Amide compound and use thereof

Abstract

Disclosed in the present application are a lactam ring compound and the use thereof, said compound having a rapid antidepressant effect.

Description

Amide compounds and uses thereof Technical Field

[0001] The present application generally belongs to the field of medicine. Specifically, the present application relates to compounds with rapid antidepressant effects and their uses. Background Art

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

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

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

[0005] However, currently, the commonly used antidepressants in clinical practice still have serious limitations, mainly slow and delayed onset of action, requiring 3 to 4 weeks of continuous medication to take effect. Many patients give up treatment before they can achieve the desired 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 can quickly (in a few hours) relieve 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. Esketamine must be used simultaneously with other oral antidepressants for refractory depression in adults. These shortcomings limit the clinical application of such drugs. Therefore, there is an urgent need for new antidepressants with rapid onset, good efficacy, and oral administration. Summary of the Invention

[0006] One or more embodiments of the present application provide a compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof:

[0007] in,

[0008] R1 and R2 are independently selected from hydrogen, R8-(CO)-, R8-(SO)-, R8-(SO2)-, R8-O(CO)-, R8R9-N(CO)-, or C1-C2-substituted by n R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0009] Or R1, R2 and the nitrogen atoms adjacent to them together form a C3-C substituted by n R8 15 Heterocycloalkyl or C5-C 15 heteroaryl;

[0010] R3 and R4 are independently selected from hydrogen, deuterium, tritium, or C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0011] Or R3, R4 and their adjacent carbon atoms together form a C3-C substituted by n R8 10 Cycloalkyl or C3-C 10 heterocycloalkyl;

[0012] X is optionally selected from -CO-, -SO-, -SO2-, -CHR8-, or

[0013] R5 and R6 are independently selected from hydrogen or C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0014] R7 is optionally selected from C3-C substituted by n R8 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl;

[0015] R8 is optionally selected from hydrogen, deuterium, tritium, halogen, oxydim, -CN, -NO2, -OR9, -NR9R 10 , -SR9, -COR9, -SOR9, -SO2R9, -NR9COR 10 、-CONR9R 10 , -OCOR9, -COOR9, -OCOOR9, -OCONR9R 10 、-NR9CONR 10 R 11 、-NR9COOR 10 、-NR9SO2R 10 、-SO2NR9R 10 , -OSO2R9, -SO3R9, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of n R 12 replace;

[0016] R9, R 10 、R 11are independently selected from hydrogen, deuterium, tritium, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by n halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0017] R 12 is selected from hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently substituted with n halogen, cyano, hydroxyl, sulfhydryl, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl, or haloalkyl;

[0018] n is an integer from 0 to 8 (eg, 0, 1, 2, 3, 4, 5, 6, 7, or 8).

[0019] One or more embodiments of the present application provide a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof:

[0020] in

[0021] R1 is C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl; optionally, the C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 The cycloalkyl or 3-15 membered heterocycloalkyl is substituted by a substituent selected from halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and carbonyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S;

[0022] R2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S;

[0023] R3 is C1-C6 alkyl or C1-C6 deuterated alkyl;

[0024] When R2 is methyl, R1 is not unsubstituted phenyl;

[0025] C * The carbon atoms are in R or S configuration;

[0026] C ** The carbon atoms are in R or S configuration.

[0027] In one or more embodiments, R3 is methyl or deuterated methyl.

[0028] In one or more embodiments, C * The carbon atom is in S configuration.

[0029] In one or more embodiments, C ** The carbon atom is in R configuration.

[0030] In one or more embodiments, R1 is C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, the C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl is substituted with a substituent selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and carbonyl; and the 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, and S.

[0031] In one or more embodiments, wherein R1 is

[0032] In one or more embodiments, R2 is C1-C4 alkyl, hydroxy C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 or 2 heteroatoms selected from N, O and S.

[0033] In one or more embodiments, R2 is methyl,

[0034] In one or more embodiments, R1 is C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, the C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl is substituted with a substituent selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and carbonyl; the 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, and S;

[0035] R2 is C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 or 2 heteroatoms selected from N, O and S.

[0036] In one or more embodiments, R1 is R2 is methyl,

[0037] One or more embodiments of the present application provide a compound of formula (III), or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof:

[0038] in

[0039] R1 is C3-C 15 Aryl or 3-15 membered heteroaryl; the 3-15 membered heteroaryl contains 1-4 heteroatoms selected from N, O and S;

[0040] R2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S;

[0041] R3 is C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 cycloalkyl, or 3-15 membered heterocycloalkyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; optionally, the 3-15 membered heterocycloalkyl is substituted by a carbonyl group.

[0042] In one or more embodiments, C * The carbon atoms are in R or S configuration.

[0043] In one or more embodiments, C * The carbon atom is in S configuration.

[0044] In one or more embodiments, C ** The carbon atoms are in R or S configuration.

[0045] In one or more embodiments, C ** The carbon atom is in R configuration.

[0046] In one or more embodiments, R1 is C5-C6 aryl or 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 or 2 N heteroatoms; R2 is C1-C4 alkyl; R3 is C5-C6 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl, or 5-6 membered heterocycloalkyl; the 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S.

[0047] In one or more embodiments, wherein R1 is R2 is methyl; R3 is

[0048] One or more embodiments of the present application provide a compound of formula (IV), or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof:

[0049] in

[0050] R1 is a C5-C6 aryl group or a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms;

[0051] R2 and R3 are each independently H or C1-C6 alkyl and are not H or C1-C6 alkyl at the same time; or R2, R3 and the carbon atom to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and S;

[0052] X1 is C or S;

[0053] R4, R5 and the X1 atom to which they are connected form a carbonyl group or a sulfone group, a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; the 3-6 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from O and S;

[0054] R6 is H or C1-C6 alkyl.

[0055] In one or more embodiments, C * The carbon atoms are in R or S configuration.

[0056] In one or more embodiments, C * The carbon atom is in S configuration.

[0057] In one or more embodiments, C ** The carbon atoms are in R or S configuration.

[0058] In one or more embodiments, C ** The carbon atom is in R configuration.

[0059] In one or more embodiments, the formula (IV) is:

[0060] in,

[0061] R1 is a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms;

[0062] R2 and R3 are each independently H or C1-C6 alkyl and are not H or C1-C6 alkyl at the same time; or R2, R3 and the carbon atom to which they are attached form a C3-C4 cycloalkyl group;

[0063] R4, R5 and the carbon atom to which they are connected form a carbonyl group or a 3-5 membered heterocycloalkyl group; the 3-5 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from O and S.

[0064] In one or more embodiments, the formula (IV) is:

[0065] in

[0066] R1 is a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms;

[0067] R2 is a C1-C4 alkyl group.

[0068] One or more embodiments of the present application provide a compound, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein the compound is selected from:

[0069] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0070] One or more embodiments of the present application provide a pharmaceutical preparation comprising a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0071] One or more embodiments of the present application provide the use of the compound of the present application or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite, the pharmaceutical composition of the present application, or the pharmaceutical formulation of the present application in the preparation of a medicament for treating and / or preventing depression.

[0072] One or more embodiments of the present application provide the use of the compound of the present application or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite, the pharmaceutical composition of the present application, or the pharmaceutical formulation of the present application in the preparation of a fast-acting drug for treating and / or preventing depression.

[0073] One or more embodiments of the present application provide the use of a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, a pharmaceutical composition of the present application, or a pharmaceutical formulation of the present application in the preparation of a medicament for treating and / or preventing irritability, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, bulimia, obesity, drug abuse, alcoholism, tobacco addiction, obsessive-compulsive disorder, panic disorder, premenstrual syndrome, migraine, bipolar disorder, neuropathic pain, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease and vasomotor symptoms or hot flashes.

[0074] In one or more embodiments, the neuropathic pain is chronic pain.

[0075] In one or more embodiments, the chronic pain is fibromyalgia.

[0076] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0077] One or more embodiments of the present application provide a pharmaceutical composition of the present application for use as a medicament.

[0078] One or more embodiments of the present application provide the pharmaceutical preparation of the present application, which is used as a medicament.

[0079] One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application, which is used for preventing and / or treating depression.

[0080] One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application, which is used for preventing and / or rapidly treating depression.

[0081] One or more embodiments of the present application provide a method for preventing and / or treating depression, comprising administering the compound, pharmaceutical composition, or pharmaceutical preparation of the present application to a subject in need thereof.

[0082] One or more embodiments of the present application provide a method for preventing and / or rapidly treating depression, comprising administering a compound, pharmaceutical composition, or pharmaceutical preparation of the present application to a subject in need thereof.

[0083] One or more embodiments of the present application provide the use of the compounds, pharmaceutical compositions or pharmaceutical formulations of the present application in the preparation of a medicament for treating and / or preventing dysphoria, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, bulimia, obesity, drug abuse, alcoholism, tobacco addiction, obsessive-compulsive disorder, panic disorder, premenstrual syndrome, migraine, bipolar disorder, neuropathic pain (e.g., chronic pain, such as fibromyalgia), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease and vasomotor symptoms or hot flashes.

[0084] One or more embodiments of the present application also provide pharmaceutical compositions or pharmaceutical preparations comprising the compounds of the present application. For example, the compounds of the present application can be administered in pure form, in combination with other active ingredients, or in combination with pharmaceutically acceptable non-toxic excipients or carriers.

[0085] The following describes the terms used in the technical solutions of this application. As used in the specification and the appended claims, unless otherwise specifically stated, the terms of this application have the following meanings.

[0086] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0087] The term "amino" refers to -NH2.

[0088] The term "hydroxy" refers to -OH.

[0089] "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when an alkyl group is substituted, it may optionally be further substituted with one or more substituents.

[0090] "Alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group of 1 to 20 carbon atoms containing one or more double bonds, preferably an alkenyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkenyl group of 1 to 6 carbon atoms, and further preferably an alkenyl group of 1 to 4 carbon atoms.

[0091] "Alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group of 1 to 20 carbon atoms containing one or more triple bonds, preferably an alkynyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkynyl group of 1 to 6 carbon atoms, and even more preferably an alkynyl group of 1 to 4 carbon atoms.

[0092] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated non-aromatic heterocyclic ring, which can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 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 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, for example, a 3-8 membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms optionally substituted in the "heterocyclyl" or "heterocycle" ring can be oxidized to various oxidation states; the "heterocyclyl" or "heterocycle" can be attached at a heteroatom or a carbon atom; the "heterocyclyl" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, glycidyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thiazolinyl, pyridinyl, piperidinyl, homopiperidinyl, pyridinyl, piperidinyl, py ... pyranyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl oxazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The “heterocyclyl” or “heterocycle” may be further substituted with one or more substituents.

[0093] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring which may be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, such as a 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms optionally substituted in the heteroaryl ring may be oxidized to various oxidation states. The heteroaryl group may be attached to a heteroatom or a carbon atom, and may be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, and pyrrolopyridinyl. The heteroaryl group may be further substituted with one or more substituents.

[0094] "Cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon group of 1 to 15 carbon atoms, which can be a monocyclic ring of 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10), a bicyclic ring of 4 to 12 carbon atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12), or a polycyclic ring system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15). The ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When a cycloalkyl group is substituted, it may be optionally further substituted by one or more substituents.

[0095] "Heterocycloalkyl" refers to a 3- to 15-membered cyclic saturated aliphatic hydrocarbon group, which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) polycyclic ring system, which can contain one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, or S, and can be monocyclic, fused, bridged, or spirocyclic.

[0096] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring of 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, 8 carbon atoms), a bicyclic ring of 5 to 12 carbon atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms), or a tricyclic ring system of 10 to 15 carbon atoms (e.g., 10, 11, 12, 13, 14, 15 carbon atoms), which can be a bridged ring or a spirocyclic ring, non-limiting examples of which include phenyl and naphthyl. The aryl group can optionally be further substituted with one or more substituents.

[0097] "Alkoxy" refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of "alkyl" is the same as that of "alkyl" described above.

[0098] Unless otherwise indicated, the term "optionally substituted" refers to groups wherein hydrogen atoms are not replaced or one or more hydrogen atoms are replaced by one or more groups independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, and trihalosulfonyl.

[0099] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that 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.

[0100] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0101] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0102] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0103] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0104] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0105] The term "compound" includes all stereoisomers, geometric isomers, and tautomers. The "compound" described herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms or mixtures thereof. The compounds herein containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. The "compound" described herein also includes geometric isomers, which refer to forms in which the substituents on the double bonds or rings of the compound have different cis-trans isomers and are not chiral. The "compound" described herein also includes tautomeric forms. Tautomeric forms can arise from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0106] The compounds herein, whether intermediates or compounds of formula (I), may also be isotopically labeled by replacing one or more atoms thereof with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds are considered to be within the scope of this invention. Examples of isotopes in the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, each having the same number of protons but different mass numbers.

[0107] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0108] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc.

[0109] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, other than the active ingredient. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0110] "Pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0111] In one or more embodiments, the compounds of the present application are more active than existing rapid antidepressant compounds. For example, compared to an existing compound (compound ZZL-7), the compounds of the present application have excellent rapid in vivo antidepressant activity and significantly better drugability (metabolic stability, AUC, bioavailability, etc.). BRIEF DESCRIPTION OF THE DRAWINGS

[0112] FIG1 shows the results of the forced swimming test of in vivo efficacy test 1 of active example 3.

[0113] FIG2 is the result of the tail suspension experiment of in vivo efficacy test 1 of active example 3.

[0114] FIG3 shows the results of the tail suspension experiment of in vivo efficacy test 2 of active example 3. DETAILED DESCRIPTION

[0115] The present application will be further described below in conjunction with the examples, and the implementation details of the present application are provided. However, it should be noted that the examples described below are exemplary and are only used to explain the present application, and should not be construed as limiting the present application. It is still within the scope of protection of the present application for those skilled in the art to modify or replace them according to the prior art. The reagents used in the examples of the present application can all be commercially available.

[0116] Preparation Example

[0117] Preparation Example 1 Preparation of Compound 1

[0118] first step

[0119] (S)-2-Amino-3-methylbutan-1-ol 1-1 (5.0 g, 48 mmol) was dissolved in 1,4-dioxane / water (50 mL / 10 mL), and a solution of phenyloxycarbonyl succinimide (12.0 g, 48 mmol) in 1,4-dioxane (50 mL) / water (10 mL) was slowly added. The reaction solution was reacted at 25°C for 16 hours. After the reaction was completed, ethyl acetate (200 mL) was added to dilute the solution, 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 crude (S)-(1-hydroxy-3-methylbutan-2-yl)carbamic acid benzyl ester 1-2 (10.4 g, white solid, 87% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 238.1 [M+H] + .

[0120] Step 2

[0121] (S)-(1-hydroxy-3-methylbutan-2-yl)carbamic acid benzyl ester 1-2 (7.0 g, 29 mmol) was dissolved in ethyl acetate (140 mL), and 2-iodoacylbenzoic acid (20.6 g, 74 mmol) was added thereto. The reaction solution was refluxed at 80 ° C for 4 hours. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated to give the crude product (S)-(3-methyl-1-oxobutan-2-yl)carbamic acid benzyl ester 1-3 (7.0 g, white solid) in a yield of 91%. The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 236.1 [M+H] + .

[0122] Step 3

[0123] (S)-(3-methyl-1-oxobutan-2-yl)benzylcarbamate 1-3 (7.0 g, 30.0 mmol) and glyoxal solution (15.4 mL, 120 mmol) were dissolved in methanol (70 mL), and aqueous ammonia (18.9 mL, 150 mmol) was slowly added thereto. 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 give crude (S)-(1-(1H-imidazol-2-yl)-2-methylpropyl)benzylcarbamate 1-4 (5.0 g, white solid) with a yield of 60%. The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 274.1 [M+H] + .

[0124] Step 4

[0125] Benzyl (S)-(1-(1H-imidazol-2-yl)-2-methylpropyl)carbamate 1-4 (3.0 g, 11 mmol) was dissolved in methanol (75 mL), followed by the addition of palladium on carbon (0.3 g, 10 wt.%). The mixture was purged with hydrogen three times, and the reaction mixture was allowed to react at 25°C under a hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated to afford crude (S)-1-(1H-imidazol-2-yl)-2-methylpropan-1-amine 1-5 (1.2 g, white solid) in a 71% yield. MS m / z (ESI): 140.1 [M+H] + .

[0126] Step 5

[0127] (S)-1-(1H-imidazol-2-yl)-2-methylpropan-1-amine 1-5 (1.2 g, 9 mmol) and N-acetyl-D-alanine (1.2 g, 9 mmol) were dissolved in N,N-dimethylformamide (12 mL). 1-Hydroxybenzotriazole (1.3 g, 9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9 mmol) were added at -20°C. The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified on a silica gel column (dichloromethane / methanol = 15 / 1) and then purified by reverse preparative method to obtain (R)-N-((S)-1-(1H-imidazol-2-yl)-2-methylpropyl)-2-acetamidopropaneamide 1 (0.6 g, white solid) in a 32% yield. MS m / z (ESI): 253.0 [M+H] + .

[0128] 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),8.08(m,2H),7.00(s,1H),6.82(s,1H),4.72(dd,J=9.1,7.4Hz,1H),4.36 (t,J=7.2Hz,1H),2.11(m,1H),1.82(s,3H),1.20(d,J=7.1Hz,3H),0.83(d,J=6.8Hz,3H),0.74(d,J=6.8Hz,3H).

[0129] Preparation Example 2 Preparation of Compound 2

[0130] first step

[0131] Compound 2-1 (4.18 g, 38.0 mmol) was dissolved in dichloromethane (40 mL). Compound 2-2 (4.74 g, 39.1 mmol) and cesium carbonate (14.86 g, 45.5 mmol) were added to the solution and stirred at 25°C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate (V / V = 1:1)) to obtain the target product 2-3 (7.61 g, white solid, 84.47%). MS (ESI) m / z: 214.0 [M+H] + .

[0132] Step 2

[0133] Compound 2-3 (7.3 g, 34.2 mmol) was dissolved in tetrahydrofuran (50 mL). The reaction system was purged with nitrogen three times, then the temperature was lowered to -60°C. A solution of isopropylmagnesium bromide in tetrahydrofuran (68.4 mL, 68.4 mmol, 1 M) was slowly added dropwise to the reaction mixture. The reaction mixture was slowly warmed to 25°C and stirred for 12 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate (V / V = 3:1)) afforded the desired product 2-4 (1.95 g, white solid, 19.88%). MS (ESI) m / z: 258.1 [M+H] + .

[0134] Step 3

[0135] Compound 2-4 (1.95 g, 7.6 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of hydrogen chloride in 1,4-dioxane (9.5 mL, 38 mmol, 4 M) was added dropwise. The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product 2-5 (1.33 g, white solid, 88.16%), which was used directly in the next step without purification. MS (ESI) m / z: 154.1 [M+H] + .

[0136] Step 4

[0137] Compound 2-6 (1.33 g, 10.1 mmol) was dissolved in dichloromethane (10 mL). 1-Hydroxybenzotriazole (2.05 g, 15.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.87 g, 20.2 mmol), and NMM (3.06 g, 30.3 mmol) were added sequentially to the solution. The reaction was stirred at 25°C for 1 hour. Compound 2-5 (1.33 g, 8.1 mmol) was then added to the reaction solution, and the reaction was stirred for another 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate (V / V = 1:1)) and SFC (CHIRALPAK AD-H 250 mm × 20 mm, 5 μm, 40% MeOH (NH4OH 0.2%): 60% CO2) to obtain 2. MS (ESI) m / z: 267.0 [M+H] + .

[0138] 1 H NMR (400MHz, CD3OD) δ6.95(d,J=1.1Hz,1H),6.88(d,J=1.1Hz,1H),4.76(d,J=9.7Hz,1H),4.26(q,J=7.2Hz,1H), 3.66(s,3H),2.27–2.24(m,1H),1.94(s,3H),1.31(d,J=7.2Hz,3H),1.00(d,J=6.7Hz,3H),0.80(d,J=6.6Hz,3H).

[0139] Preparation Example 3 Preparation of Compound 3

[0140] first step

[0141] To a solution of compound 3-1 (1.50 g, 12.00 mmol) in dichloromethane (30 mL) were added 2-2 (1.45 g, 12 mmol) and cesium carbonate (4.69 g, 14.4 mmol) in sequence. The reaction was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 5:1) as eluents to obtain the desired product 3-2 (2 g, colorless liquid, 73.0%). MS (ESI) m / z: 229.1 [M+H] + .

[0142] Step 2

[0143] To a solution of compound 3-2 (1.80 g, 7.89 mmol) in tetrahydrofuran (15 mL) was added dropwise a solution of isopropylmagnesium bromide in tetrahydrofuran (11.80 mL, 1 N, 11.80 mmol) at -78°C under nitrogen. The reaction mixture was stirred at -78°C for 1 hour. After quenching with saturated ammonium chloride solution, the mixture was warmed to room temperature and diluted with ethyl acetate (60 mL). The reaction mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 4:1) as eluent to afford the desired product 3-3 (650 mg, colorless liquid, 30.4%). MS (ESI) m / z: 273.0 [M+H] + .

[0144] Step 3

[0145] To a solution of compound 3-3 (650 mg, 2.39 mmol) in tetrahydrofuran (40 mL) was added HCl / dioxane (3 mL, 4 N, 12 mmol) at 0°C, and the reaction was stirred at 0°C for 1 hour. The reaction solution was rotary evaporated to dryness, then slurried with petroleum ether (10 mL) and filtered. The filter cake was collected and air-dried to obtain the desired product 3-4 (500 mg, off-white solid, 100%). MS (ESI) m / z: 169.1 [M+H] + .

[0146] Step 4

[0147] To a solution of compound 2-6 (388 mg, 2.97 mmol) in dichloromethane (30 mL) at 0°C were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (854 mg, 4.46 mmol), 1-hydroxybenzotriazole (602 mg, 4.46 mmol), N,N-diisopropylethylamine (1153 mg, 8.92 mmol), and 3-4 (500 mg, 2.97 mmol) in sequence. The reaction was stirred at 0°C for 2 hours. The reaction solution was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane and methanol (V / V = 20:1) as eluents and lyophilized to obtain the desired product (585 mg, white solid, 70.0%). MS (ESI) m / z: 282.0 [M+H] + .

[0148] 1H NMR (400MHz, CD3OD) δ8.43(d,J=2.8Hz,1H),7.59–7.54(m,1H),7.44–7.38(m,1H),4.78–4.75(m,1H),4.46– 4.40(m,1H),2.30–2.15(m,1H),2.01–1.94(m,3H),1.40–1.25(m,3H),1.02–0.90(m,3H),0.86–0.76(m,3H).

[0149] Preparation Example 4 Preparation of Compound 4

[0150] first step

[0151] Compound 1-5 (2.45 g, 17.6 mmol), compound 4-1 (3.33 g, 17.6 mmol) and N-methylmorpholine (5.33 g, 52.8 mmol) were added to dichloromethane (20 mL), the reaction temperature was lowered to 0 ° C, 1-hydroxybenzotriazole (3.56 g, 26.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.04 g, 26.4 mmol), the reaction was stirred at 20°C for 2 hours, extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V = 1:1) as eluent to obtain the target product 4-2 (3.45 g, colorless oil, 63.1%). MS (ESI) m / z: 311.0 [M+H] + .

[0152] Step 2

[0153] Compound 4-2 (3.45 g, 11.1 mmol) and triethylamine (2.24 g, 22.2 mmol) were added to dichloromethane (30 mL). The reaction temperature was lowered to 0°C. Benzyloxycarbonyl succinimide (3.04 g, 12.2 mmol) was slowly added to the reaction solution. The reaction was stirred at 20°C for 2 hours, and then extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V = 2:1) as eluent to obtain the target product 4-3 (3.61 g, colorless oil, 72.9%). MS (ESI) m / z: 445.2 [M+H] + .

[0154] Step 3

[0155] Compound 4-3 (3.61 g, 8.1 mmol) was added to dichloromethane (30 mL), the reaction temperature was lowered to 0°C, trifluoroacetic acid (10 mL) was slowly added to the reaction solution, and the reaction was stirred at 20°C for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, and the pH value was adjusted to 9. The solution was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 4-4 (2.3 g, colorless oil, 81.4%). MS (ESI) m / z: 345 [M+H] + .

[0156] Step 4

[0157] Compound 4-4 (2.3 g, 6.6 mmol), compound 4-5 (0.63 g, 6.6 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (9.22 g, 19.8 mmol) and N,N-diisopropylethylamine (3.45 g, 26.4 mmol) were added to dichloroethane (20 mL). The reaction was stirred at 20°C for 16 hours, and then extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with dichloromethane and methanol (V / V = 15:1) as eluent to obtain the target product 4-6 (350 mg, colorless oil, 12.4%). MS (ESI) m / z: 422.1 [M+H] + .

[0158] Step 5

[0159] Compound 4-6 (350 mg, 0.82 mmol) was dissolved in tert-butanol (20 mL). Pd / C (120 mg) was then added to the reaction mixture, and the hydrogen atmosphere was replaced three times. The reaction mixture was stirred at 20°C for 16 hours while bubbling with hydrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC [CH3CN-H2O (0.1% TFA), CH3CN (30%-70%)] and lyophilized to obtain the desired product 4 (180.79 mg, white solid, 86.1%). MS (ESI) m / z: 288.2 [M+H] + .

[0160] 1H NMR (400MHz, CDCl3) δ10.10(d,J=7.6Hz,1H),8.65(d,J=4.3Hz,1H),8.11(t,J =7.4Hz,1H),7.85(d,J=7.8Hz,1H),7.58(dd,J=7.2,5.0Hz,1H),7.46(s,1H),7 .45(s,1H),7.43(s,1H),5.16(t,J=8.4Hz,1H),4.04(d,J=6.4Hz,1H),2.37–2. 30(m,1H),1.48(d,J=6.5Hz,3H),0.98(d,J=6.5Hz,3H),0.76(d,J=6.7Hz,3H).

[0161] Preparation Example 5 Preparation of Compound 5

[0162] first step

[0163] To a solution of compound 5-1 (15 g, 0.21 mol) in dichloromethane (250 mL) were added 5-2 (27.5 g, 0.23 mol) and anhydrous copper sulfate (8.6 g, 0.05 mol), and the reaction was stirred at 25°C for 24 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V = 10:1) as eluents to obtain the desired product 5-3 (7 g, white oil, 42%). MS (ESI) m / z: 176.0 [M+H] + .

[0164] Step 2

[0165] Compound 1,3-oxazole (1 g, 0.01 mol) and borane tetrahydrofuran solution (22 mL) were dissolved in tetrahydrofuran (30 mL) solution, and then the reaction solution was cooled to -78 ° C and n-butyl lithium (2.4 M, 10 mL, 24 mmol) was added. After stirring for 30 minutes, 5-3 (2.5 g, 0.01 mol) was slowly added, and the reaction solution was stirred at -78 ° C (nitrogen protection) for 3 hours. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane and methanol (V / V = 10:1) as eluents to give the desired product 5-4 (1 g, white solid, 90.1%). MS (ESI) m / z: 245.2 [M+H] + .

[0166] Step 3

[0167] To compound 5-4 (1 g, 4.10 mmol) was added a solution of 1,4-dioxane hydrochloride (10 mL), and the reaction was stirred at 0°C for 1 hour. The reaction solution was rotary evaporated to dryness to obtain the target product 5-5 (400 mg, white solid, 36%). MS (ESI) m / z: 141.2 [M+H] + .

[0168] Step 4

[0169] Compound 5-5 (400 mg, 2.91 mmol), 5-6 (621 mg, 3.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (729 mg, 3.81 mmol), N,N-diisopropylethylamine (1890 mg, 14.62 mmol), and 1-hydroxybenzotriazole (593 mg, 4.39 mmol) were dissolved in dichloromethane (30 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed sequentially with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated sodium chloride solution (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a reverse column chromatography (CH3CN-H2O (0.1% TFA), CH3CN (30%-70%)) and lyophilized to obtain the desired product 5 (340 mg, white solid, 80.7%). MS (ESI) m / z: 316.1 [M+H] + .

[0170] 1 H NMR (400MHz, DMSO-d6) δ8.88–8.47(m,1H),8.55–8.47(m,1H),8.08–8.03(m,1H),7.50–7.47(m,1H),7.36–7.23(m,4H ),7.15–7.11(m,1H),5.67–5.62(m,1H),4.81–4.72(m,1H),2.16–2.04(m,1H),1.90–1.88(m,3H),0.93–0.62(m,6H).

[0171] Preparation Example 6 Preparation of Compound 6

[0172] first step

[0173] Dissolve the compound 2-iodopyrimidine (2 g, 9.71 mmol) in dichloromethane (30 mL). Then, cool the reaction solution to -78°C and add n-butyllithium (2.4 M, 4 mL, 9.6 mmol). Stir the reaction for 30 minutes, then slowly add 5-3 (1.7 g, 9.71 mmol) and stir the reaction solution at -78°C (nitrogen protection) for 3 hours. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated sodium chloride solution (10 mL × 2). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane and methanol (V / V = 10:1) as eluents to give the target product 6-1 (500 mg, yellow oil, 22.5%). MS (ESI) m / z: 256.1 [M+H] + .

[0174] Step 2

[0175] To compound 6-1 (500 mg, 1.96 mmol) was added a solution of 1,4-dioxane hydrochloride (10 mL) at 0°C, and the reaction was stirred at 0°C for 1 hour. The filter cake was filtered to obtain the desired product 6-2 (320 mg, yellow oil, 57.6%). MS (ESI) m / z: 152.2 [M+H] + .

[0176] Step 3

[0177] Compound 6-2 (320 mg, 2.12 mmol), 5-6 (450 mg, 2.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (527 mg, 2.75 mmol), N,N-diisopropylethylamine (1367 mg, 10.58 mmol), and 1-hydroxybenzotriazole (429 mg, 3.17 mmol) were dissolved in dichloromethane (30 mL). The reaction was stirred at room temperature for 2 hours. The reaction was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated sodium chloride solution (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a reverse column chromatography [CH3CN-H2O (0.1% TFA), CH3CN (30%-70%)] and lyophilized to obtain the target product 6 (230 mg, white solid, 64.7%). MS (ESI) m / z: 327 [M+H] + .

[0178] 1H NMR (400MHz, DMSO-d6) δ8.81–8.47(m,1H),7.43–7.20(m,6H),5.75–5.67(m,1H),4.82–4. 72(m,1H),2.21-2.08(m,J=27.5,13.7,6.8Hz,1H),1.92–1.86(m,3H),0.91–0.57(m,6H).

[0179] Preparation Example 7 Preparation of Compound 7

[0180] To a solution of compound 5-6 (500 mg, 2.59 mmol) in dichloromethane (20 mL) at 0°C were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (744 mg, 3.88 mmol), 1-hydroxybenzotriazole (524 mg, 3.88 mmol), N-methylmorpholine (785 mg, 7.76 mmol), and 1-5 (540 mg, 3.88 mmol) in sequence. The reaction was stirred at 0°C for 2 hours. The reaction solution was rotary evaporated to dryness, and the resulting residue was purified by silica gel column chromatography using dichloromethane and methanol (v / v = 10:1) as eluents. The crude product was then purified by preparative column chromatography (developing solvent: dichloromethane:methanol = 10:1) and lyophilized to yield the desired product 7 (425 mg, white solid, 52.3%). MS (ESI) m / z: 315.2 [M+H] + .

[0181] 1 H NMR (400MHz, CD3OD) δ7.44–7.42(m,1H),7.37–7.22(m,4H),6.96–6.88(m,2H),5.44–5.42(m,1H), 4.79–4.66(m,1H),2.21–2.14(m,1H),1.99(s,3H),0.98(d,J=6.7Hz,1.5H),0.77–0.65(m,4.5H).

[0182] Preparation Example 8 Preparation of Compound 8

[0183] In a 200 mL single-necked bottle, compound 5-5 (2.2 g, 15.69 mmol), compound 8-1 (3.3 g, 17.26 mmol), and dichloromethane (100 mL) were added, and the temperature was lowered to -10 ° C. N, N-diisopropylethylamine (10.14 g, 78.45 mmol) was slowly added, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g, 23.54 mmol) was added, and 1-hydroxybenzotriazole (3.2 g, 23.54 mmol) was added, and the reaction was carried out at -10 ° C for 2 hours. After monitoring by LCMS and TLC showed that the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: dichloromethane = 3:1) to obtain compound 8 (1.4 g, 4.44 mmol, yield 28.29%).

[0184] ESI-LCMS: m / z 316.2 [M+H] +.

[0185] 1 H NMR (400MHz, DMSO-d6) δ8.91(d,J=8.9Hz,1H),8.55(d,J=8.4Hz,1H),8.08(d, J=0.7Hz,1H),7.48(d,J=7.2Hz,2H),7.33(t,J=7.3Hz,2H),7.29–7.23(m,1H), 7.19(d,J=0.6Hz,1H),5.67(d,J=8.4Hz,1H),4.74(t,J=8.2Hz,1H),2.06(dq, J=13.7,6.8Hz,1H),1.88(s,3H),0.69(d,J=6.7Hz,3H),0.63(d,J=6.7Hz,3H).

[0186] Preparation Example 9 Preparation of Compound 9

[0187] In a 200 mL single-necked bottle, compound 5-5 (2.1 g, 14.98 mmol) and compound 9-1 (3.18 g, 16.48 mmol) were added, and dichloromethane (100 mL) was added. The temperature was lowered to -20 ° C. N, N-diisopropylethylamine (9.6 g, 74.90 mmol) was slowly added. After stirring at -20 ° C for 10 minutes, N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (6.8 g, 17.97 mmol) was added and the reaction was carried out at -20 ° C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: dichloromethane = 3:1) to give compound 9 (605 mg, 1.92 mmol, yield 12.8%).

[0188] ESI-LCMS: m / z 316.2[M+H] + .

[0189] 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=8.7Hz,1H),8.50(d,J=8.2Hz,1H),7.98(s,1H),7.35(d,J=7.1Hz,2H),7.25(ddd,J=10.7,9.8,5.3Hz,3H),7. 11(s,1H),5.63(d,J=8.3Hz,1H),4.79(t,J=8.2Hz,1H),2.16(dq,J=13. 8, 6.8Hz, 1H), 1.90 (s, 3H), 0.93 (d, J = 6.7Hz, 3H), 0.79 (d, J = 6.7Hz, 3H).

[0190] Preparation Example 10 Preparation of Compound 10

[0191] first step

[0192] Compound 10-1 (1.00 g, 8.06 mmol) was dissolved in dichloromethane (15 mL). Compound 5-2 (1.27 g, 10.48 mmol) and cesium carbonate (5.25 g, 16.12 mmol) were added to the solution, and the reaction was stirred at 25°C for 12 hours. TLC and LCMS monitoring were performed. After the reaction, dichloromethane (50 mL) was added to the reaction solution, followed by washing once with water (50 mL). The aqueous phase was extracted twice with dichloromethane (50 mL). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target product 10-2 (1.70 g, 7.48 mmol, yellow oil, 92%). MS (ESI) m / z: 228.2 [M+H] + .

[0193] Step 2

[0194] Compound 10-2 (1.70 g, 7.48 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction system was purged with nitrogen three times, then the temperature was lowered to -60°C. At this temperature, a solution of isopropylmagnesium bromide in tetrahydrofuran (8.13 mL, 18.70 mmol, 2.3 M) was slowly added dropwise to the reaction mixture. The reaction mixture was slowly warmed to 25°C and stirred for 3 hours. TLC and LCMS monitoring were performed. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography afforded the desired product 10-3 (950 mg, 3.50 mmol, white solid, 46%). MS (ESI) m / z: 272.3 [M+H] + .

[0195] Step 3

[0196] Compound 10-3 (0.95 g, 3.50 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of hydrogen chloride in 1,4-dioxane (4.4 mL, 17.5 mmol, 4 M) was added dropwise. The reaction was stirred at 25°C for 1 hour and monitored by TLC and LCMS. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product 10-4 (0.58 g, 3.47 mmol, yellow solid), which was used directly in the next reaction without purification. MS (ESI) m / z: 168.2 [M+H] + .

[0197] Step 4

[0198] Compound 10-4 (0.58 g, 2.86 mmol) was dissolved in dichloromethane (10 mL). 2-6 (0.41 g, 3.15 mmol), HATU (1.30 g, 3.43 mmol), and DIPEA (1.11 g, 8.58 mmol) were added sequentially to the solution. The reaction was stirred at -20°C for 3 hours and monitored by TLC and LCMS. After completion of the reaction, dichloromethane (50 mL) was added to the reaction solution, followed by washing with water (50 mL). The aqueous phase was extracted twice with dichloromethane (50 mL). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the product (0.20 g, 0.71 mmol, 20%) as a white solid. MS (ESI) m / z: 281.1 [M+H] + .

[0199] 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=9.0Hz,1H),7.98(d,J=7.7Hz,1H),7.38(t,J=7.6,1H),7.28(t,J=7.3,1H),7.22–7.09(m,2H) ,4.84(m,1H),4.43–4.31(m,1H),1.93(m,1H),1.78(s,3H),1.21(d,J=7.1Hz,3H),0.89(d,J=6.7Hz,3H),0.73(d,J=6.7Hz,3H).

[0200] Preparation Example 11 Preparation of Compound 11

[0201] first step:

[0202] Compound 11-1 (1.40 g, 10.0 mmol) was dissolved in dichloromethane (20 mL). Compound 5-2 (1.57 g, 13.00 mmol) and cesium carbonate (6.50 g, 20.00 mmol) were added to the reaction solution. The mixture was stirred at room temperature overnight and monitored by TLC. After the reaction was complete, the mixture was filtered and the filter cake was washed with 20 mL of dichloromethane. The mixture was mixed with silica gel and separated by column chromatography to obtain compound 11-2 (2.14 g, 8.80 mmol, yield: 88%). MS-ESI: M / Z = 244.2 [M+H] + .

[0203] Step 2:

[0204] Compound 11-2 (2.14 g, 8.80 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction system was purged with nitrogen three times, then the temperature was lowered to below -60°C. A solution of isopropylmagnesium bromide in tetrahydrofuran (4.7 mL, 2.8 mol / L) was slowly added dropwise. After the addition was complete, the mixture was incubated for 1 hour, then slowly warmed to room temperature and stirred for 12 hours. The reaction was monitored for completion by TLC. After the reaction was complete, saturated ammonium chloride solution (20 mL) was slowly added dropwise to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and coated with silica gel. The mixture was separated by column chromatography to afford compound 11-3 (1.50 g, 5.22 mmol, yield: 59%). MS-ESI: M / Z = 288.2 [M+H] + .

[0205] Step 3:

[0206] Compound 11-3 (1.50 g, 5.22 mmol) was added to tetrahydrofuran (15 mL). A 4.0 mol / L solution of hydrogen chloride in dioxane (10 mL, 40 mmol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was recovered to dryness to obtain the crude hydrochloride of compound 11-4 (1.03 g, 4.70 mmol, yield: 85%). MS-ESI: M / Z = 183.1 [M+H] + .

[0207] Step 4:

[0208] Compound 11-4 (224 mg, 1.02 mmol) and N-acetyl-D-alanine (160 mg, 1.22 mmol) were added to a reaction flask containing dichloromethane (15 mL). The temperature was lowered to -20°C, and HATU (463 mg, 1.22 mmol) and N,N-diisopropylethylamine (263 mg, 2.04 mmol) were slowly added. The temperature was maintained and stirring was continued. The reaction was monitored by TLC and LCMS. After the reaction was completed, water (20 mL) was added, the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and passed through a silica gel column to obtain compound 11 (245 mg, 0.83 mmol, yield: 82%). MS-ESI: M / Z = 297.2 [M+H] + .

[0209] 1H NMR (400MHz, DMSO-d6) δ8.27(d,J=9.0Hz,1H),8.00(d,J=7.6Hz,1H),7.45–7.16(m,4H),4.54(t,J=8.5Hz,1H),4.36(p,J= 7.1Hz, 1H), 2.04–1.87 (m, 1H), 1.81 (d, J = 12.7Hz, 3H), 1.19 (t, J = 8.9Hz, 3H), 0.86 (t, J = 8.0Hz, 3H), 0.72 (d, J = 6.7Hz, 3H).

[0210] Preparation Example 12 Preparation of Compound 12

[0211] first step:

[0212] Compound 12-1 (1.36 g, 10.00 mmol) was dissolved in dichloromethane (20 mL). 5-2 (1.57 g, 13.00 mmol) and cesium carbonate (6.50 g, 20.00 mmol) were added to the reaction solution. The mixture was stirred at room temperature overnight and monitored by TLC. After the reaction was complete, the mixture was filtered and the filter cake was washed with 20 mL of dichloromethane. The mixture was mixed with silica gel and separated by chromatography to obtain compound 12-2 (2.25 g, 9.41 mmol, yield: 94%). MS-ESI: M / Z = 240.2 [M+H] + .

[0213] Step 2:

[0214] 12-2 (2.25 g, 9.41 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction system was purged with nitrogen three times, then the temperature was lowered to below -60°C. A solution of isopropylmagnesium bromide in tetrahydrofuran (5.0 mL, 2.8 mol / L) was slowly added dropwise. After the addition was complete, the mixture was incubated for 1 hour, then slowly warmed to room temperature and stirred for 12 hours. The reaction was monitored for completion by TLC. After the reaction was complete, saturated ammonium chloride solution (20 mL) was slowly added dropwise to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and coated with silica gel. The mixture was separated by column chromatography to afford compound 12-3 (0.45 g, 1.59 mmol, yield: 15%). MS-ESI: M / Z = 284.1 [M+H] + .

[0215] Step 3:

[0216] Compound 12-3 (0.45 g, 1.59 mmol) was added to tetrahydrofuran (15 mL). A 4.0 mol / L solution of hydrogen chloride in dioxane (10 mL, 40 mmol) was slowly added dropwise at room temperature. After the addition was complete, stirring was continued at room temperature and monitored by TLC. After the reaction was complete, the solvent was recovered to dryness to obtain compound 12-4 (0.33 g, 1.53 mmol, yield: 96%). MS-ESI: M / Z = 180.1 [M+H] + .

[0217] Step 4:

[0218] Compound 12-4 (215 mg, 1.00 mmol) and compound 2-6 (179 mg, 1.37 mmol) were added to a reaction flask containing dichloromethane (15 mL). The temperature was lowered to -20°C, and HATU (456 mg, 1.20 mmol) and N,N-diisopropylethylamine (387 mg, 3.00 mmol) were slowly added. The temperature was maintained and stirring was continued. The reaction was monitored by TLC and LCMS. After the reaction was completed, water (20 mL) was added, the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and passed through a silica gel column to obtain compound 12 (270 mg, 0.92 mmol, yield: 92%). MS-ESI: M / Z = 293.2 [M+H] + .

[0219] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=9.2Hz,1H),7.98(d,J=7.6Hz,1H),7.27–7.15(m,1H),6.89–6.72(m,3H),4.51(t,J=8.5Hz,1H),4. 38(m,1H),3.73(d,J=4.2Hz,3H),2.01–1.86(m,1H),1.79(s,3H),1.21(d,J=7.0Hz,3H),0.84(d,J=6.6Hz,3H),0.72(d,J=6.7Hz,3H).

[0220] Preparation Example 13 Preparation of Compound 13

[0221] first step

[0222] In a 250 mL single-necked flask, compound 13-1 (2.00 g, 21.03 mmol) was dissolved in dichloromethane (40 mL). Compound 5-2 (2.55 g, 21.03 mmol) and cesium carbonate (13.70 g, 42.06 mmol) were added to the solution, and the reaction was stirred at 25°C for 12 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash preparative chromatography to obtain compound 13-2 (2.00 g, 10.09 mmol, yield 47.98%). ESI-LCMS: m / z 199.1 [M+H] + .

[0223] Step 2

[0224] In a 250 mL three-necked flask, compound 13-2 (1.7 g, 8.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The reaction system was purged with nitrogen three times, then the temperature was lowered to -60°C. At this temperature, a solution of isopropylmagnesium bromide in tetrahydrofuran (20 mL, 40 mmol, 2.0 M) was slowly added dropwise to the reaction solution. The reaction was slowly warmed to 25°C and stirred for 12 hours. After LCMS and TLC monitoring indicated the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 13-3 (1.60 g, 6.60 mmol, yield 77.01%). ESI-LCMS: m / z 243.2 [M+H] + .

[0225] Step 3

[0226] In a 100 mL single-necked flask, compound 13-3 (400 mg, 1.65 mmol) was dissolved in dioxane hydrochloride solution (4.0 M, 5 mL). The reaction mixture was stirred at room temperature for 2 hours. After LCMS and TLC monitoring showed the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product, compound 13-4 (250 mg, 1.43 mmol, 86.67% yield), which was used directly in the next reaction. ESI-LCMS: m / z 139.1 [M+H] + .

[0227] Step 4

[0228] In a 100 mL single-necked flask, compound 2-6 (190 mg, 1.45 mmol) and N,N-diisopropylethylamine (562 mg, 4.35 mmol) were added to a solution of compound 13-4 (250 mg, 1.43 mmol) in DMF (5 mL). The temperature was lowered to -10°C, and HATU (825 mg, 2.17 mmol) was added. The reaction solution was stirred at -10°C for 3 hours. After LCMS and TLC monitoring indicated the reaction was complete, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and further purified by reverse phase MPLC to obtain product 13 (23 mg, 0.09 mmol, yield 6.29%). ESI-LCMS: m / z 252.2 [M+H] + .

[0229] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.05(d,J=7.6Hz,1H),7.87(d,J=9.4Hz,1H),6.59(q,J=2.3Hz,1H),5.93–5.81(m,2H),4.66(d d,J=9.4,7.1Hz,1H),4.32(p,J=7.1Hz,1H),1.92(h,J=6.9Hz,1H),1.83(s,3H),1.14(d,J=7.0Hz,3H),0.77(dd,J=22.2,6.7Hz,6H).

[0230] Preparation Example 14 Preparation of Compound 14

[0231] first step

[0232] In a 250 mL single-necked flask, compound 14-1 (2.00 g, 20.81 mmol) was dissolved in dichloromethane (40 mL). Compound 5-2 (2.52 g, 20.81 mmol) and cesium carbonate (13.56 g, 41.62 mmol) were added to the solution, and the reaction was stirred at 25°C for 12 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash preparative chromatography to obtain compound 14-2 (3.00 g, 15.05 mmol, yield 72.32%). ESI-LCMS: m / z 200.1 [M+H] + .

[0233] Step 2

[0234] In a 250 mL three-necked flask, compound 14-2 (2.00 g, 10.04 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The reaction system was purged with nitrogen three times, then the temperature was lowered to -60°C. At this temperature, a solution of isopropylmagnesium bromide in tetrahydrofuran (25 mL, 50 mmol, 2 M) was slowly added dropwise to the reaction solution. The reaction was slowly warmed to 25°C and stirred for 12 hours. After LCMS and TLC monitoring indicated the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 14-3 (2.20 g, 9.04 mmol, yield 90.04%). ESI-LCMS: m / z 244.2 [M+H] + .

[0235] Step 3

[0236] In a 100 mL single-necked flask, compound 14-3 (1.00 g, 4.11 mmol) was dissolved in dioxane hydrochloride solution (4.0 M, 10 mL). The reaction mixture was stirred at room temperature for 2 hours. After LCMS and TLC monitoring showed the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product, compound 14-4 (600 mg, 3.42 mmol, 83.21% yield), which was used directly in the next reaction. ESI-LCMS: m / z 140.1 [M+H] + .

[0237] Step 4

[0238] In a 100 mL single-necked flask, compound 5-6 (661 mg, 3.42 mmol) and N,N-diisopropylethylamine (884 mg, 6.84 mmol) were added to a solution of compound 14-4 (600 mg, 3.42 mmol) in DMF (10 mL). T3P (3.26 g, 5.13 mmol, 50% DMF solution) was then added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and further purified by reverse-phase MPLC to obtain the product, compound 14 (140 mg, 0.45 mmol, yield 13.16%). ESI-LCMS: m / z 315.2 [M+H] + .

[0239] 1H NMR (400MHz, DMSO-d6) δ12.53(d,J=31.7Hz,1H),8.72–8.37(m,2H),7.67–7.19(m,6H),6.08(d,J=81.5Hz,1H),5.62(d,J=8. 3Hz, 1H), 4.73 (s, 1H), 2.09–1.94 (m, 1H), 1.89 (d, J = 13.2Hz, 3H), 0.82 (dd, J = 29.1, 6.7Hz, 3H), 0.62 (dd, J = 14.2, 6.7Hz, 3H).

[0240] Preparation Example 15 Preparation of Compound 15A and Compound 15B

[0241] first step:

[0242] Compound 5-5 (4 g, 22.6 mmol), compound 15-1 (6 g, 23.8 mmol), compound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.6 g, 29.4 mmol), N,N-diisopropylethylamine (14.6 g, 112.8 mmol), and 1-hydroxybenzotriazole (4.6 g, 33.8 mmol) were dissolved in dichloromethane (50 mL). The reaction was stirred at room temperature for 2 hours. Extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (50 mL × 2), saturated ammonium chloride solution (50 mL × 2), and saturated sodium chloride solution (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 1:1) as eluent to obtain a mixture of compound 15-2 (4 g, white solid, 38%). MS (ESI) m / z: 373 [M+H] + .

[0243] Step 2:

[0244] A trifluoroacetic acid / dichloromethane (v / v = 1:2) solution (40 mL) was added to compound 15-2 (4 g, 10.7 mol) and the mixture was stirred at 25°C for 2 hours. The reaction solution was rotary evaporated to dryness and lyophilized to obtain the title product, compound 15-3 (4 g, white solid). MS (ESI) m / z: 274 [M+H] + .

[0245] Step 3:

[0246] A mixture of compound 15-3 (4 g, 14.6 mmol) and N,N-diisopropylethylamine (11.3 g, 87.6 mmol) was dissolved in dichloromethane (40 mL) at 0°C, and compound 9 (1.4 g, 17.5 mmol) was slowly added dropwise. The reaction was stirred at 0°C for 1 hour. The product was purified using a reverse phase column (acetonitrile-water (0.1% trifluoroacetic acid), acetonitrile (30%-70%)). The resulting residue was freeze-dried and basified to give compounds 15A and 15B.

[0247] Compound 15A (1 g, white solid, 22%). MS (ESI) m / z: 319 [M+H] + .

[0248] 1 HNMR (400MHz, DMSO-d6) δ8.79(d,J=8.7Hz,1H),8.50(d,J=8.2Hz,1H),7.98(s,1H),7.35-7.22(m,5H),7.11(s,1H),5. 63(d,J=8.3Hz,1H), 4.79(t,J=8.2Hz,1H), 2.14(dt,J=13.9,6.9Hz,1H), 0.93(d,J=6.7Hz,3H), 0.79(d,J=6.7Hz,3H).

[0249] Compound 15B (1 g, white solid, 22%). MS (ESI) m / z: 319 [M+H] + .

[0250] 1 HNMR(400MHz, DMSO-d6)δ8.91(d,J=8.8Hz,1H),8.56(d,J=8.4Hz,1H),8.09(s,1H),7.49–7.25(m,5H),7.19(s,1H),5. 67(d,J=8.4Hz,1H), 4.74(t,J=8.3Hz,1H), 2.07(dt,J=13.9,6.8Hz,1H), 0.69(d,J=6.7Hz,3H), 0.63(d,J=6.7Hz,3H).

[0251] Preparation Example 16 Preparation of Compound 16

[0252] first step:

[0253] Compound 16-1 (2.5 g, 10.2 mmol), 1-hydroxybenzotriazole (2.07 g, 15.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g, 15.3 mmol) were added to dichloromethane (20 mL), the reaction temperature was lowered to -15°C, and compound 5-5 (1.8 g, 10.2 mmol) and N-methylmorpholine (4.13 g, 40.8 mmol) were slowly added to the reaction solution. After stirring at -15°C for 2 hours, the reaction was extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluents of dichloromethane and ethyl acetate (V / V=3:1) to obtain the title product compound 16-2 (1.95 g, white solid, 52.1%). MS (ESI) m / z: 390 [M+Na] + .

[0254] Step 2:

[0255] Compound 16-2 (1.95 g, 5.3 mmol) was added to dichloromethane (10 mL). The reaction temperature was lowered to 0°C. Trifluoroacetic acid (5 mL) was slowly added to the reaction solution. After stirring at 20°C for 1 hour, saturated sodium bicarbonate solution was added to the reaction solution. The pH was adjusted to 8. The solution was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product, compound 16-3 (1.38 g, colorless oil, 97.2%). MS (ESI) m / z: 268 [M+H] + .

[0256] Step 3:

[0257] Compound 16-3 (1.38 g, 4.5 mmol) was dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (2.68 g, 20.8 mmol) was then added to the reaction mixture. The nitrogen atmosphere was replaced three times, and the reaction temperature was lowered to 0°C. Compound 5 (0.47 g, 5.7 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 1 hour, and then saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography using dichloromethane and ethyl acetate (V / V = 3:1) as eluent to obtain compound 16 (1.14 g, white solid, 70.2%). MS (ESI) m / z: 313 [M+H] + .

[0258] 1 HNMR (400MHz, CDCl3) δ7.60(s,1H),7.07(s,1H),6.90(d,J=8.6Hz,1H),5.96(d,J=8.0Hz,1H),5.04(dd,J=8.8,6.2Hz,1H),4.51(td,J=7.9,5.2 Hz, 1H), 2.23 (dq, J = 13.4, 6.7Hz, 1H), 1.93 (dd, J = 14.4, 5.1Hz, 1H), 1.45 (dd, J = 14.4, 7.7Hz, 1H), 0.93 (d, J = 4.1Hz, 12H), 0.87 (d, J = 6.8Hz, 3H).

[0259] Preparation Example 17 Preparation of Compound 17

[0260] first step:

[0261] To a solution of compound 17-1 (1.8 g, 7.3 mmol) in dichloromethane (18 mL) were added compound 5-5 (1.68 g, 9.49 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 10.95 mmol), 1-hydroxybenzotriazole (1.48 g, 10.95 mmol) and N,N-diisopropylethylamine (2.83 g, 21.9 mmol), and the reaction solution was stirred at room temperature for 18 hours. Dilute with 50 mL of water and extract with dichloromethane (20 mL x 3). The combined organic phases were washed sequentially with sodium bicarbonate solution (50 mL x 2) and saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate (V / V = 1:1) as eluents to obtain the title product, compound 17-2 (2.6 g, light yellow solid, 87%). MS (ESI) m / z: 368.2 [M+H] + .

[0262] Step 2:

[0263] Compound 17-2 (2.6 g, 7.1 mmol) was dissolved in dichloromethane (21 mL), trifluoroacetic acid (7 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title product, compound 17-3 (2.7 g, yellow oil, crude product). MS (ESI) m / z: 268.2 [M+H] + .

[0264] Step 3:

[0265] To a solution of compound 17-3 (2.7 g, 8.9 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethylamine (4.59 g, 35.5 mmol). The mixture was cooled to 0°C in an ice bath, and deuterated acetyl chloride (0.87 g, 10.65 mmol) was slowly added. The reaction mixture was stirred at 25°C for 5 hours. The mixture was diluted with 50 mL of water and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed sequentially with sodium bicarbonate solution (50 mL x 2) and saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate (V / V = 3:1) as eluents to afford the title product, compound 17 (960 mg, 42%, as a pale yellow solid). MS (ESI) m / z: 312.9 [M+H] + .

[0266] 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),7.04(s,1H),6.96(d,J=8.6Hz,1H),5.91(d,J=8.4Hz,1H),5.03(dd,J=8.9,6.0Hz,1H),4.57(td,J=8.3,4.3Hz,1H) ,2.23(dd,J=13.1,6.6Hz,1H),1.98(dd,J=14.5,4.3Hz,1H),1.45(dd,J=1 4.5, 8.1Hz, 1H), 0.97 (s, 9H), 0.94 (d, J = 6.8Hz, 3H), 0.90 (d, J = 6.8Hz, 3H).

[0267] Preparation Example 18 Preparation of Compound ZZL-7

[0268] first step:

[0269] Add (tert-Butyloxycarbonyl)-L-alanine (4.5 g, 23.78 mmol) to a dry single-necked flask, dissolve in dichloromethane (50 mL), place in an ice bath and stir for 10 min, then add L-valine methyl ester (3.12 g, 23.78 mmol), N,N-diisopropylethylamine (6.15 g, 47.56 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.01 g, 26.16 mmol) to the flask in sequence and stir at room temperature for 2 h. After TLC showed that the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was adjusted to acidity with 2M hydrochloric acid and extracted with dichloromethane (50 mL × 2). The organic phases were combined and adjusted to alkalinity with saturated sodium bicarbonate and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE: EA = 2: 1) to obtain the intermediate (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol, yield 90.39%). LCMS (M+H + )=) + =303.1.

[0270] Step 2:

[0271] To a dry, single-necked flask, add (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol) and dissolve in dichloromethane (30 mL). Then, add hydrochloric acid-1,4-dioxane (10 mL, 4 M) and stir at room temperature for 2 h. After TLC showed the reaction was complete, the organic phase was concentrated and purified 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%). LCMS (M+H + )=203.3.

[0272] 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).

[0273] Step 3:

[0274] L-Alanyl-L-valine methyl ester (3.7 g, 18.32 mmol) and N,N-diisopropylethylamine (4.72 g, 36.64 mmol) were dissolved in tetrahydrofuran (50 mL), the atmosphere was thoroughly purged with nitrogen, and the mixture was stirred at 0°C. After 10 minutes, acetic anhydride (2.8 g, 27.48 mmol) was slowly added dropwise. The mixture was stirred at this temperature for 10 minutes and then moved to room temperature and stirred for 2 hours. After TLC indicated the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was acidified with 2M hydrochloric acid. The mixture was extracted with dichloromethane (50 mL x 4). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1). Compound ZZL-7 (acetyl-L-alanyl-L-valine methyl ester, 2.6 g, 10.67 mmol, yield 58.23%) was obtained. LCMS (M+H + )=) + =245.3. 1 HNMR (400MHz, CDCl3) δ6.68(d,J=8.5Hz,1H),6.21(d,J=7.1Hz,1H),4.57–4.47(m,1H),4.44(dd,J=8.7,4. 9Hz, 1H), 3.68 (s, 3H), 2.18–2.04 (m, 1H), 1.94 (s, 3H), 1.31 (d, J = 7.0Hz, 3H), 0.85 (dd, J = 10.1, 6.9Hz, 6H).

[0275] Preparation Example 19 Preparation of Compound 19

[0276] first step

[0277] The intermediate raw material 4-2 (0.46 g, 1.48 mmol) and dioxane hydrochloride solution (4.0 M, 5 mL) were added to a dry 50 mL three-necked flask and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC and LCMS, the reaction solution was concentrated to obtain compound 19-1 (0.30 g, 1.43 mmol, light yellow solid) with a yield of 96%.

[0278] Step 2

[0279] Compound 19-1 (0.10 g, 0.48 mmol) was dissolved in dry dichloromethane (10 mL). After thorough stirring, the temperature was lowered to approximately 0°C, and cyclopropylcarbonyl chloride (25 mg, 0.24 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol) were slowly added dropwise. After the addition was complete, the temperature was maintained for 1 hour. After completion of the reaction as monitored by TLC and LCMS, the reaction solution was washed with water. After separation, the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification by MPLC, compound 19 (21 mg, 0.08 mmol, white solid) was obtained in a 15% yield. MS m / z (ESI): 279.2 [M+H] + .

[0280] 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.31(d,J=7.6Hz,1H),8.12(d,J=9.3Hz,1H),7.00(s,1H),6.82(s,1H),4.7 3(dd,J=9.1,7.2Hz,1H),4.44–4.35(m,1H),2.67(s,0.5H),2.33(s,0.5H),2.18–1.13(m,6H),0.95–0.49(m,8H).

[0281] Preparation Example 20 Preparation of Compound 20

[0282] first step

[0283] In a 100 mL three-necked flask, sodium hydride (800 mg, 20 mmol) was added and the atmosphere was replaced with nitrogen three times. Then, a solution of 4-1 (378 mg, 2 mmol) in anhydrous tetrahydrofuran (6 mL) was added under ice-bath. After stirring for 30 minutes, a solution of iodomethane (2.84 g, 20 mmol) in anhydrous tetrahydrofuran (2 mL) was added and the reaction continued for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, saturated sodium bicarbonate solution (50 mL) was added to quench the reaction. The reaction was extracted with ethyl acetate (50 mL × 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to obtain 20-1 (295 mg, 1.45 mmol, yield 72.5%). ESI-LCMS: m / z 202.1 [MH] - .

[0284] Step 2

[0285] In a 100 mL three-necked flask, 20-1 (295 mg, 1.45 mmol), 1-5 (202 mg, 1.45 mmol), N,N-diisopropylethylamine (561 mg, 4.35 mmol), and anhydrous dichloromethane (7 mL) were added sequentially. The reaction mixture was stirred in an ice bath for 10 minutes, followed by the addition of 1-hydroxybenzotriazole (294 mg, 2.18 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (418 mg, 2.18 mmol). The mixture was allowed to slowly warm to room temperature and react for 3 hours. After completion as monitored by LCMS and TLC, the reaction was quenched by the addition of saturated brine (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to afford 20-2 (110 mg, 0.34 mmol, yield 23.4%). ESI-LCMS: m / z 325.2[M+H] + .

[0286] Step 3

[0287] In a 100 mL three-necked flask, 20-2 (110 mg, 0.34 mmol), anhydrous dichloromethane (2 mL), and a 1,4-dioxane solution of hydrochloric acid (4.0 M, 2 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as monitored by LCMS and TLC, the reaction mixture was concentrated and diluted with dichloromethane (50 mL). Subsequently, the mixture was concentrated again to remove the residual dioxane hydrochloric acid solution. The residue was purified by reverse-phase silica gel column and lyophilized to obtain 20-3 (69 mg, 0.31 mmol, 91.2% yield). ESI-LCMS: m / z 225.2 [M+H] + .

[0288] Step 4

[0289] In a 100 mL three-necked flask, 20-3 (69 mg, 0.31 mmol), anhydrous dichloromethane (6 mL), and triethylamine (173 mg, 1.71 mmol) were added. After stirring on an ice bath for ten minutes, a solution of acetyl chloride (73 mg, 0.93 mmol) in anhydrous dichloromethane (1 mL) was slowly added dropwise. After the reaction was complete as monitored by LCMS and TLC, dichloromethane (50 mL) was added for dilution and an equal volume of saturated aqueous sodium bicarbonate solution was added for quenching. The aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to afford compound 20 (12 mg, 0.05 mmol, yield 16.1%). MS (ESI) m / z: 267.2 [M+H] + .

[0290] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.12(dd,J=128.7,9.0Hz,1H),6.93(d,J=2.8Hz,2H),5.08–4.47(m,2H),2.74(d,J=81.2Hz,3H ), 2.17–2.04(m,1H),1.99(d,J=8.0Hz,3H),1.27(dd,J=26.5,7.1Hz,3H),0.85(dd,J=10.4,6.7Hz,3H),0.72(dd,J=8.4,6.7Hz,3H).

[0291] Preparation Example 21 Preparation of Compound 21

[0292] first step:

[0293] Intermediate starting material 1-5 (0.40 g, 2.90 mmol) and 2-(tert-Butylamido)-2-cyclopropylacetic acid (0.60 g, 2.80 mmol) were dissolved in DMF (10 mL) and cooled to approximately -10°C. HOBt (0.40 g, 3.00 mmol) and EDCI (0.58 g, 3.00 mmol) were added to the reaction solution. The reaction solution was then slowly warmed to room temperature and stirred overnight. After completion of the reaction as monitored by TLC, ethyl acetate (50 mL) was added to the reaction solution for dilution, followed by washing with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by MPLC afforded 21-1 (0.78 g, 2.32 mmol, yield: 80%). MS (ESI) m / z: 337.3 [M+H] + .

[0294] Step 2:

[0295] 21-1 (0.78 g, 2.32 mmol) was added to a mixed solution of ethyl acetate (20 mL) and methanol (5 mL). A 4.0 M solution of hydrogen chloride in dioxane (5 mL, 20.0 mmol) was slowly added dropwise at room temperature. After the addition was complete, stirring was continued at room temperature until the reaction was complete as monitored by TLC. The mixture was then concentrated under reduced pressure to afford the crude hydrochloride of 21-2 (0.62 g, 2.27 mmol, yield: 98%), which was used directly in the next reaction. MS-ESI: M / Z = 237.2 [M+H] + .

[0296] Step 3:

[0297] 21-2 hydrochloride (0.62 g, 2.27 mmol) was added to acetic anhydride (10 mL), followed by triethylamine (0.69 g, 6.81 mmol) and the reaction was heated to 60°C for 3 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After MPLC purification, compound 21 (0.18 g, 0.64 mmol, yield: 28%) was obtained. MS (ESI) m / z: 279.2 [M+H] + .

[0298] 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H), δ8.28–8.10(m,1H),7.98(d,J=9.1Hz,1H),6.92(s,2H),4.78–4.66(m,1H),3.82–3.74(m,1 H),2.22–1.94(m,1H),1.83(d,J=5.2Hz,3H),1.06–0.94(m,1H),0.85(d,J=6.8Hz,3H),0.74(d,J=6.8Hz,3H),0.49–0.14(m,4H).

[0299] Activity Test Example 1 Plasma Stability Determination

[0300] After thawing the mouse plasma in a water bath at 37°C, centrifuge to remove the upper clot and record the pH at 7-8. Take a certain volume of acetonitrile stock solution of the test compound (concentration of 10mM) and dilute it to 1mM with acetonitrile as an intermediate solution. Propantheline is used as a positive control. Take a certain volume of the compound intermediate 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. Make a curve based on the remaining percentage of the compound and the incubation time to obtain the k value and calculate the half-life of each compound. The formula is as follows:

[0301] Table 1 shows the plasma stability data of some compounds. The results show that the compounds of the present application exhibit excellent plasma stability, which is significantly better than ZZL-7.

[0302] Table 1 Plasma stability data of some compounds Note: If the remaining percentage of the compound is still greater than 80% after 120 minutes, then T 1 / 2 Recorded as >372.68min.

[0303] Activity Experiment Example 2 Pharmacokinetics Test

[0304] Compound pharmacokinetics were assessed in 6-8 week old CD1 mice. Test compounds were dissolved in a 10% hydroxypropyl-β-cyclodextrin aqueous solution containing 10% DMSO and administered intravenously or orally. Plasma concentrations were analyzed by LC-MS / MS. Pharmacokinetic calculations were performed using WinNonlin (Phoenix™, version 8.3) or other similar software. The following pharmacokinetic parameters were calculated based on plasma concentration versus time data:

[0305] Oral administration: AUC last , bioavailability (F).

[0306] The above parameter data were statistically calculated.

[0307] Table 2 shows the area under the drug-dose curve (AUC) and bioavailability (F) data of the compound of the present application after oral administration. The results show that the compound of the present application has good pharmacokinetic properties and is significantly better than compound ZZL-7.

[0308] Table 2 Pharmacokinetic data of some compounds

[0309] Activity Experiment Example 3

[0310] In vivo efficacy testing 1

[0311] 6-8 week-old C57 / B6 mice were induced with a 28-day chronic unpredictable mild stress (CUMS) model. The open field test (OFT) was used to assess the model's success before drug efficacy evaluation. The experimental group consisted of a blank control, a model group, a vehicle control group, a fluoxetine control group, and a compound group. The test compound was administered intravenously (iv) at a dose of 100 mg / kg. Two hours later, the tail suspension test (TST) and forced swimming test (FST) were performed to assess depression in the mice. Prolonged immobility in the TST and FST indicated behavioral despair. Data were aggregated and analyzed using SPSS statistical software, and graphs were plotted using Graph Pad software based on the SPSS analysis results.

[0312] The test results show (see Figures 1 and 2) that Compound 1 and Compound 5 can quickly reverse the prolonged immobility time in the forced swimming and tail suspension tests in mice with chronic unpredictable stress models, demonstrating that the compounds of the present application have a rapid antidepressant effect.

[0313] In vivo efficacy testing 2

[0314] 6-8 week old C57 / B6 mice were used to establish a 28-day chronic unpredictable mild stress (CUMS) model. The open field test (OFT) was used to evaluate the model's success before evaluating the drug's efficacy. The experiment was divided into a blank control group (Control), a model group (Model), a vehicle control group (Vehicle), a fluoxetine control group, a ZZL-7 control group, and a compound group. The test compound was administered orally at a single dose of 25 mg / kg. Two hours later, a tail suspension test (TST) was performed to assess depression in the mice. Prolonged immobility in the TST indicates behavioral despair. Data were aggregated and analyzed using SPSS statistical software, and graphs were plotted using Graph Pad software based on the SPSS analysis results.

[0315] The test results show (see FIG3 ) that compound 16 can quickly reverse the prolonged immobility time in the tail suspension test of mice in the chronic unpredictable stress model, demonstrating that the compound of the present application has a rapid antidepressant effect.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof: in, R1 and R2 are independently selected from hydrogen, R8-(CO)-, R8-(SO)-, R8-(SO2)-, R8-O(CO)-, R8R9-N(CO)-, or C1-C2-substituted by n R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; Or R1, R2 and the nitrogen atoms adjacent to them together form a C3-C substituted by n R8 15 Heterocycloalkyl or C5-C 15 heteroaryl; R3 and R4 are independently selected from hydrogen, deuterium, tritium, or C1-C 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; Or R3, R4 and the carbon atoms adjacent to them together form a C3-C substituted by n R8 10 Cycloalkyl or C3-C 10 Heterocycloalkyl; X is optionally selected from -CO-, -SO-, -SO2-, -CHR8-, or R5 and R6 are independently selected from hydrogen or C1-C6 substituted by n R8 15 Chain alkyl, C1-C 15 Heterochain alkyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; R7 is optionally selected from C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C5-C 15 Aryl, C5-C 15 heteroaryl; R8 is selected from hydrogen, deuterium, tritium, halogen, oxydeoxy, -CN, -NO2, -OR9, -NR9R 10 , -SR9, -COR9, -SOR9, -SO2R9, -NR9COR 10 、-CONR9R 10 , -OCOR9, -COOR9, -OCOOR9, -OCONR9R 10 、-NR9CONR 10 R 11 、-NR9COOR 10 、-NR9SO2R 10 、-SO2NR9R 10 , -OSO2R9, -SO3R9, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of n R 12 replace; R9, R 10 , R 11 are independently selected from hydrogen, deuterium, tritium, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by n halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl; R 12 is selected from hydrogen, deuterium, tritium, 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 n halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl; n＝0-8。 2. A compound of formula (II), or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof: in, R1 is C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 cycloalkyl, or 3-15 membered heterocycloalkyl; optionally, the C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 The cycloalkyl or 3-15 membered heterocycloalkyl is substituted by a substituent selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and carbonyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; R2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; R3 is C1-C6 alkyl or C1-C6 deuterated alkyl; preferably, R3 is methyl or deuterated methyl; When R2 is methyl, R1 is not unsubstituted phenyl; Preferably, C * The carbon atoms are in R or S configuration; more preferably, C * The carbon atom is in S configuration; Preferably, C ** The carbon atoms are in R or S configuration; more preferably, C ** The carbon atom is in R configuration.

3. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R1 is C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, the C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl is substituted with a substituent selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and carbonyl; and the 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S.

4. The compound of claim 3, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R1 is 5. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R2 is C1-C4 alkyl, hydroxy C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; wherein the 5-6 membered heteroaryl contains 1 or 2 heteroatoms selected from N, O and S.

6. The compound of claim 5, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R2 is methyl, 7. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein: R1 is C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, the C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl is substituted by a substituent selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and carbonyl; the 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S; R2 is C1-C4 alkyl, hydroxy C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 or 2 heteroatoms selected from N, O and S.

8. The compound of claim 7, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein: R1 is R2 is methyl, 9. A compound of formula (III), or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof: in R1 is C3-C 15 Aryl or 3-15 membered heteroaryl; the 3-15 membered heteroaryl contains 1-4 heteroatoms selected from N, O and S; R2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; R3 is C3-C 15 Aryl, 3-15 membered heteroaryl, C3-C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O and S; optionally, the 3-15 membered heterocycloalkyl is substituted by carbonyl; Preferably, C * The carbon atoms are in R or S configuration; more preferably, C * The carbon atom is in S configuration; Preferably, C ** The carbon atoms are in R or S configuration; more preferably, C ** The carbon atom is in R configuration.

10. The compound of claim 9, or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R1 is a C5-C6 aryl group or a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms; R2 is a C1-C4 alkyl group; R3 is C5-C6 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl, or 5-6 membered heterocycloalkyl; the 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S.

11. The compound of claim 10, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R1 is R2 is methyl; R3 is 12. A compound of formula (IV), or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof: in R1 is a C5-C6 aryl group or a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms; R2 and R3 are each independently H or C1-C6 alkyl and are not H or C1-C6 alkyl at the same time; or R2, R3 and the carbon atom to which they are connected form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and S; X1 is C or S; R4, R5 and the X1 atom to which they are connected form a carbonyl group or a sulfone group, a C3-C6 cycloalkyl group or a 3-6-membered heterocycloalkyl group; the 3-6-membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from O and S; R6 is H or C1-C6 alkyl; Preferably, C * The carbon atoms are in R or S configuration; more preferably, C * The carbon atom is in S configuration; Preferably, C ** The carbon atoms are in R or S configuration; more preferably, C ** The carbon atom is in R configuration.

13. The compound of claim 12, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein the formula (IV) is: in, R1 is a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms; R2 and R3 are each independently H or C1-C6 alkyl and are not H or C1-C6 alkyl at the same time; or R2, R3 and the carbon atom to which they are connected form a C3-C4 cycloalkyl group; R4, R5 and the carbon atom to which they are connected form a carbonyl group or a 3-5 membered heterocycloalkyl group; the 3-5 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from O and S.

14. The compound of claim 12, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein the formula (IV) is: in R1 is a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms; R2 is a C1-C4 alkyl group.

15. A compound, or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, selected from:

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

17. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

18. Use of the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, the pharmaceutical composition of claim 16, or the pharmaceutical preparation of claim 17 in the preparation of a medicament for treating and / or preventing depression.

19. Use of the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, the pharmaceutical composition of claim 16, or the pharmaceutical preparation of claim 17 in the preparation of a fast-acting drug for treating and / or preventing depression.

20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, a pharmaceutical composition according to claim 16, or a pharmaceutical preparation according to claim 17 in the preparation of a medicament for treating and / or preventing dysphoria, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, bulimia, obesity, drug abuse, alcoholism, tobacco addiction, obsessive-compulsive disorder, panic disorder, premenstrual syndrome, migraine, bipolar disorder, neuropathic pain, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease and vasomotor symptoms or hot flashes.

21. The use according to claim 20, wherein the neuropathic pain is chronic pain.

22. The use according to claim 21, wherein the chronic pain is fibromyalgia.

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