%). 1H 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).

[0393] Step 5 - Component 2

[0394] Dissolve intermediate B-2-10e (0.8 g, 2.4 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (8 ml), react at room temperature for 2 hours, and concentrate to obtain crude intermediate B-2-10f.

[0395] Step 6 - Component 2

[0396] Dissolve the crude intermediate B-2-10f in tetrahydrofuran (20ml) and add N,N-diisopropylethylamine (1.02g, 7.86mmol). Slowly drop acetic anhydride (0.6g, 5.9mmol) in an ice bath. Continue the reaction for 30 minutes and move to room temperature. After 2 hours of reaction, TLC shows that the reaction is complete. Add methanol (2mL), concentrate, and separate by silica gel column chromatography to obtain product B-2-10 (0.33g, 1.2mmol, 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).

[0397] Preparation Example 41 Compound B-2-11

[0398]

[0399] first step

[0400] Dissolve B-2-11a (1g, 9.33mmol) in ultra-dry dichloromethane (100ml), and add cesium carbonate (3.65g, 11.20mmol) and (S)-tert-butylsulfenamide (1.13g, 9.33mmol) in turn. React at room temperature for 2 hours, TLC shows that the reaction is complete. Add water (100ml) and extract with dichloromethane (50ml×2). Combine the organic phases, wash the organic phases with saturated brine (100ml), dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain intermediate B-2-11b (1.90g, 9.01mmol, yield 97.3%).

[0401] Step 2

[0402] Dissolve the intermediate B-2-11b (1.90 g, 9.01 mmol) in ultra-dry tetrahydrofuran (100 ml), cool to -78 °C under nitrogen protection, and slowly drop 1M isopropylmagnesium bromide (10 ml). After continuing 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 × 2). Combine the organic phases, wash the organic phases with saturated sodium chloride solution (200 ml), dry over anhydrous sodium sulfate, and obtain two single-configuration components by silica gel column chromatography.

[0403] 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.

[0404] 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.

[0405] Step 3

[0406] Dissolve intermediate B-2-11c (0.94 g, 3.54 mmol) in dichloromethane (10 ml), add 4M hydrogen chloride in dioxane solution (5 ml), react at room temperature for 3 hours, TLC shows the reaction is complete, concentrate to obtain crude intermediate B-2-11d.

[0407] Step 4

[0408] 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 in sequence. After reacting at room temperature overnight, water (50 ml) was added, and the mixture was extracted with dichloromethane (50 ml × 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 of two steps 25.4%). 1 H 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).

[0409] Step 5

[0410] Dissolve intermediate B-2-11e (0.30 g, 0.9 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (8 ml), react at room temperature for 2 hours, TLC shows the reaction is complete, concentrate to obtain crude intermediate B-2-11f.

[0411] Step 6

[0412] The crude intermediate B-2-11f was dissolved in tetrahydrofuran (20 ml), and N,N-diisopropylethylamine (0.21 g, 1.62 mmol) was added under ice bath, and then acetic anhydride (0.12 g, 1.22 mmol) was slowly added. After the addition was completed, the reaction was continued for 30 minutes under ice bath, and then moved to room temperature. After 2 hours of reaction, TLC showed that the reaction was complete. Methanol (5 mL) was added, concentrated, and purified by silica gel column chromatography to obtain product B-2-11 (80 mg, 0.29 mmol, total yield of two steps 32.2%). 1H 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).

[0413] Preparation Example 42 Preparation of Compound ZZL-7

[0414]

[0415] first step

[0416] Add (tert-butyloxycarbonyl)-L-alanine (4.5 g, 23.78 mmol) to a dry single-necked bottle, dissolve in dichloromethane (50 mL), place in an ice bath and stir for 10 min, then add L-valine methyl ester (3.12 g, 23.78 mmol), N,N-diisopropylethylamine (6.15 g, 47.56 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.01 g, 26.16 mmol) to the bottle in sequence, and stir at room temperature for 2 h. After TLC showed that the reaction was completed, water (50 mL) was added to quench, and the mixture was adjusted to acidity with 2M hydrochloric acid, extracted with dichloromethane (50 mL*2), and the organic phases were combined. The organic phase was adjusted to alkalinity with saturated sodium bicarbonate, extracted with dichloromethane (50 mL*2), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (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%).

[0417] LCMS (M+H + )=303.1

[0418] Step 2

[0419] Add (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol) to a dry single-mouth bottle, dissolve in dichloromethane (30 mL), then add hydrochloric acid-1.4-dioxane (10 mL, 4 M) to the bottle, and stir at room temperature for 2 hours. After TLC shows that the reaction is complete, concentrate the organic phase and purify by silica gel column chromatography (DCM: MeOH = 10: 1) to obtain the intermediate L-alanyl-L-valine methyl ester (3.7 g, 18.32 mmol, yield 87.22%).

[0420] LCMS (M+H + )=203.3

[0421] 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).

[0422] Step 3

[0423] The compound L-alanyl-L-valine methyl ester (3.7g, 18.32mmol) and N,N-diisopropylethylamine (4.72g, 36.64mmol) were dissolved in tetrahydrofuran (50mL), fully replaced with nitrogen and stirred at 0℃. After 10min, acetic anhydride (2.8g, 27.48mmol) was slowly added dropwise, stirred at this temperature for 10min, and stirred at room temperature for 2h. After TLC showed that the reaction was completed, water (50mL) was added to quench, and 2M hydrochloric acid was used to adjust to acidity, extracted with dichloromethane (50mL*4), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=5:1). The compound acetyl-L-alanyl-L-valine methyl ester (2.6g, 10.67mmol, yield 58.23%) was obtained, namely ZZL-7.

[0424] LCMS (M+H + )=245.3

[0425] 1HNMR(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).

[0426] Preparation Example 43 Preparation of Compound A-2-38

[0427]

[0428] first step

[0429] A-2-38a (3.00 g, 13.82 mmol) was dissolved in dichloromethane (50 mL) and stirred at 40 °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 at once. After stirring at room temperature for 12 h, TLC showed that the reaction was complete. Water (50 ml) was added to quench the reaction and the mixture was extracted with dichloromethane (50 ml × 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-2-38b (2.50 g, 8.30 mmol, yield 60.0%).

[0430] Step 2

[0431] Dissolve intermediate A-2-38b (2.50 g, 8.30 mmol) in dichloromethane (20 ml), add 4M hydrogen chloride in dioxane solution (20 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-38c, which is used directly in the next step without purification.

[0432] Step 3

[0433] 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, react under ice bath for 1 hour, and then move to room temperature. After reacting overnight, TLC shows that the reaction is complete, add water (50 ml), and extract with dichloromethane (50 ml×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%).

[0434] 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).

[0435] Step 4

[0436] Dissolve intermediate A-2-38d (1.10 g, 2.86 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (10 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-38e, which is used directly in the next step without purification.

[0437] Step 5

[0438] Dissolve the crude intermediate A-2-38e in tetrahydrofuran (20 ml), add N,N-diisopropylethylamine (1.11 g, 8.58 mmol). Stir for 10 min in an ice bath, then slowly drop acetic anhydride (0.58 g, 5.72 mmol). After reacting for 30 min, move to room temperature. After continuing the reaction for 2 h, TLC shows that 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 of two steps 64.3%).

[0439] 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).

[0440] Preparation Example 44 Preparation of Compound A-2-39

[0441]

[0442] first step

[0443] A-2-38a (2.00 g, 9.21 mmol) was dissolved in dichloromethane (50 ml), and 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 in an ice bath. After the addition, the mixture was stirred at room temperature for 12 h. TLC showed that the reaction was complete. Water (50 ml) was added and extracted with dichloromethane (50 ml × 3). The organic phases were combined and washed with saturated brine (200 ml) in turn, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2-39a (1.50 g, 5.18 mmol, yield 56.2%).

[0444] Step 2

[0445] Dissolve intermediate A-2-39a (1.50 g, 5.18 mmol) in dichloromethane (20 ml), add 4M hydrogen chloride in dioxane solution (20 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-39b, which is used directly in the next step without purification.

[0446] Step 3

[0447] 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. After the addition, continue the reaction for 1 hour in an ice bath and then move to room temperature. After reacting overnight, TLC shows that the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml × 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%).

[0448] 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).

[0449] Step 4

[0450] Dissolve intermediate A-2-39c (1.10 g, 2.95 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (10 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-39d, which is used directly in the next step without purification.

[0451] Step 5

[0452] 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 for 10 min in an ice bath, acetic anhydride (0.60 g, 5.90 mmol) was slowly added dropwise, and the reaction was continued for 30 min. After moving to room temperature and continuing the reaction for 2 h, TLC showed that the reaction was complete, and ethanol (10 mL) was added, concentrated, and purified by silica gel column chromatography to obtain the product A-2-39 (0.24 g, 0.76 mmol, total yield of two steps 25.8%).

[0453] 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).

[0454] Preparation Example 45 Preparation of Compound A-2-40

[0455]

[0456] first step

[0457] 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 in an ice bath. After the addition was completed, the mixture was moved to room temperature and the reaction was continued for 12 hours. TLC showed that the reaction was complete. Water (50 ml) was added and extracted with dichloromethane (50 ml × 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, yield 55.2%).

[0458] Step 2

[0459] 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 reacting at room temperature for 2 h, TLC showed that the reaction was complete. The crude intermediate A-2-40b was concentrated and used directly in the next step without purification.

[0460] Step 3

[0461] 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 bath. After addition, react for 1 hour and move to room temperature. React overnight. TLC shows that the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml × 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 of 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).

[0462] Step 4

[0463] Dissolve intermediate A-2-40c (2.50 g, 6.29 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (10 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-40d, which is directly used in the next step without purification.

[0464] Step 5

[0465] Dissolve the crude intermediate A-2-40d in tetrahydrofuran (20ml) and add N,N-diisopropylethylamine (2.44g, 18.87mmol). After stirring for 10min in an ice bath, slowly drop acetic anhydride (1.28g, 12.58mmol), continue to react for 30min and move to room temperature. After continuing to react for 2h, TLC shows that the reaction is complete. Add ethanol (10mL), concentrate and purify by silica gel column chromatography to obtain product A-2-40 (1.00g, 2.95mmol, total yield of two steps 46.8%). 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).

[0466] Preparation Example 46 Preparation of Compound A-2-41

[0467]

[0468] first step

[0469] 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 in an ice bath. After the addition was completed, the mixture was moved to room temperature and the reaction was continued for 12 hours. TLC showed that the reaction was complete. Water (50 ml) was added and extracted with dichloromethane (50 ml × 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, yield 39.4%).

[0470] Step 2

[0471] Dissolve intermediate A-2-41a (1.50 g, 5.45 mmol) in dichloromethane (20 ml), add 4M hydrogen chloride in dioxane solution (20 ml). After reacting at room temperature for 2 hours, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-41b, which is directly used in the next step without purification.

[0472] Step 3

[0473] 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 bath. After addition, react for 1 hour and move to room temperature. React overnight. TLC shows that the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml × 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 of 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).

[0474] Step 4

[0475] Dissolve intermediate A-2-41c (1.00 g, 2.79 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (10 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-41d, which is used directly in the next step without purification.

[0476] Step 5

[0477] Dissolve the crude intermediate A-2-41d in tetrahydrofuran (20ml) and add N,N-diisopropylethylamine (1.08g, 8.37mmol). After stirring for 10min in an ice bath, slowly drop acetic anhydride (0.57g, 5.58mmol), continue to react for 30min and move to room temperature. After continuing to react for 2h, TLC shows that the reaction is complete. Add ethanol (10mL), concentrate and purify by silica gel column chromatography to obtain product A-2-41 (0.30g, 1.00mmol, total yield of two steps 35.8%). 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).

[0478] Preparation Example 47 Preparation of Compound A-2-42

[0479]

[0480] first step

[0481] 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 in an ice bath. After the addition was completed, the mixture was moved to room temperature and the reaction was continued for 12 hours. TLC showed that the reaction was complete. Water (50 ml) was added and extracted with dichloromethane (50 ml × 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, yield 66.2%).

[0482] Step 2

[0483] Dissolve intermediate A-2-42a (2.50 g, 9.15 mmol) in dichloromethane (20 ml), add 4M hydrogen chloride in dioxane solution (20 ml). After reacting at room temperature for 2 hours, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-42b, which is directly used in the next step without purification.

[0484] Step 3

[0485] 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 bath. After addition, react for 1 hour and move to room temperature. React overnight. TLC shows that the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml×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 of 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).

[0486] Step 4

[0487] Dissolve intermediate A-2-42c (2.00 g, 5.61 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (10 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-42d, which is used directly in the next step without purification.

[0488] Step 5

[0489] Dissolve the crude intermediate A-2-42d in tetrahydrofuran (20ml) and add N,N-diisopropylethylamine (2.18g, 16.83mmol). After stirring for 10min in an ice bath, slowly drop acetic anhydride (1.15g, 11.22mmol), continue to react for 30min and move to room temperature. After continuing to react for 2h, TLC shows that the reaction is complete. Add ethanol (10mL), concentrate and purify by silica gel column chromatography to obtain product A-2-42 (0.60g, 2.01mmol, total yield of two steps 35.8%). 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).

[0490] Preparation Example 48 Preparation of Compound A-2-43

[0491]

[0492] first step

[0493] 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 in an ice bath. After the addition was completed, the mixture was moved to room temperature and the reaction was continued for 12 hours. TLC showed that the reaction was complete. Water (50 ml) was added and extracted with dichloromethane (50 ml × 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, yield 53.3%).

[0494] Step 2

[0495] The intermediate A-2-43a (3.50 g, 12.28 mmol) was dissolved in dichloromethane (20 ml), and a 4M solution of hydrogen chloride in dioxane (ml) was added. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. The crude intermediate A-2-43b was concentrated and used directly in the next step without purification.

[0496] Step 3

[0497] 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 bath. After addition, react for 1 hour and move to room temperature. React overnight. TLC shows that the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml×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).

[0498] Step 4

[0499] Dissolve intermediate A-2-43c (2.00 g, 5.43 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (10 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-43d, which is used directly in the next step without purification.

[0500] Step 5

[0501] Dissolve the crude intermediate A-2-43d in tetrahydrofuran (20ml) and add N,N-diisopropylethylamine (2.11g, 16.29mmol). After stirring for 10min in an ice bath, slowly drop acetic anhydride (1.11g, 10.86mmol), continue to react for 30min and then move to room temperature. After continuing to react for 2h, TLC shows that the reaction is complete. Add ethanol (10mL), concentrate and purify by silica gel column chromatography to obtain product A-2-43 (0.80g, 2.58mmol, total yield of two steps 47.5%). 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).

[0502] Preparation Example 49 Preparation of Compound A-2-44

[0503]

[0504] first step

[0505] 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 in turn under ice bath. After addition, the mixture was moved to room temperature and the reaction was continued for 12 hours. TLC showed that the reaction was complete. Water (50 ml) was added and extracted with dichloromethane (50 ml × 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, yield 59.1%).

[0506] Step 2

[0507] 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 reacting at room temperature for 2 h, TLC showed that the reaction was complete. The crude intermediate A-2-44b was concentrated and used directly in the next step without purification.

[0508] Step 3

[0509] 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) in an ice bath. After the addition is complete, react for 1 hour and move to room temperature. React overnight. TLC shows that the reaction is complete. Add water (50 ml) and extract with dichloromethane (50 ml×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%).

[0510] 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).

[0511] Step 4

[0512] Dissolve intermediate A-2-44c (1.50 g, 4.41 mmol) in dichloromethane (5 ml), add 4M hydrogen chloride in dioxane solution (10 ml). Stir at room temperature for 2 h, TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate A-2-44d, which is used directly in the next step without purification.

[0513] Step 5

[0514] 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 for 10 min in an ice bath, acetic anhydride (0.90 g, 8.82 mmol) was slowly added dropwise, and the reaction was continued for 30 min before being moved to room temperature. After continuing the reaction for 2 h, TLC showed that the reaction was complete. Ethanol (10 mL) was added, concentrated and purified by silica gel column chromatography to obtain the product A-2-44 (0.60 g, 2.12 mmol, total yield of two steps 48.2%). 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).

[0515] Preparation Example 50 Preparation of Compounds B-2-12 and B-2-13

[0516]

[0517] first step

[0518] 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. After the addition, react overnight. TLC shows that the reaction is complete. Filter, wash the filtrate with saturated brine (100×2 mL), dry with 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.

[0519] Step 2

[0520] Dissolve the intermediate B-2-12b (4.50 g, 21.50 mmol) in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (40.00 mL, 40.00 mmol). After addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain two components.

[0521] The component 1 with a 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).

[0522] 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).

[0523] Step 3 - Component 1

[0524] Dissolve the intermediate B-2-12c (1.00 g, 3.95 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain the crude intermediate B-2-12d, which is directly used in the next reaction without purification.

[0525] Step 4 - Component 1

[0526] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 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).

[0527] Step 5 - Component 1

[0528] The intermediate B-2-12e (0.55 g, 1.65 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-12f, which was directly used in the next reaction without purification.

[0529] Step 6 - Component 1

[0530] 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 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 the product B-2-12 (86.2 mg, 0.31 mmol, total yield of 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).

[0531] Step 3 - Component 2

[0532] Dissolve intermediate B-2-13c (0.24 g, 0.95 mmol) in dichloromethane (2 mL), add 4M hydrogen chloride in dioxane solution (4 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-13d, which is directly used in the next reaction without purification.

[0533] Step 4 - Component 2

[0534] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and 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 intermediate B-2-13e (0.32 g, 0.96 mmol, total yield of two steps 100%). MS-ESI theoretical value [M-Boc+2H] + : 233.2; measured value: 233.2.

[0535] Step 5 - Component 2

[0536] The intermediate B-2-13e (0.32 g, 0.96 mmol) was dissolved in dichloromethane (3 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (6 mL) was added 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.

[0537] Step 6 - Component 2

[0538] 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 h, water (5 mL) was added and 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 the product B-2-13 (118.2 mg, 0.43 mmol, total yield of 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).

[0539] Preparation Example 51 Preparation of Compounds B-2-14 and B-2-15

[0540]

[0541] first step

[0542] 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 in sequence. After the addition, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete. The product was filtered and 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 obtain intermediate B-2-14b (6.00 g, 24.6 mmol, yield 86.5%).

[0543] Step 2

[0544] The intermediate B-2-14b (5.00 g, 20.51 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, 1N isopropylmagnesium bromide in tetrahydrofuran solution (41.0 mL, 41.00 mmol) was slowly added dropwise. After addition, the reaction was continued at -78 ° C for 2 h, and 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 turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0545] The component 1 with a shorter retention time is intermediate B-2-14c (0.70 g, 2.43 mmol, yield 11.9%).

[0546] The component 2 with a longer retention time is intermediate B-2-15c (2.00 g, 6.94 mmol, yield 33.9%).

[0547] Step 3 - Component 1

[0548] Dissolve intermediate B-2-14c (0.70 g, 2.43 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, concentrate to obtain crude intermediate B-2-14d, which is directly used in the next reaction without purification.

[0549] Step 4 - Component 1

[0550] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-14e (0.45 g, 1.23 mmol, total yield of two steps 50.5%). MS-ESI theoretical value [M-Boc+2H] + : 267.1; measured value: 267.1.

[0551] Step 5 - Component 1

[0552] The intermediate B-2-14e (0.45 g, 1.23 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added 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.

[0553] Step 6 - Component 1

[0554] 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 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 the product B-2-14 (155.0 mg, 0.50 mmol, total yield of two steps 40.8%). MS-ESI theoretical value [M+H] + : 309.1; measured value: 309.1. 1H 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).

[0555] Step 3 - Component 2

[0556] Dissolve the intermediate B-2-15c (2.00 g, 6.95 mmol) in dichloromethane (20 mL), add 4M hydrogen chloride in dioxane solution (40 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain the crude intermediate B-2-15d, which is directly used in the next reaction without purification.

[0557] Step 4 - Component 2

[0558] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×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 of two steps 27.5%). MS-ESI theoretical value [M-Boc+2H] + : 267.1; measured value: 267.1.

[0559] Step 5 - Component 2

[0560] The intermediate B-2-15e (0.70 g, 1.91 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-2-15f, which was used directly in the next reaction without purification.

[0561] Step 6 - Component 2

[0562] 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 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 the product B-2-15 (74.0 mg, 0.24 mmol, total yield of two steps 12.5%). MS-ESI theoretical value [M+H] + : 309.1; measured value: 309.1. 1 H 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).

[0563] Preparation Example 52 Preparation of Compounds B-2-16 and B-2-17

[0564]

[0565] first step

[0566] 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 in sequence. After the addition, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete, and the mixture 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%).

[0567] Step 2

[0568] Dissolve the intermediate B-2-16b (5.00 g, 22.39 mmol) in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (44.5 mL, 40.50 mmol). After addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine (100 mL × 2) in turn, dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain two components.

[0569] The component 1 with a 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. 1 H 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).

[0570] 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).

[0571] Step 3 - Component 1

[0572] Dissolve the intermediate B-2-16c (1.86 g, 6.96 mmol) in dichloromethane (15 mL), add 4M hydrogen chloride in dioxane solution (30 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain the crude intermediate B-2-16d, which is directly used in the next reaction without purification.

[0573] Step 4 - Component 1

[0574] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×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 of two steps 53.9%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.3.

[0575] Step 5 - Component 1

[0576] The intermediate B-2-16e (1.00 g, 2.89 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-2-16f, which was directly used in the next reaction without purification.

[0577] Step 6 - Component 1

[0578] 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 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 the product B-2-16 (331.5 mg, 1.15 mmol, total yield of two steps 39.8%). MS-ESI theoretical value [M+H] + : 289.2; measured value: 289.4. 1H 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).

[0579] Step 3 - Component 2

[0580] Dissolve intermediate B-2-17c (0.50 g, 1.87 mmol) in dichloromethane (5 mL), add 4M hydrogen chloride in dioxane solution (10 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-17d, which is directly used in the next reaction without purification.

[0581] Step 4 - Component 2

[0582] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 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 of two steps 77.0%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.4.

[0583] Step 5 - Component 2

[0584] The intermediate B-2-17e (0.50 g, 1.44 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added 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.

[0585] Step 6 - Component 2

[0586] 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 h, water (5 mL) was added and 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 the 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. 1 H 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).

[0587] Preparation Example 53 Preparation of Compounds B-2-18 and B-2-19

[0588]

[0589] first step

[0590] 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, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete, and the mixture 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%).

[0591] Step 2

[0592] Dissolve the intermediate B-2-18b (5.00 g, 22.39 mmol) in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (44.5 mL, 44.50 mmol). After addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine (100 mL × 2) in turn, dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain two components.

[0593] The component 1 with a 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.

[0594] 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.

[0595] Step 3 - Component 1

[0596] Dissolve intermediate B-2-18c (0.95 g, 3.55 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-18d, which is directly used in the next reaction without purification.

[0597] Step 4 - Component 1

[0598] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and 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 intermediate B-2-18e (1.30 g, 3.75 mmol, total yield of two-step reaction 100%). MS-ESI theoretical value [M-Boc+2H] +: 247.2; measured value: 247.4.

[0599] Step 5 - Component 1

[0600] The intermediate B-2-18e (1.30 g, 3.75 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-2-18f, which was used directly in the next reaction without purification.

[0601] Step 6 - Component 1

[0602] 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 ethyl diisopropylamine (1.57 g, 12.18 mmol) were added. After reacting at -10 °C for 1 h, water (10 mL) was added and 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 the product B-2-18 (192.1 mg, 0.67 mmol, total yield of 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).

[0603] Step 3 - Component 2

[0604] Dissolve intermediate B-2-19c (0.50 g, 1.87 mmol) in dichloromethane (5 mL), add 4M hydrogen chloride in dioxane solution (10 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-19d, which is directly used in the next reaction without purification.

[0605] Step 4 - Component 2

[0606] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and 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 intermediate B-2-19e (0.55 g, 1.59 mmol, total yield of two steps 84.9%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.3.

[0607] Step 5 - Component 2

[0608] The intermediate B-2-19e (0.55 g, 1.59 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added 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.

[0609] Step 6 - Component 2

[0610] 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 h, water (5 mL) was added and 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 the product B-2-19 (99.9 mg, 0.35 mmol, total yield of 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).

[0611] Preparation Example 54 Preparation of Compounds B-2-20 and B-2-21

[0612]

[0613] first step

[0614] 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 in sequence. After the addition, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete, and the mixture 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%).

[0615] Step 2

[0616] Dissolve the intermediate B-2-20b (5.00 g, 22.00 mmol) in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (40.00 mL, 40.00 mmol). After addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain two components.

[0617] The component 1 with a shorter retention time is intermediate B-2-20c (1.12 g, 4.12 mmol, yield 18.8%).

[0618] The component 2 with a longer retention time is intermediate B-2-21c (1.12 g, 4.12 mmol, yield 18.8%).

[0619] Step 3 - Component 1

[0620] Intermediate B-2-20c (1.12 g, 4.12 mmol) was dissolved in dichloromethane (10 mL), and 4M hydrogen chloride in dioxane solution (20 mL) was added under ice bath. After the reaction was continued under ice bath for 1 h, the mixture was concentrated to obtain the crude intermediate B-2-20d, which was directly used in the next reaction without purification.

[0621] Step 4 - Component 1

[0622] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3) in sequence, 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 of two-step reaction 38.1%). MS-ESI theoretical value [M-Boc+2H] + : 251.2; measured value: 251.2.

[0623] Step 5 - Component 1

[0624] The intermediate B-2-20e (0.55 g, 1.57 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-20f, which was directly used in the next reaction without purification.

[0625] Step 6 - Component 1

[0626] 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 h, water (5 mL) was added and 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 the product B-2-20 (76.7 mg, 0.26 mmol, total yield of 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).

[0627] Step 3 - Component 2

[0628] Dissolve intermediate B-2-21c (1.12 g, 4.19 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, concentrate to obtain crude intermediate B-2-21d, which is directly used in the next reaction without purification.

[0629] Step 4 - Component 2

[0630] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×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 of two steps 100%). MS-ESI theoretical value [M-Boc+2H] + : 251.1; measured value: 251.3.

[0631] Step 5 - Component 2

[0632] The intermediate B-2-21e (1.00 g, 2.85 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-2-21f, which was directly used in the next reaction without purification.

[0633] Step 6 - Component 2

[0634] 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 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 the product B-2-21 (0.49 g, 1.68 mmol, total yield of 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).

[0635] Preparation Example 55 Preparation of Compounds B-2-22 and B-2-23

[0636]

[0637] first step

[0638] 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 in sequence. After the addition was completed, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete, and the mixture 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%).

[0639] Step 2

[0640] The intermediate B-2-22b (5.00 g, 18.03 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, 1N isopropylmagnesium bromide in tetrahydrofuran solution (36.0 mL, 36.0 mmol) was slowly added dropwise. After addition, the reaction was continued at -78 ° C for 2 h, and 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.

[0641] The component 1 with a 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).

[0642] 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. 1H 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).

[0643] Step 3 - Component 1

[0644] Dissolve the intermediate B-2-22c (1.00 g, 3.11 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain the crude intermediate B-2-22d, which is directly used in the next reaction without purification.

[0645] Step 4 - Component 1

[0646] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 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 of two-step reaction 88.3%).

[0647] Step 5 - Component 1

[0648] The intermediate B-2-22e (1.10 g, 2.75 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-2-22f, which was used directly in the next reaction without purification.

[0649] Step 6 - Component 1

[0650] 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 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 the product B-2-22 (152.1 mg, 0.44 mmol, total yield of two steps 16.2%). MS-ESI theoretical value [M+H] + : 343.2; measured value: 343.2. 1 H 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).

[0651] Step 3 - Component 2

[0652] Dissolve intermediate B-2-23c (1.00 g, 3.11 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, concentrate to obtain crude intermediate B-2-23d, which is directly used in the next reaction without purification.

[0653] Step 4 - Component 2

[0654] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 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 of two steps 80.3%).

[0655] Step 5 - Component 2

[0656] The 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.

[0657] Step 6 - Component 2

[0658] Dissolve the crude intermediate B-2-23f in dichloromethane (10 mL), cool to -10 ° C, add acetyl chloride (0.20 g, 2.56 mmol) and ethyl diisopropylamine (0.90 g, 6.99 mmol). After reacting at -10 ° C for 1 h, add water (10 mL) and extract with dichloromethane (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain the product B-2-23 (284.6 mg, 0.83 mmol, two-step total yield 33.2%). MS-ESI theoretical value [M+H] + : 343.2; measured value: 343.2. 1H 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).

[0659] Preparation Example 56 Preparation of Compound B-2-24

[0660]

[0661] first step

[0662] Dissolve B-2-24a (4.00 g, 29.38 mmol) in dichloromethane (50 mL), and add (R)-tert-butylsulfenamide (4.57 g, 29.38 mmol) and anhydrous copper sulfate (4.69 g, 29.38 mmol) in sequence. After the addition, react overnight. TLC shows that the reaction is complete. Filter, wash the filtrate with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify 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.

[0663] Step 2

[0664] Dissolve the intermediate B-2-24b (2.00 g, 8.36 mmol) in tetrahydrofuran (20 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (16.72 mL, 16.72 mmol). After the addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated brine (20 mL × 2) in turn, dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain a mixture of two components, recorded 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.

[0665] Step 3

[0666] Dissolve intermediate B-2-24c component 1 (1.00 g, 3.53 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, concentrate to obtain crude intermediate B-2-24d, which is directly used in the next reaction without purification.

[0667] Step 4

[0668] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-24e (1.20 g, 3.31 mmol, total yield of two-step reaction 93.8%). MS-ESI theoretical value [M-Boc+2H] + : 263.2; measured value: 263.2.

[0669] Step 5

[0670] The intermediate B-2-24e (1.20 g, 3.31 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-2-24f, which was used directly in the next reaction without purification.

[0671] Step 6 - Component 1

[0672] 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 ethyl diisopropylamine (1.27 g, 9.84 mmol) were added. After reacting at -10 °C for 1 h, water (10 mL) was added and 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 the product B-2-24 (332.9 mg, 1.09 mmol, total yield of 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).

[0673] Preparation Example 57 Preparation of Compound B-2-25

[0674]

[0675] first step

[0676] Dissolve B-2-25a (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. After the addition, react overnight. TLC shows that the reaction is complete. Filter, wash the filtrate with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify 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.

[0677] Step 2

[0678] Dissolve the intermediate B-2-25b (5.00 g, 17.05 mmol) in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (41.78 mL, 41.78 mmol). After the addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain a mixture of two components, recorded 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.

[0679] Step 3

[0680] Dissolve intermediate B-2-25c component 1 (1.30 g, 4.59 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, concentrate to obtain crude intermediate B-2-25d, which is directly used in the next reaction without purification.

[0681] Step 4

[0682] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-25e (1.50 g, 4.14 mmol, total yield of two-step reaction 90.2%). MS-ESI theoretical value [M-Boc+2H] + : 263.2; measured value: 263.4.

[0683] Step 5

[0684] The intermediate B-2-25e (1.50 g, 4.14 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-2-25f, which was used directly in the next reaction without purification.

[0685] Step 6

[0686] Dissolve the crude intermediate B-2-25f in dichloromethane (10 mL), cool to -10 ° C, add acetyl chloride (0.33 g, 4.19 mmol) and ethyl diisopropylamine (1.48 g, 11.43 mmol). After reacting at -10 ° C for 1 h, add water (10 mL) and extract with dichloromethane (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain product B-2-25 (431.5 g, 1.44 mmol, total yield of two steps 34.9%). MS-ESI theoretical value [M+H] + : 305.2; measured value: 305.2. 1 H 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).

[0687] Preparation Example 58 Preparation of Compound B-2-26

[0688]

[0689] first step

[0690] 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. After addition, react overnight. TLC shows that the reaction is complete. Filter, wash the filtrate with saturated brine (100 mL × 2), dry with 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.

[0691] Step 2

[0692] Dissolve the intermediate B-2-26b (5.00 g, 20.89 mmol) in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (41.78 mL, 41.78 mmol). After the addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine (100 mL × 2) in turn, dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain a mixture of two components, recorded 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.

[0693] Step 3

[0694] Dissolve the intermediate B-2-26c (1.50 g, 5.29 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain the crude intermediate B-2-26d, which is directly used in the next reaction without purification.

[0695] Step 4

[0696] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and 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 intermediate B-2-26e (1.70 g, 4.69 mmol, total yield of two-step reaction 88.7%). MS-ESI theoretical value [M-Boc+2H] + : 263.2; measured value: 263.2.

[0697] Step 5

[0698] The intermediate B-2-26e (1.00 g, 2.76 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-2-26f, which was directly used in the next reaction without purification.

[0699] Step 6

[0700] 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 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 the product B-2-26 (199.8 mg, 0.66 mmol, total yield of two steps 23.8%). 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).

[0701] Preparation Example 59 Preparation of Compounds B-2-27 and B-2-28

[0702]

[0703] first step

[0704] 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, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete. The product was filtered and 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-2-27b (4.00 g, 16.04 mmol, yield 46.9%). MS-ESI theoretical value [M+H] + : 250.1; measured value: 250.1.

[0705] Step 2

[0706] The intermediate B-2-27b (4.00 g, 16.04 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, 1N isopropylmagnesium bromide in tetrahydrofuran solution (32.00 mL, 32.00 mmol) was slowly added dropwise. After addition, the reaction was continued at -78 ° C for 2 h, and 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.

[0707] The component 1 with a 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).

[0708] 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. 1HNMR(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).

[0709] Step 3 - Component 1

[0710] Dissolve intermediate B-2-27c (1.00 g, 3.41 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (10 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-27d, which is directly used in the next reaction without purification.

[0711] Step 4 - Component 1

[0712] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-27e (0.80 g, 2.15 mmol, total yield of two-step reaction 63.0%). MS-ESI theoretical value [M-Boc+2H] + : 273.2; measured value: 273.2.

[0713] Step 5 - Component 1

[0714] The intermediate B-2-27e (0.50 g, 1.34 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (5 mL) was added 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.

[0715] Step 6 - Component 1

[0716] 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 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 the product B-2-27 (75.0 mg, 0.24 mmol, total yield of two steps 17.8%). MS-ESI theoretical value [M+H] + : 315.2; measured value: 315.2. 1 H 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).

[0717] Step 3 - Component 2

[0718] Dissolve intermediate B-2-28c (1.00 g, 3.41 mmol) in dichloromethane (2 mL), add 4M hydrogen chloride in dioxane solution (4 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-28d, which is directly used in the next reaction without purification.

[0719] Step 4 - Component 2

[0720] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-28e (0.80 g, 2.15 mmol, total yield of two steps 63.0%).

[0721] Step 5 - Component 2

[0722] The intermediate B-2-28e (0.80 g, 2.15 mmol) was dissolved in dichloromethane (10 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added 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.

[0723] Step 6 - Component 2

[0724] 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 h, water (5 mL) was added and 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 the product B-2-28 (189.0 g, 0.60 mmol, total yield of 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).

[0725] Preparation Example 60 Preparation of Compounds B-2-29 and B-2-30

[0726]

[0727] first step

[0728] 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, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete. The product was filtered and 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-2-29b (7.00 g, 24.53 mmol, yield 89.4%). MS-ESI theoretical value [M+H] + : 286.1; measured value: 286.2.

[0729] Step 2

[0730] 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 addition, the reaction was continued at -78 °C for 2 h, and 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.

[0731] The component 1 with a 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.

[0732] 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.

[0733] Step 3 - Component 1

[0734] Dissolve intermediate B-2-29c (1.20 g, 3.64 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (10 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-29d, which is directly used in the next reaction without purification.

[0735] Step 4 - Component 1

[0736] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-29e (0.98 g, 2.40 mmol, total yield of two-step reaction 65.9%). MS-ESI theoretical value [M-Boc+2H] + : 309.2; measured value: 309.1.

[0737] Step 5 - Component 1

[0738] The intermediate B-2-29e (0.98 g, 2.40 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-29f, which was directly used in the next reaction without purification.

[0739] Step 6 - Component 1

[0740] 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 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 the product B-2-29 (0.45 g, 1.28 mmol, total yield of two steps 53.5%). MS-ESI theoretical value [M+H] + : 351.2; measured value: 351.3. 1H 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).

[0741] Step 3 - Component 2

[0742] Dissolve intermediate B-2-30c (1.40 g, 4.25 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (10 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain crude intermediate B-2-30d, which is directly used in the next reaction without purification.

[0743] Step 4 - Component 2

[0744] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-30e (0.80 g, 1.96 mmol, total yield of two steps 46.1%). MS-ESI theoretical value [M-Boc+2H] + : 309.2; measured value: 308.9.

[0745] Step 5 - Component 2

[0746] The intermediate B-2-30e (0.80 g, 1.96 mmol) was dissolved in dichloromethane (3 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (6 mL) was added and the reaction was continued for 2 h. The mixture was concentrated to obtain the crude intermediate B-2-30f, which was directly used in the next reaction without purification.

[0747] Step 6 - Component 2

[0748] 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 ethyl diisopropylamine (0.76 g, 5.85 mmol) were added. After reacting at -10 °C for 1 h, water (5 mL) was added and 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 the product B-2-30 (0.49 g, 1.40 mmol, total yield of two steps 71.3%). MS-ESI theoretical value [M+H] + : 351.2; measured value: 351.3. 1 H 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).

[0749] Preparation Example 61 Preparation of Compounds B-2-31 and B-2-32

[0750]

[0751] first step

[0752] 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, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete. The mixture was filtered and 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-2-31b (6.53 g, 24.5 mmol, yield 100%). MS-ESI theoretical value [M+H] + : 267.1; measured value: 267.2.

[0753] Step 2

[0754] Dissolve the intermediate B-2-31b (5.00 g, 18.77 mmol) in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, slowly add 1N isopropylmagnesium bromide in tetrahydrofuran solution (37.5 mL, 37.5 mmol). After addition, continue to react at -78 ° C for 2 hours, and TLC shows that the reaction is complete. Adjust the pH to 6 with saturated ammonium chloride solution and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain two components.

[0755] The component 1 with a 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.

[0756] 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.

[0757] Step 3 - Component 1

[0758] Dissolve the intermediate B-2-31c (1.12 g, 3.62 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (10 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain the crude intermediate B-2-31d, which is directly used in the next reaction without purification.

[0759] Step 4 - Component 1

[0760] The crude product of 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 in sequence at -10 °C. After the addition was completed, the reaction was continued at -10 °C for 2 h, and 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 intermediate B-2-31e (0.90 g, 2.31 mmol, total yield of two-step reaction 63.8%).

[0761] Step 5 - Component 1

[0762] The intermediate B-2-31e (0.90 g, 2.31 mmol) was dissolved in dichloromethane (10 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (10 mL) was added 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.

[0763] Step 6 - Component 1

[0764] 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 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 the product B-2-31 (0.40 g, 1.21 mmol, total yield of 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).

[0765] Step 3 - Component 2

[0766] Dissolve the intermediate B-2-32c (0.45 g, 1.45 mmol) in dichloromethane (5 mL), add 4M hydrogen chloride in dioxane solution (5 mL) under ice bath, continue to react under ice bath for 1 h, and concentrate to obtain the crude intermediate B-2-32d, which is directly used in the next reaction without purification.

[0767] Step 4 - Component 2

[0768] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and water (5 mL) was added, and the mixture was extracted with dichloromethane (10 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 intermediate B-2-32e (0.38 g, 0.98 mmol, total yield of two steps 67.6%).

[0769] Step 5 - Component 2

[0770] The intermediate B-2-32e (0.38 g, 0.98 mmol) was dissolved in dichloromethane (5 mL). Under an ice bath, 4 M hydrogen chloride solution in dioxane (5 mL) was added 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.

[0771] Step 6 - Component 2

[0772] 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 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 the product B-2-32 (71.4 mg, 0.22 mmol, total yield of two steps 22.0%). MS-ESI theoretical value [M+H] + : 332.1; measured value: 332.2. 1HNMR(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).

[0773] Preparation Example 62 Preparation of Compound B-2-33

[0774]

[0775] first step

[0776] 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. After the addition, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete. The product was filtered and 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-2-33b (7.50 g, 30.2 mmol, yield 97.4%). MS-ESI theoretical value [M+H] + : 249.1; measured value: 249.1.

[0777] Step 2

[0778] Intermediate B-2-33b (5.00 g, 20.13 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen protection and cooling to -78 ° C, 1N isopropylmagnesium bromide in tetrahydrofuran solution (40.26 mL, 40.26 mmol) was slowly added dropwise. After addition, the reaction was continued at -78 ° C for 2 h, and 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 turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a mixture of two components, recorded as intermediate B-2-33c (3.70 g, 12.7 mmol, yield 62.8%).

[0779] Step 3

[0780] Dissolve the intermediate B-2-33c (1.40 g, 4.79 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (10 mL) under ice bath, continue to react for 1 h under ice bath, and concentrate to obtain the crude intermediate B-2-33d, which is directly used in the next reaction without purification.

[0781] Step 4

[0782] The crude product of 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 in sequence at -10°C. After the addition was completed, the reaction was continued at -10°C for 2 h, and 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 intermediate B-2-33e (0.93 g, 2.50 mmol, total yield of two-step reaction 52.3%). MS-ESI theoretical value [M+H] + : 372.2; measured value: 372.3.

[0783] Step 5

[0784] The intermediate B-2-33e (0.93 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-2-33f, which was used directly in the next reaction without purification.

[0785] Step 6

[0786] 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 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 the product B-2-33 (272.5 mg, 0.87 mmol, total yield of 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).

[0787] Preparation Example 63 Preparation of Compounds B-2-34 and B-2-35

[0788]

[0789] first step

[0790] 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 in sequence. After the addition, the reaction was allowed to proceed overnight. TLC showed that the reaction was complete. Water (100 mL) was added and extracted with dichloromethane (100 mL×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, yield 81.3%). 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).

[0791] Step 2

[0792] 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 addition, the reaction was continued at -78 ° C for 2 h, and 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 turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0793] The component 1 with a 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).

[0794] 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).

[0795] Step 3 - Component 1

[0796] Intermediate B-2-34c (1.40 g, 4.21 mmol) was dissolved in methanol (10 mL), and 4 M hydrogen chloride ethyl acetate solution (5 mL) was added under ice bath. The mixture was transferred to room temperature and continued to react for 3 h, then concentrated to obtain the crude intermediate B-2-34d, which was directly used in the next reaction without purification.

[0797] Step 4 - Component 1

[0798] Intermediate A-2-7b (1.09 g, 5.41 mmol) was dissolved in dichloromethane (20 mL), and 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 in sequence 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 showed that the reaction was complete. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL×3). The organic phases were combined and washed 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, total yield of two-step reaction 44.4%). MS-ESI theoretical value [M-Boc+2H] + : 311.1; measured value: 311.2.

[0799] Step 5 - Component 1

[0800] Dissolve the intermediate B-2-34e (0.77 g, 1.87 mmol) in methanol (10 mL), cool to -5 °C, and add 4M hydrogen chloride ethyl acetate solution (10 mL). Transfer to room temperature and continue to react for 2 h, then concentrate to obtain the crude intermediate B-2-34f, which is used directly in the next step without purification. Free ammonia MS-ESI theoretical value [M+H] + : 311.1, measured value: 311.2.

[0801] Step 6 - Component 1

[0802] 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 × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product B-2-34 (496 mg, 1.40 mmol, total yield of 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).

[0803] Step 3 - Component 2

[0804] Dissolve intermediate B-2-35c (1.44 g, 4.33 mmol) in methanol (10 mL), add 4M hydrogen chloride ethyl acetate solution (5 mL) under ice bath. Move to room temperature and continue to react for 3 h. TLC shows that the reaction is complete. Concentrate to obtain the crude intermediate B-2-35d, which is directly used in the next step without purification.

[0805] Step 4 - Component 2

[0806] Intermediate A-2-7b (1.09 g, 5.41 mmol) was dissolved in dichloromethane (20 mL), and 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 in sequence 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 showed that the reaction was complete. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL×3). The organic phases were combined and washed 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-step reaction 56.4%). MS-ESI theoretical value [M-Boc+2H] + : 311.1; measured value: 311.2.

[0807] Step 5 - Component 2

[0808] The intermediate B-2-35e (1.00, 2.43 mmol) was dissolved in methanol (10 mL), and a 4 M hydrogen chloride ethyl acetate solution (10 mL) was added under an ice bath and the reaction was continued for 2 h, and concentrated to obtain a crude intermediate B-2-35f, which was directly used in the next reaction without purification. MS-ESI theoretical value [M+H]+: 311.1, found value: 311.2.

[0809] Step 6 - Component 2

[0810] 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 and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product B-2-35 (0.74 g, 2.10 mmol, total yield of 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).

[0811] Preparation Example 64 Preparation of Compound B-2-36

[0812]

[0813] first step

[0814] 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 in sequence. After the addition was completed, the reaction was allowed to proceed for 2 h. TLC showed that the reaction was complete. Water (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×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, yield 94.6%). 1 H NMR (400MHz, Chloroform-d) δ8.47 (s, 1H), 7.70–7.63 (m, 2H), 7.19 (d, J = 7.9Hz, 2H), 2.33 (s, 3H), 1.18 (s, 9H).

[0815] Step 2

[0816] 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 addition, the reaction was continued at -78 °C for 2 h, and 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.

[0817] The one with shorter retention time is intermediate B-2-36c (2.01 g, 7.52 mmol, yield 21.0%). The other component is discarded.

[0818] Step 3

[0819] Dissolve intermediate B-2-36c (2.00 g, 7.48 mmol) in methanol (10 mL), add 4M hydrogen chloride ethyl acetate solution (10 mL) under ice bath, transfer to room temperature, continue to react for 3 h, and then concentrate to obtain crude intermediate B-2-36d, which is directly used in the next step without purification.

[0820] Step 4

[0821] 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 in sequence 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 showed that the reaction was complete. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL×3). The organic phases were combined and washed 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-step reaction 81.6%). MS-ESI theoretical value [M-Boc+2H] + : 247.2; measured value: 247.3.

[0822] Step 5

[0823] Dissolve the intermediate B-2-36e (2.11 g, 6.09 mmol) in methanol (10 mL), cool to -5 °C, and add 4M hydrogen chloride ethyl acetate solution (10 mL). Transfer to room temperature and continue to react for 2 h, then concentrate to obtain the crude intermediate B-2-36f, which is used directly in the next step without purification. Free ammonia MS-ESI theoretical value [M+H] + : 247.2, measured value: 247.3.

[0824] Step 6

[0825] 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 and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product B-2-36 (1.43 g, 4.96 mmol, total yield of 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).

[0826] Preparation Example 65 Preparation of Compound B-2-37

[0827]

[0828] first step

[0829] Dissolve B-2-37a (5.00 g, 52.04 mmol) in dichloromethane (100 mL), and add (R)-tert-butylsulfenamide (6.31 g, 52.04 mmol) and cesium carbonate (33.91 g, 104.08 mmol) in sequence. After addition, react for 2 h. TLC shows that the reaction is complete. Add water (100 mL) and extract with dichloromethane (100 mL×2). Combine the organic phases, wash with saturated brine (200 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify 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.

[0830] Step 2

[0831] 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 isopropylmagnesium bromide in tetrahydrofuran solution (50.0 mL, 50.0 mmol) was slowly added dropwise. After addition, the reaction was continued at -78 ° C for 2 h, and 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.

[0832] The intermediate B-2-37c (1.37 g, 7.68 mmol, yield 15.3%) has a shorter retention time. MS-ESI theoretical value [M+H] + : 244.1; Measured value: 244.3. The other component was discarded.

[0833] Step 3

[0834] Intermediate B-2-37c (1.87 g, 7.68 mmol) was dissolved in methanol (10 mL), and 4 M hydrogen chloride ethyl acetate solution (5 mL) was added under ice bath. The mixture was transferred to room temperature and continued to react for 3 h, then concentrated to obtain the crude intermediate B-2-37d, which was directly used in the next step without purification.

[0835] Step 4

[0836] 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 in sequence 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 showed that the reaction was complete. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL×3). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain intermediate B-2-37e (0.91 g, 2.82 mmol, total yield of two-step reaction 36.7%). MS-ESI theoretical value [M-Boc+2H] + : 223.1; measured value: 223.3.

[0837] Step 5

[0838] Dissolve intermediate B-2-37e (0.91 g, 2.82 mmol) in methanol (10 mL), cool to -5 °C, add 4M hydrogen chloride ethyl acetate solution (10 mL), transfer to room temperature, and continue to react for 2 h, then concentrate to obtain the crude intermediate B-2-37f, which is directly used in the next step without purification.

[0839] Step 6

[0840] 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 showed that the reaction was complete. Water (30 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product B-2-37 (0.57 g, 2.16 mmol, total yield of 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).

[0841] Preparation Example 66 Preparation of Compound B-2-38

[0842]

[0843] first step

[0844] 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 in sequence. After the addition was completed, the reaction was allowed to proceed for 2 h. TLC showed that the reaction was complete. Water (100 mL) was added and extracted with dichloromethane (100 mL×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, yield 86.5%).

[0845] Step 2

[0846] 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 addition, the reaction was continued at -78 °C for 2 h, and 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.

[0847] The component 1 with a 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 = 3.3 Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 4.45–4.38 (m, 2H), 2.21–2.12 (m, 1H), 1.21 (s, 9H), 0.87 (dd, J = 6.8, 3.8 Hz, 6H).

[0848] The other component is discarded.

[0849] Step 3

[0850] Dissolve intermediate B-2-38c (2.51 g, 9.63 mmol) in methanol (10 mL), add 4M hydrogen chloride ethyl acetate solution (5 mL) under ice bath, transfer to room temperature, continue to react for 3 h, and then concentrate to obtain crude intermediate B-2-38d, which is directly used in the next step without purification.

[0851] Step 4

[0852] 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 in sequence 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 showed that the reaction was complete. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL×3). The organic phases were combined and 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%).

[0853] Step 5

[0854] Dissolve intermediate B-2-38e (1.38 g, 4.07 mmol) in methanol (10 mL), cool to -5 °C, add 4M hydrogen chloride ethyl acetate solution (10 mL), transfer to room temperature, and continue to react for 2 h, concentrate to obtain the crude intermediate B-2-38f, which is directly used in the next step without purification.

[0855] Step 6

[0856] 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 and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product B-2-38 (496.0 mg, 1.40 mmol, total yield of 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).

[0857] Preparation Example 67 Preparation of Compounds B-2-39 and B-2-40

[0858]

[0859] first step

[0860] Dissolve B-2-40a (5.00 g, 44.58 mmol) in dichloromethane (100 mL), and add (R)-tert-butylsulfenamide (5.40 g, 44.58 mmol) and cesium carbonate (29.05 g, 89.16 mmol) in sequence. After addition, react for 2 h. TLC shows that the reaction is complete. Add water (100 mL) and extract with dichloromethane (100 mL×2). Combine the organic phases, wash with saturated brine (200 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain intermediate B-2-40b (7.87 g, 36.55 mmol, yield 92.0%). [M+H] + : 216.0, measured value: 216.2.

[0861] Step 2

[0862] The 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 addition, the reaction was continued at -78 ° C for 2 h, and 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 turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain two components.

[0863] The component 1 with a shorter retention time is intermediate B-2-40c (2.51 g, 9.68 mmol, yield 41.7%).

[0864] The component 2 with a longer retention time is intermediate B-2-39c (0.76 g, 2.90 mmol, yield 12.6%).

[0865] Step 3 - Component 1

[0866] Dissolve intermediate B-2-40c (1.12 g, 4.30 mmol) in methanol (10 mL), add 4M hydrogen chloride ethyl acetate solution (10 mL) under ice bath, transfer to room temperature, continue to react for 3 h, and then concentrate to obtain crude intermediate B-2-40d, which is directly used in the next reaction without purification.

[0867] Step 4 - Component 1

[0868] 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 in sequence 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 showed that the reaction was complete. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL×3). The organic phases were combined and washed 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.

[0869] Step 5 - Component 1

[0870] Dissolve intermediate B-2-40e (742.0 mg, 2.19 mmol) in methanol (10 mL), cool to -5 °C, add 4M hydrogen chloride ethyl acetate solution (10 mL), transfer to room temperature, and continue to react for 2 h, concentrate to obtain the crude intermediate B-2-40f, which is directly used in the next step without purification.

[0871] Step 6 - Component 1

[0872] 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 the product B-2-40 (468.0 mg, 1.67 mmol, total yield of 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).

[0873] Step 3 - Component 2

[0874] Intermediate B-2-39c (0.76 g, 2.90 mmol) was dissolved in methanol (5 mL), and 4 M hydrogen chloride ethyl acetate solution (5 mL) was added under ice bath. The mixture was transferred to room temperature and continued to react for 3 h, then concentrated to obtain the crude intermediate B-2-39d, which was directly used in the next reaction without purification.

[0875] Step 4 - Component 2

[0876] 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 in sequence 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 showed that the reaction was complete. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL×3). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain intermediate B-2-39e (0.74 g, 2.19 mmol, total yield of two-step reaction 75.5%).

[0877] Step 5 - Component 2

[0878] Dissolve intermediate B-2-39e (0.74 g, 2.19 mmol) in methanol (10 mL), cool to -5 °C, add 4M hydrogen chloride ethyl acetate solution (10 mL), transfer to room temperature, and continue to react for 2 h, concentrate to obtain the crude intermediate B-2-39f, which is directly used in the next step without purification.

[0879] Step 6 - Component 2

[0880] 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 × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product B-2-39 (0.37 g, 1.32 mmol, total yield of two steps 60.3%). MS-ESI theoretical value [M+H] + : 281.1; measured value: 282.4. 1H NMR(400MHz,Chloroform-d)δ8.40(d,J=9.2Hz,1H),7.09(dd,J=5.1,1.2Hz,1H ),6.86(dd,J=5.1,3.5Hz,1H),6.80(dt,J=3.5,1.1Hz,1H),5.05(dd,J=8.9,6.2 Hz,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).

[0881] Preparation Example 68 Preparation of Compound B-2-41

[0882]

[0883] Dissolve intermediate B-2-3b (1.10 g, 4.93 mmol) and N,N-diisopropylethylamine (2.55 g, 19.73 mmol) in anhydrous dichloromethane (20 mL) and cool to -10 ° C. Slowly add acetyl chloride (0.77 g, 9.86 mmol). The reaction solution was stirred at 0 ° C for 2 hours, and TLC showed that the reaction was complete. Add water (50 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify 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).

[0884] Preparation Example 69 Preparation of Compound B-2-42

[0885]

[0886] first step

[0887] Dissolve B-2-2a (10.00 g, 138.68 mmol) in dichloromethane (300 mL), add (S)-tert-butyl sulfonamide (16.81 g, 138.68 mmol) and copper sulfate (5.53 g, 34.67 mmol). React for 16 h, TLC shows that the reaction is complete. Filter, concentrate, add ethyl acetate (150 mL) to dissolve, slowly add petroleum ether (450 mL), stir for 12 h, filter, and concentrate the filtrate to obtain the crude intermediate B-2-42a (15.00 g, 85.6 mmol, yield 61.7%).

[0888] Step 2

[0889] Under nitrogen protection, oxazole (17.73 g, 256.71 mmol) was added to 1M borane tetrahydrofuran solution (171.14 mL, 171.14 mmol), and the temperature was lowered to -78 ° C. 2.5M n-butyl lithium was slowly added to obtain tetrahydrofuran solution (171.14 mmol, 68.46 mmol), and the reaction was continued for 30 min, and the crude intermediate B-2-42a (15.00 g, 85.6 mmol) was slowly added. After continuing the reaction for 4 h, TLC showed that the reaction was complete, and the reaction was also poured into a saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (100 mL×3). 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-2-42b (10.0 g, 40.9 mmol, yield 47.8%).

[0890] Step 3

[0891] Dissolve the intermediate B-2-42b (10.0 g, 40.9 mmol) in methanol (200 mL), and add a 4 M solution of hydrogen chloride in dioxane (200 mL) at 0°C. Continue the reaction for 2 h, and TLC shows that the reaction is complete. Adjust the pH to 7 with ammonia water and concentrate. Dissolve the resulting residue in methanol (50 mL), add to 60°C and stir for 1 h, add acetonitrile (500 mL) and continue stirring for 1 h, slowly cool to room temperature and precipitate solids. Filter and dry to obtain the 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).

[0892] Step 4

[0893] 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 min, intermediate B-2-42c (1.00 g, 7.14 mmol) and N,N-diisopropylethylamine (2.76 g, 21.39 mmol) were added, and the reaction was continued for 3 h. TLC showed that the reaction was complete. Dichloromethane (50 mL) was added and 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, yield 26.1%).

[0894] Step 5

[0895] Intermediate B-2-42d (0.60 g, 1.86 mmol) was dissolved in dichloromethane (25 mL), and 4M hydrogen chloride in dioxane solution (5 mL) was added. After 1 h of reaction, TLC showed that the reaction was complete, and the mixture was concentrated to obtain a crude intermediate B-2-42e, which was directly used in the next step without purification.

[0896] Step 6

[0897] 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 min of reaction, the crude intermediate B-2-42e and N, N-diisopropylethylamine (1.29 g, 10 mmol) were added in sequence. The reaction was continued for 16 h, and TLC showed that the reaction was complete. Water (80 mL) was added and extracted with ethyl acetate (60 mL×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 the product B-2-42 (45.1 mg, 0.17 mmol, total yield of two-step reaction 9.0%). 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).

[0898] Preparation Example 70 Preparation of Compound B-2-43

[0899]

[0900] first step

[0901] The 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 min, the intermediate B-2-42c (1.00 g, 7.14 mmol) and N, N-diisopropylethylamine (2.76 g, 21.39 mmol) were added, and the reaction was continued for 3 h. TLC showed that the reaction was complete. Dichloromethane (50 mL) was added and 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 the intermediate B-2-43a (0.40 g, 1.24 mmol, yield 17.3%).

[0902] Step 2

[0903] Intermediate B-2-43a (0.40 g, 1.24 mmol) was dissolved in dichloromethane (25 mL), and 4M hydrogen chloride in dioxane solution (5 mL) was added. After 1 h of reaction, TLC showed that the reaction was complete, and the mixture was concentrated to obtain a crude intermediate B-2-43b, which was directly used in the next step without purification.

[0904] Step 3

[0905] 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 min of reaction, the crude intermediate B-2-43b and N, N-diisopropylethylamine (0.61 g, 4.71 mmol) were added in sequence. The reaction was continued for 16 h, and TLC showed that the reaction was complete. Water (80 mL) was added and extracted with ethyl acetate (60 mL×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 the product B-2-43 (78.2 mg, 0.29 mmol, total yield of two-step reaction 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).

[0906] Preparation Example 71 Preparation of Compound B-2-44

[0907]

[0908] first step

[0909] A-2-38a (3.00 g, 13.81 mmol) was dissolved in methanol, and 2-bromoethylamine hydrobromide (2.83 g, 13.81 mmol), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine chloride (3.82 g, 13.81 mmol) and 4-methylmorpholine (1.40 g, 13.81 mmol) were added in sequence. After the addition was completed, the mixture was reacted at room temperature for 1 h, and a methanol solution of sodium hydroxide (2.71 g, 48.24 mmol, dissolved in 125 mL of methanol) was added. After reflux reaction for 2.5 h, the mixture was concentrated. Water (100 mL) was added to the residue, and the mixture was extracted with dichloromethane (100 mL×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.

[0910] Step 2

[0911] Dissolve intermediate B-2-44a (1.80 g, 7.43 mmol) in dichloromethane (10 mL), add 4M hydrogen chloride in dioxane solution (20 mL) under ice bath. After addition, react for 2 h, concentrate to obtain crude intermediate B-2-44b, which is used directly in the next step without purification. MS-ESI theoretical value [M+H] + : 179.1; measured value: 179.1.

[0912] Step 3

[0913] Dissolve the intermediate B-2-44b in dichloromethane (10 mL) and add the intermediate A-2-7b (1.13 g, 5.60 mmol). After cooling to -10 °C, add 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), and continue the reaction for 3 h. Concentrate, add water (20 mL), and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated brine (20 × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain the intermediate B-2-44c (1.80 g, 5.24 mmol, total yield of two-step reaction 70.5%). MS-ESI theoretical value [M+H] + : 362.2; measured value: 362.4.

[0914] Step 4

[0915] Under ice bath, intermediate B-2-44c (1.20 g, 3.32 mmol) was dissolved in dichloromethane (10 mL), 4M hydrogen chloride solution in dioxane (20 mL) was added, and after reacting for 2 h, the mixture was concentrated to obtain the crude intermediate B-2-44d, which was directly used in the next step without purification. MS-ESI theoretical value [M+H] + : 262.1; measured value: 262.1.

[0916] Step 5

[0917] 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 × 3). Combine the organic phases, wash with saturated brine (20 mL × 2), dry with 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 two-step reaction 79.3%). MS-ESI theoretical value [M+H] + : 304.1; measured value: 304.1.

[0918] Step 6

[0919] Dissolve the intermediate B-2-44e (0.46 g, 1.5 mmol) in methanol (10 mL), add potassium hydroxide (0.35 g, 6.30 mmol) and heat under reflux for 2.5 h. After the reaction is completed, spin dry the solvent, add water (10 mL), and extract with ethyl acetate (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify 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. 1H 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).

[0920] Comparative Example 1: Compound D4-pEL

[0921]

[0922] first step

[0923] In a 100mL three-necked flask, D4-pEL-1 (1.00g, 4.36mmol), L-leucine tert-butyl ester hydrochloride (0.98g, 5.23mmol), triethylamine (1.32g, 13.08mmol), N,N-dimethylformamide (20mL), 1-hydroxybenzotriazole (1.18g, 8.72mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.25g, 6.54mmol) were added in sequence. After the addition was completed, the reaction was allowed to react at room temperature for 5 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was diluted with saturated brine (100mL), extracted with ethyl acetate (100mL×3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by normal phase chromatography. D4-pEL-3 (1.3g, 3.26mmol, yield 74.8%) was obtained. ESI-LCMS: m / z 243.2 [M- t Bu-Boc+H] + .

[0924] Step 2

[0925] In a 100mL three-necked flask, add D4-pEL-3 (1.3g, 3.26mmol) and a 1,4-dioxane solution of hydrochloric acid (4.0M, 20mL). The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was concentrated and diluted with dichloromethane (50mL). Subsequently, the solution was concentrated under reduced pressure to remove the residual 1,4-dioxane solution of hydrochloric acid. The residue was purified by multiple reverse phase chromatography columns and freeze-dried to obtain D4-pEL (200mg, 0.83mmol, yield 25.5%). ESI-LCMS: m / z243.3[M+H]+ .

[0926] 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).

[0927] Comparative Example 2: Compound D5-PA

[0928]

[0929] D5-PA was purchased from Shanghai BiDe Pharmaceutical Technology Co., Ltd., product number BD133842, batch DSY151, with a purity of 97%.

[0930] Experimental Example 1 Plasma Stability Determination

[0931] Mouse plasma (purchased from IPHASE, batch number 23B007) was thawed in a 37°C water bath, centrifuged to remove the upper clot, and the pH was recorded as 7-8. Take a certain volume of acetonitrile stock solution (concentration of 10mM) of the test compound and dilute it to 1mM with acetonitrile as the test solution. Take a certain volume of the test solution, add the corresponding volume of plasma and mix evenly, so that the concentration of the test compound in the incubation system is 5μM, and the content of organic solvent acetonitrile is 0.5%. Take 50μL of mixed plasma in a 96-well plate (N=2), incubate in a 37°C water bath for a certain period of time, add 300μL of methanol solution containing the internal standard to terminate the reaction, vortex centrifuge and take the supernatant for LC-MS / MS analysis. Propantheline and ZZL-7 were used as positive controls and were treated and tested under the same conditions as the test compounds. The k value was obtained by making a curve based on the remaining percentage of the compound and the incubation time, and the half-life of each compound was calculated. The formula is as follows:

[0932]

[0933] Table 1 Plasma stability data of some compounds

[0934]

[0935]

[0936]

[0937] Note: If after 120 minutes, the remaining percentage of the compound is still greater than 75%, then T1 / 2 Recorded as >289.1min.

[0938] 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.

[0939] Experimental Example 2 Compound Permeability Detection

[0940] MDR1-MDCKⅡ cells (from the Netherlands Cancer Institute) were seeded in a 96-well cell plate at a density of 3.33×10 per ml. 5 cells, cultured in a carbon dioxide incubator for 4-7 days to form a monolayer of cells. Hank's balanced salt buffer (HBSS, pH 7.40±0.05) containing 10.0mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) was used as the transport buffer. The compound DMSO stock solution was diluted to 2μM (DMSO<1.0%) with transport buffer and added to the basal end (B) and apical end (A) (N=2). The P-gp substrate digoxin was incubated at a concentration of 10μM in both directions (AB and BA), and the hypotonic control nadolol and the hypertonic control metoprolol were incubated at a concentration of 2μM in one direction (AB). After the cell plate was incubated in a cell culture incubator at 37°C, 5% CO2 and saturated humidity for 2.5 hours, the final samples at the receiving end and the dosing end were collected, and appropriate proportions of transport buffer and precipitant were added for LC-MS / MS analysis to calculate the apparent permeability coefficient, efflux rate and solution recovery rate.

[0941] After the transport experiment, the integrity of the MDR1-MDCKⅡ cell layer was tested by the fluorescent yellow detection experiment. The remaining solution in the apical and basal end holes was removed, and 75 μL of transport buffer containing 100 μM fluorescent yellow was added to the apical hole, and 250 μL of transport buffer was added to the basal end hole. The cell plate was incubated in a cell culture incubator at 37°C, 5% CO2 and saturated humidity for 30 minutes, and then 20 μL of sample was taken from the apex and mixed with 60 μL of transport buffer, and 80 μL of sample was taken from the basal end. The relative fluorescence intensity was detected at 425 / 528 nm (excitation / emission) spectrum using an ELISA reader, and the fluorescent yellow transmittance was calculated.

[0942] The apparent permeability coefficient (P app ), efflux ratio (ER), and solution recovery (% Solution Recovery) were calculated using the following formulas:

[0943]

[0944] VR 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 on the top and base sides 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 drug delivery end, C0 is the initial peak area ratio of the compound at the drug delivery 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 P app (AB) are the apparent permeability coefficients from the base end to the apex end and from the apex end to the base end, respectively.

[0945] The transmittance of fluorescent yellow (%Lucifer Yellow) is calculated using the following formula:

[0946]

[0947] RFU Apical and RFU Basolateral are the relative fluorescence intensities of fluorescent yellow at the top and bottom, respectively. Apical With V Basolateral The loading volumes are apical and basolateral (0.075 and 0.25 mL, respectively).

[0948] Table 2 Permeability data of some compounds

[0949]

[0950] The compound of this patent has moderate permeability and is superior to the control substances D4-pEL and D5-PA.

[0951] Experimental Example 3: Pharmacokinetics in mice

[0952] 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.

[0953] Table 3 Oral pharmacokinetic data of some compounds in mice

[0954]

[0955]

[0956] Note: The dosage of ZZL-7 is 100 mg / kg, PO.

[0957] Experimental Example 4 Pharmacokinetics in rats

[0958] The test was conducted 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.

[0959] Table 4 Oral pharmacokinetic data of some compounds in rats

[0960] Compound <![CDATA[AUC last (mg / mL)]]> F(％) B-2-3 24315 65.97 D4-pEL 98.6 1.04 D5-PA 11.5 0.71

[0961] Tables 3 and 4 show the area under the concentration-time curve (AUC) and bioavailability (F) data of some compounds for oral administration. The results show that the example compounds of the present invention have good pharmacokinetic properties and are significantly better than ZZL-7, D4-pEL, and D5-PA.

[0962] Experimental Example 5 In vivo drug efficacy detection (1)

[0963] 6-8 week old C57 / B6 mice (purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd.) were used to establish the 28-day chronic unpredictable mild stress (CUMS) model. The experimental procedure was described in the literature. [1,2] The animals were adapted for one week, and seven experiments were randomly performed within one week, including fasting and water deprivation, electrical stimulation of the soles of the feet, moist bedding, cage tilt, behavioral restraint, shaking basket, and olfactory stimulation, to achieve unpredictability. The stimulation lasted for 4 weeks. Open Field Test (OFT) [3]After the evaluation model is successful, the efficacy evaluation is carried out. The experiment is divided into a blank control group (Control), a model group (Model), a solvent control group (Vehicle), a fluoxetine control group, a ZZL-7 experimental group and a compound group. The test compound is orally administered at a dose of 25 mg / kg, and a tail suspension test (TST) is performed 2 hours later. [4,5] The depression of mice was evaluated. The prolonged immobility time of mice in TST indicated that the mice were in despair. After the data were summarized and analyzed, SPSS statistical software was used for analysis. Graph Pad software was used to draw images based on the SPSS analysis results.

[0964] The results of the tail suspension test are as follows Figure 1 and 2 As shown, the test results show that compounds B-2-3 and B-2-41 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in the tail suspension test, proving that the example compounds of the present invention have a rapid antidepressant effect.

[0965] Experimental Example 6 In vivo drug efficacy detection (2)

[0966] 6-8 week old C57 / B6 mice (purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd.) were used to establish the 28-day chronic unpredictable mild stress (CUMS) model. The experimental procedure was described in the literature. [1,2] The animals were adapted for one week, and seven experiments were randomly performed within one week, including fasting and water deprivation, electrical stimulation of the soles of the feet, moist bedding, cage tilt, behavioral restraint, shaking basket, and olfactory stimulation, to achieve unpredictability. The stimulation lasted for 4 weeks. Open Field Test (OFT) [3] After the evaluation model is successful, the efficacy evaluation is carried out. The experiment is divided into a blank control group (Control), a model group (Model), a solvent control group (Vehicle), a fluoxetine control group and a compound group. The test compound is administered by a single intravenous injection (iv) at a dose of 100 mg / kg, and a tail suspension test (TST) and a forced swimming test (FST) are performed 2 hours later. [4,5] The depression of mice was evaluated. The prolonged immobility time of mice in TST and FST indicated that the mice were in despair. After the data were summarized and analyzed, SPSS statistical software was used for analysis, and Graph Pad software was used to draw images based on the SPSS analysis results.

[0967] The results of the forced swim test are shown in Figure 3 , the tail suspension test results are shown in Figure 4 The test results showed that compounds A-1-7, A-1-1 and A-2-1 could quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in forced swimming and tail suspension tests, proving that the embodiments of the present invention have a rapid antidepressant effect.

[0968] References:

[0969] [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.

[0970] [2]Chen Z, Gu J, Lin S, et al. Saffron essential oil ameliorates CUMS-induced depression-like behavior in mice via the MAPK-CREB1-BDNF signaling pathway[J]. Journal of Ethnopharmacology, 2023, 300:115719.

[0971] [3] Pentkowski, Nathan S., et al. "Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology." Neuroscience&BiobehavioralReviews 127(2021):647-658.

[0972] [4] Can, Adem, et al. "The mouse forced swim test." JoVE (Journal of Visualized Experiments) 59 (2012): e3638.

[0973] [5]Can,Adem,et al."The tail suspension test."JoVE(Journal ofVisualized 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 to 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 contain 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 by 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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