Amide compound and application thereof

Abstract

The invention discloses a lactam ring compound and application thereof. The lactam ring compound has a rapid anti-depression effect.

Description

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 use. Background Art

[0002] Depression is a common mental illness with significant and persistent low mood as its main clinical feature. Clinically, it can be seen that the mood is low and disproportionate to the situation. The depressed mood can range from melancholy to grief, inferiority and depression, and even pessimism and world-weariness. In severe cases, psychotic symptoms such as hallucinations and delusions may occur.

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

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

[0005] However, the commonly used antidepressants in clinical practice still have serious limitations, mainly slow and delayed onset of action, requiring 3 to 4 weeks of continuous medication to take effect. Many patients give up treatment when they cannot 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 (several 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 deficiencies 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]

[0008] in,

[0009] R 1 , R 2 Each independently selected from hydrogen, R 8 -(CO)-, R 8 -(SO)-, R 8 -(SO 2 )-、R 8 -O(CO)-、R 8 R 9 -N(CO)-, or n R 8 Substituted C 1 -C 15 Chain alkyl, C 1 -C 15 Heterochain alkyl, C 3 -C 15 Cycloalkyl, C 3 -C 15 Heterocycloalkyl, C 5 -C 15 Aryl, C 5 -C 15 heteroaryl;

[0010] or R 1 , R 2 Together with the nitrogen atoms adjacent to them, they form a group consisting of n R 8 Substituted C 3 -C15 Heterocycloalkyl or C 5 -C 15 heteroaryl;

[0011] R 3 , R 4 Each independently selected from hydrogen, deuterium, tritium, or n R 8 Substituted C 1 -C 15 Chain alkyl, C 1 -C 15 Heterochain alkyl, C 3 -C 15 Cycloalkyl, C 3 -C 15 Heterocycloalkyl, C 5 -C 15 Aryl, C 5 -C 15 heteroaryl;

[0012] or R 3 , R 4 Together with their adjacent carbon atoms, they form a group consisting of n R 8 Substituted C 3 -C 10 Cycloalkyl or C 3 -C 10 Heterocycloalkyl;

[0013] X is selected from -CO-, -SO-, -SO 2 -、-CHR 8 -,or

[0014] R 5 , R 6 Each independently selected from hydrogen or n R 8 Substituted C 1 -C 15 Chain alkyl, C 1 -C 15 Heterochain alkyl, C 3 -C 15 Cycloalkyl, C 3 -C 15 Heterocycloalkyl, C 5 -C 15 Aryl, C 5 -C 15 heteroaryl;

[0015] R 7 Choose from n R 8 Substituted C 3 -C 15 Cycloalkyl, C 3 -C 15Heterocycloalkyl, C 5 -C 15 Aryl, C 5 -C 15 heteroaryl;

[0016] R 8 Selected from hydrogen, deuterium, tritium, halogen, oxydimide, -CN, -NO 2 、-OR 9 、-NR 9 R 10 、-SR 9 、-COR 9 、-SOR 9 、-SO 2 R 9 、-NR 9 COR 10 、-CONR 9 R 10 、-OCOR 9 、-COOR 9 、-OCOOR 9 、-OCONR 9 R 10 、-NR 9 CONR 10 R 11 、-NR 9 COOR 10 、-NR 9 SO 2 R 10 、-SO 2 NR 9 R 10 、-OSO 2 R 9 、-SO 3 R 9 , linear alkyl, hetero-linear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each linear alkyl, hetero-linear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of n R 12 replace;

[0017] R 9 , 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, sulfonate, sulfonamide, alkyl or haloalkyl;

[0018] R 12is 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;

[0019] n is an integer from 0 to 8 (eg, 0, 1, 2, 3, 4, 5, 6, 7, or 8).

[0020] 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:

[0021]

[0022] in

[0023] R 1 C 3 -C 15 Aryl, 3-15 membered heteroaryl, C 3 -C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl; optionally, the C 3 -C 15 Aryl, 3-15 membered heteroaryl, C 3 -C 15 Cycloalkyl, or 3-15 membered heterocycloalkyl is selected from halogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 The 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl group contains 1-4 heteroatoms selected from N, O and S;

[0024] R 2 C 1 -C 6 Alkyl, hydroxyl C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1-C 6 Alkylamino, C 3 -C 15 Aryl, 3-15 membered heteroaryl, C 3 -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;

[0025] R 3 C 1 -C 6 Alkyl or C 1 -C 6 Deuterated alkyl;

[0026] When R 2 When it is methyl, R 1 is not an unsubstituted phenyl group;

[0027] C * The carbon atom is in R or S configuration;

[0028] C ** The carbon atoms are in R or S configuration.

[0029] In one or more embodiments, R 3 It is methyl or deuterated methyl.

[0030] In one or more embodiments, C * The carbon atom is in S configuration.

[0031] In one or more embodiments, C ** The carbon atom is in R configuration.

[0032] In one or more embodiments, R 1 C 5 -C 6 Aryl, 5-6 membered heteroaryl, C 5 -C 6 Cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, the C 5 -C 6 Aryl, 5-6 membered heteroaryl, C 5 -C 6 Cycloalkyl, or 5-6 membered heterocycloalkyl is selected from halogen, C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4The 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N, O and S.

[0033] In one or more embodiments, wherein R 1 for

[0034] In one or more embodiments, R 2 C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Alkylamino, C 3 -C 6 Cycloalkyl, C 5 -C 6 The 5-6 membered heteroaryl group comprises 1 or 2 heteroatoms selected from N, O and S.

[0035] In one or more embodiments, R 2 Methyl,

[0036] In one or more embodiments, R 1 C 5 -C 6 Aryl, 5-6 membered heteroaryl, C 5 -C 6 Cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, the C 5 -C 6 Aryl, 5-6 membered heteroaryl, C 5 -C 6 Cycloalkyl, or 5-6 membered heterocycloalkyl is selected from halogen, C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 The 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N, O and S;

[0037] R2 C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Alkylamino, C 3 -C 6 Cycloalkyl, C 5 -C 6 The 5-6 membered heteroaryl group comprises 1 or 2 heteroatoms selected from N, O and S.

[0038] In one or more embodiments, R 1 for R 2 Methyl,

[0039] 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:

[0040]

[0041] in

[0042] R 1 C 3 -C 15 Aryl or 3-15 membered heteroaryl; the 3-15 membered heteroaryl contains 1-4 heteroatoms selected from N, O and S;

[0043] R 2 C 1 -C 6 Alkyl, hydroxyl C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 3 -C 15 Aryl, 3-15 membered heteroaryl, C 3 -C 15Cycloalkyl, 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;

[0044] R 3 C 3 -C 15 Aryl, 3-15 membered heteroaryl, C 3 -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.

[0045] In one or more embodiments, C * The carbon atoms are in R or S configuration.

[0046] In one or more embodiments, C * The carbon atom is in S configuration.

[0047] In one or more embodiments, C ** The carbon atoms are in R or S configuration.

[0048] In one or more embodiments, C ** The carbon atom is in R configuration.

[0049] In one or more embodiments, R 1 C 5 -C 6 Aryl or 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 or 2 N heteroatoms; R 2 C 1 -C 4 Alkyl; R 3 C 5 -C 6 Aryl, 5-6 membered heteroaryl, C 3 -C 6 The 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N, O and S.

[0050] In one or more embodiments, wherein R 1 for R 2 is methyl; R 3 for

[0051] 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:

[0052]

[0053] in

[0054] R 1 C 5 -C 6 Aryl or 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 or 2 N heteroatoms;

[0055] R 2 , R 3 Each is independently H or C 1 -C 6 Alkyl and not H or C 1 -C 6 Alkyl; or R 2 , R 3 The carbon atom to which it is attached forms a C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and S;

[0056] X 1 is C or S;

[0057] R 4 , R 5 X connected to it 1 Atoms form a carbonyl group or a sulfone group, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and S;

[0058] R 6 H or C 1 -C 6 alkyl.

[0059] In one or more embodiments, C * The carbon atoms are in R or S configuration.

[0060] In one or more embodiments, C * The carbon atom is in S configuration.

[0061] In one or more embodiments, C ** The carbon atoms are in R or S configuration.

[0062] In one or more embodiments, C** The carbon atom is in R configuration.

[0063] In one or more embodiments, the formula (IV) is:

[0064]

[0065] in,

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

[0067] R 2 , R 3 Each is independently H or C 1 -C 6 Alkyl and not H or C 1 -C 6 Alkyl; or R 2 , R 3 The carbon atom to which it is attached forms C 3 -C 4 Cycloalkyl;

[0068] R 4 , R 5 The carbon atom to which it is connected forms 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.

[0069] In one or more embodiments, the formula (IV) is:

[0070]

[0071] in

[0072] R 1 is a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 or 2 N heteroatoms;

[0073] R 2 C 1 -C 4 alkyl.

[0074] 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:

[0075]

[0076] 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.

[0077] 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.

[0078] 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 preparation of the present application in the preparation of a drug for treating and / or preventing depression.

[0079] 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 preparation of the present application in the preparation of a fast-acting drug for treating and / or preventing depression.

[0080] 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 preparation of the present application in the preparation of a drug 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.

[0081] In one or more embodiments, the neuropathic pain is chronic pain.

[0082] In one or more embodiments, the chronic pain is fibromyalgia.

[0083] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0084] One or more embodiments of the present application provide the pharmaceutical composition of the present application, which is used as a medicament.

[0085] One or more embodiments of the present application provide the pharmaceutical preparation of the present application, which is used as a medicament.

[0086] 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.

[0087] 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.

[0088] One or more embodiments of the present application provide a method for preventing and / or treating depression, which comprises administering the compound, pharmaceutical composition or pharmaceutical preparation of the present application to a subject in need thereof.

[0089] One or more embodiments of the present application provide a method for preventing and / or rapidly treating depression, which comprises administering the compound, pharmaceutical composition or pharmaceutical preparation of the present application to a subject in need thereof.

[0090] One or more embodiments of the present application provide the use of the compound, pharmaceutical composition or pharmaceutical preparation 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.

[0091] One or more embodiments of the present application also provide a pharmaceutical composition or pharmaceutical preparation comprising the compound of the present application. For example, the compound of the present application can be administered in pure form, in combination with other active ingredients, or in combination with a pharmaceutically acceptable non-toxic excipient or carrier.

[0092] The following is an explanation of the terms used in the technical solution of the present application. As used in the specification and the appended claims, unless otherwise specifically stated, the terms of the present application have the following meanings.

[0093] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0094] The term "amino" refers to -NH 2 .

[0095] The term "hydroxy" refers to -OH.

[0096] "Alkyl" refers to a straight 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 further 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 the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

[0097] "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.

[0098] "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 further preferably an alkynyl group of 1 to 4 carbon atoms.

[0099] "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 optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be attached to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of “heterocyclyl” or “heterocycle” include oxirane, oxirane, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, piperidinyl, homopiperidinyl, pyridinyl, piperidinyl, piperidinyl, py ... pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, py pyranyl, thiophene, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, oxazolyl, benzopyridyl, pyrrolopyridyl, 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]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

[0100] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 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 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, such as a 5-8 membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. Heteroaryl can be connected to a heteroatom or a carbon atom, and can be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted by one or more substituents.

[0101] "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), and the ring carbon atoms are preferably 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When the cycloalkyl is substituted, it can be optionally further substituted by one or more substituents.

[0102] "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 a monocyclic, fused, bridged or spirocyclic ring.

[0103] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring of 3 to 8 carbons (e.g., 3, 4, 5, 6, 7, 8 carbons), a bicyclic ring of 5 to 12 carbons (e.g., 5, 6, 7, 8, 9, 10, 11, 12 carbons), or a tricyclic ring system of 10 to 15 carbons (e.g., 10, 11, 12, 13, 14, 15 carbons), which can be a bridged ring or a spirocyclic ring, non-limiting examples include phenyl and naphthyl. The aryl group can be optionally further substituted by one or more substituents.

[0104] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with 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.

[0105] Unless otherwise indicated, the term "optionally substituted" refers to groups wherein hydrogen atoms are not substituted or one or more hydrogen atoms are substituted 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.

[0106] "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, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0107] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0108] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0109] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure states of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including both binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0110] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0111] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.

[0112] 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 specified, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms or mixtures thereof. The compounds containing asymmetric carbon atoms herein can be isolated in optically pure forms or racemic forms. 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 isomeric forms, which refer to forms in which the substituents on the double bonds or rings of the compound have different cis-trans isomers without chirality. The "compound" described herein also includes tautomeric forms. Tautomeric forms can be derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0113] The compounds herein, whether intermediates or compounds of formula (I), can also be isotopically labeled by replacing one or more atoms therein 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.

[0114] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared from the compounds having specific substituents discovered in the present invention and pharmaceutically acceptable acids or bases.

[0115] 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, and representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc.

[0116] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Part IV or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0117] "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.

[0118] In one or more embodiments, the compounds of the present application are more active than existing rapid antidepressant compounds. For example, compared with existing compounds (compound ZZL-7), the compounds of the present application have excellent rapid antidepressant activity in vivo, and their drugability (metabolic stability, AUC, bioavailability, etc.) is significantly better. BRIEF DESCRIPTION OF THE DRAWINGS

[0119] Figure 1 This is the result of the forced swimming test of in vivo efficacy test 1 of active example 3.

[0120] Figure 2 The results of the tail suspension experiment of in vivo efficacy test 1 of active example 3 are shown in FIG.

[0121] Figure 3 The following are the results of the tail suspension experiment of in vivo efficacy test 2 of active example 3. DETAILED DESCRIPTION

[0122] The present application is further described below in conjunction with the embodiments, and the implementation details of the present application are given, but it should be noted that the embodiments described below are exemplary and are only used to explain the present application, and cannot be construed as limiting the present application. It is still within the protection scope 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 present application embodiments can all be obtained commercially.

[0123] Preparation Example

[0124] Preparation Example 1 Preparation of Compound 1

[0125]

[0126] first step

[0127] (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 1,4-dioxane (50 mL) / water (10 mL) of benzyloxycarbonyl succinimide (12.0 g, 48 mmol) was slowly added thereto. The reaction solution was reacted at 25°C for 16 hours. After the reaction was completed, ethyl acetate was added for dilution (200 mL), and then washed with 5% sodium bicarbonate solution and 5% citric acid solution respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product (S)-(1-hydroxy-3-methylbutan-2-yl)carbamic acid benzyl ester 1-2 (10.4 g, white solid, yield 87%). The crude product was directly used for the next step reaction without further purification. MS m / z (ESI): 238.1 [M+H] + .

[0128] Step 2

[0129] (S)-(1-hydroxy-3-methylbutyl-2-yl)benzyl carbamate 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 diatomaceous earth, and the filtrate was concentrated to obtain a crude product (S)-(3-methyl-1-oxobutyl-2-yl)benzyl carbamate 1-3 (7.0 g, white solid), with a yield of 91%. The crude product was directly used in the next step without further purification. MSm / z(ESI): 236.1[M+H] + .

[0130] Step 3

[0131] (S)-(3-methyl-1-oxobutan-2-yl)benzyl carbamate 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, and the temperature was maintained below 10°C during the addition. The reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was poured into ice water, and the precipitated solid was collected by filtration. The filter cake was washed with water and dried to obtain a crude product (S)-(1-(1H-imidazole-2-yl)-2-methylpropyl)benzyl carbamate 1-4 (5.0 g, white solid) with a yield of 60%. The crude product was directly used in the next step without further purification. MS m / z(ESI): 274.1[M+H] + .

[0132] Step 4

[0133] (S)-(1-(1H-imidazole-2-yl)-2-methylpropyl)carbamic acid benzyl ester 1-4 (3.0 g, 11 mmol) was dissolved in methanol (75 mL), followed by addition of palladium carbon (0.3 g, 10 wt.%). The mixture was ventilated with hydrogen three times, and the reaction solution was reacted at 25° C. for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product (S)-1-(1H-imidazole-2-yl)-2-methylpropan-1-amine 1-5 (1.2 g, white solid) with a yield of 71%. MS m / z (ESI): 140.1 [M+H] + .

[0134] Step 5

[0135] (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), and 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 solution was stirred at 0°C for 3 hours. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column (dichloromethane / methanol=15 / 1) and then purified by reverse preparation to obtain (R)-N-((S)-1-(1H-imidazole-2-yl)-2-methylpropyl)-2-acetylaminopropaneamide 1 (0.6 g, white solid) with a yield of 32%. MS m / z (ESI): 253.0 [M+H] + .

[0136] 1 H NMR (400 MHz, DMSO-d 6 )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=7.2H z, 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).

[0137] Preparation Example 2 Preparation of Compound 2

[0138]

[0139] first step

[0140] Compound 2-1 (4.18 g, 38.0 mmol) was dissolved in dichloromethane (40 mL), and compound 2-2 (4.74 g, 39.1 mmol) and cesium carbonate (14.86 g, 45.5 mmol) were added to the solution, and the reaction was stirred at 25°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase was 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] + .

[0141] Step 2

[0142] Compound 2-3 (7.3 g, 34.2 mmol) was dissolved in tetrahydrofuran (50 mL), the reaction system was replaced with nitrogen three times, and then the temperature was lowered to -60 ° C. At this temperature, a tetrahydrofuran solution of isopropyl magnesium bromide (68.4 mL, 68.4 mmol, 1 M) was slowly added dropwise to the reaction solution, and the reaction was slowly heated to 25 ° C and stirred for 12 hours. The reaction was quenched with a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase was petroleum ether and ethyl acetate (V / V = 3: 1)) to obtain the target product 2-4 (1.95 g, white solid, 19.88%). MS (ESI) m / z: 258.1 [M+H] + .

[0143] Step 3

[0144] Compound 2-4 (1.95 g, 7.6 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of hydrogen chloride in 1,4-dioxane (9.5 mL, 38 mmol, 4 M) was added dropwise to the solution. The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product 2-5 (1.33 g, white solid, 88.16%) was used directly in the next step without purification. MS (ESI) m / z: 154.1 [M+H] + .

[0145] Step 4

[0146] 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 to the solution in sequence, and the reaction was stirred at 25°C for 1 hour, and then compound 2-5 (1.33 g, 8.1 mmol) was added to the reaction solution, and the reaction was continued to stir for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase was petroleum ether and ethyl acetate (V / V=1:1)) and SFC (CHIRALPAK AD-H 250 mm×20 mm, 5 μm, 40% MeOH (NH 4 OH 0.2%): 60%CO 2 ) to obtain 2. MS (ESI) m / z: 267.0 [M+H] + .

[0147] 1 H NMR (400 MHz, CD 3 OD) 66.95 (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).

[0148] Preparation Example 3 Preparation of Compound 3

[0149]

[0150] first step

[0151] 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, the filtrate was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with an eluent of petroleum ether and ethyl acetate (V / V=5:1) to obtain the target product 3-2 (2 g, colorless liquid, 73.0%). MS (ESI) m / z: 229.1 [M+H] + .

[0152] Step 2

[0153] At -78°C, under nitrogen protection, a solution of isopropylmagnesium bromide in tetrahydrofuran (15 mL) was added dropwise with isopropylmagnesium bromide (11.80 mL, 1N, 11.80 mmol) and 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), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V=4:1) to obtain the target product 3-3 (650 mg, colorless liquid, 30.4%). MS (ESI) m / z: 273.0 [M+H] + .

[0154] Step 3

[0155] At 0°C, HCl / dioxane (3 mL, 4N, 12 mmol) was added to a solution of compound 3-3 (650 mg, 2.39 mmol) in tetrahydrofuran (40 mL), 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 target product 3-4 (500 mg, off-white solid, 100%). MS (ESI) m / z: 169.1 [M+H] + .

[0156] Step 4

[0157] At 0°C, 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), 3-4 (500 mg, 2.97 mmol) were added to a solution of compound 2-6 (388 mg, 2.97 mmol) in dichloromethane (30 mL) 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 residue was purified by silica gel column chromatography with dichloromethane and methanol (V / V=20:1) as eluent and freeze-dried to obtain the target product (585 mg, white solid, 70.0%). MS (ESI) m / z: 282.0 [M+H] + .

[0158] 1 H NMR (400 MHz, CD 3OD) 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).

[0159] Preparation Example 4 Preparation of Compound 4

[0160]

[0161] first step

[0162] 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 mixture was cooled 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 eluent petroleum ether and ethyl acetate (V / V = 1: 1) to obtain the target product 4-2 (3.45 g, colorless oil, 63.1%). MS (ESI) m / z: 311.0 [M+H] + .

[0163] Step 2

[0164] 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, and benzoyloxycarbonyl 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 an eluent of petroleum ether and ethyl acetate (V / V=2:1) ​​to obtain the target product 4-3 (3.61 g, colorless oil, 72.9%). MS (ESI) m / z: 445.2 [M+H] + .

[0165] Step 3

[0166] 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, the reaction was stirred at 20°C for 1 hour, saturated sodium bicarbonate solution was added to the reaction solution, the pH value was adjusted to 9, and dichloromethane was extracted (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] + .

[0167] Step 4

[0168] 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), and 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 eluent dichloromethane and methanol (V / V=15:1) to obtain the target product 4-6 (350 mg, colorless oil, 12.4%). MS (ESI) m / z: 422.1 [M+H] + .

[0169] Step 5

[0170] Compound 4-6 (350 mg, 0.82 mmol) was dissolved in tert-butyl alcohol (20 mL), and then Pd / C (120 mg) was added to the reaction solution. The hydrogen was replaced three times, and the reaction solution was stirred at 20°C for 16 hours after hydrogen was introduced. The filtrate was concentrated under reduced pressure and analyzed by high performance liquid chromatography [CH 3 CN-H 2 O (0.1% TFA), CH 3 CN (30%-70%)] and lyophilized to obtain the target product 4 (180.79 mg, white solid, 86.1%). MS (ESI) m / z: 288.2 [M+H] + .

[0171] 1 H NMR (400 MHz, CDCl 3)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).

[0172] Preparation Example 5 Preparation of Compound 5

[0173]

[0174] first step

[0175] 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 an eluent of petroleum ether and ethyl acetate (V / V=10:1) to obtain the target product 5-3 (7 g, white oil, 42%). MS (ESI) m / z: 176.0 [M+H] + .

[0176] Step 2

[0177] 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 the reaction 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, extracted with ethyl acetate (50 mL×3), and the organic phases were combined and washed with saturated sodium bicarbonate solution (10 mL×2), saturated ammonium chloride solution (10 mL×2), and saturated sodium chloride solution (10 mL×2) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane and methanol (V / V=10:1) as eluent to obtain the target product 5-4 (1 g, white solid, 90.1%). MS (ESI) m / z: 245.2 [M+H] + .

[0178] Step 3

[0179] At 0°C, add 1,4-dioxane hydrochloride solution (10 mL) to compound 5-4 (1 g, 4.10 mmol), and stir the reaction 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] + .

[0180] Step 4

[0181] 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), 1-hydroxybenzotriazole (593 mg, 4.39 mmol) were dissolved in dichloromethane (30 mL) solution. 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 with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated sodium chloride solution (10 mL × 2) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The reaction mixture was purified by reverse column (CH 3 CN-H 2 O (0.1% TFA), CH 3 CN (30%-70%)) and lyophilized to obtain the target product 5 (340 mg, white solid, 80.7%). MS (ESI) m / z: 316.1 [M+H] + .

[0182] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0183] Preparation Example 6 Preparation of Compound 6

[0184]

[0185] first step

[0186] The compound 2-iodopyrimidine (2 g, 9.71 mmol) was dissolved in dichloromethane (30 mL) solution, and then the reaction solution was cooled to -78 ° C, and n-butyl lithium (2.4 M, 4 mL, 9.6 mmol) was added. After stirring the reaction for 30 minutes, 5-3 (1.7 g, 9.71 mmol) 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, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed 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 with dichloromethane and methanol (V / V=10:1) as eluent to obtain the target product 6-1 (500 mg, yellow oil, 22.5%). MS (ESI) m / z: 256.1 [M+H] + .

[0187] Step 2

[0188] At 0°C, add 1,4-dioxane hydrochloride (10 mL) solution to compound 6-1 (500 mg, 1.96 mmol), and stir the reaction at 0°C for 1 hour. Filter and filter the cake to obtain the target product 6-2 (320 mg, yellow oil, 57.6%). MS (ESI) m / z: 152.2 [M+H] + .

[0189] Step 3

[0190] 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-di-isopropylethylamine (1367 mg, 10.58 mmol), 1-hydroxybenzotriazole (429 mg, 3.17 mmol) were dissolved in dichloromethane (30 mL) solution. 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 with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated sodium chloride solution (10 mL × 2) in sequence, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The reaction mixture was purified by reverse column [CH 3 CN-H 2 O (0.1% TFA), CH 3 CN (30%-70%)] and the resulting residue was purified and freeze-dried to obtain the target product 6 (230 mg, white solid, 64.7%). MS (ESI) m / z: 327 [M+H] + .

[0191] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0192] Preparation Example 7 Preparation of Compound 7

[0193]

[0194] At 0°C, 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) were added to a solution of compound 5-6 (500 mg, 2.59 mmol) in dichloromethane (20 mL) in sequence. The reaction was stirred at 0°C for 2 hours. The reaction solution was rotary evaporated to dryness, and the residue was purified by silica gel column chromatography with dichloromethane and methanol (V / V=10:1) as eluent. The crude product was purified by column chromatography using a preparative plate (developing solvent: dichloromethane: methanol=10:1) and lyophilized to obtain the target product 7 (425 mg, white solid, 52.3%). MS (ESI) m / z: 315.2 [M+H] + .

[0195] 1 H NMR (400 MHz, CD 3 OD) 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).

[0196] Preparation Example 8 Preparation of Compound 8

[0197]

[0198] In a 200mL single-necked bottle, add compound 5-5 (2.2g, 15.69mmol), compound 8-1 (3.3g, 17.26mmol), add dichloromethane (100mL), cool to -10°C, slowly add N,N-diisopropylethylamine (10.14g, 78.45mmol), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5g, 23.54mmol), add 1-hydroxybenzotriazole (3.2g, 23.54mmol), and react at -10°C for 2 hours. After monitoring by LCMS and TLC, the reaction was shown to be complete, and water was added to quench the reaction. 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 chromatographed on a silica gel column (ethyl acetate: dichloromethane=3:1) to give compound 8 (1.4 g, 4.44 mmol, yield 28.29%).

[0199] ESI-LCMS: m / z 316.2 [M+H]+.

[0200] 1 H NMR (400 MHz, DMSO-d 6 )68.91 (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).

[0201] Preparation Example 9 Preparation of Compound 9

[0202]

[0203] In a 200 mL single-necked bottle, compound 5-5 (2.1 g, 14.98 mmol), compound 9-1 (3.18 g, 16.48 mmol), and dichloromethane (100 mL) were added, and 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 mixture was reacted at -20°C for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (ethyl acetate: dichloromethane=3:1) to give compound 9 (605 mg, 1.92 mmol, yield 12.8%).

[0204] ESI-LCMS: m / z 316.2 [M+H] + .

[0205] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0206] Preparation Example 10 Preparation of Compound 10

[0207]

[0208] first step

[0209] Compound 10-1 (1.00 g, 8.06 mmol) was dissolved in dichloromethane (15 mL), and 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, after the reaction was completed, dichloromethane (50 mL) was added to the reaction solution, and then washed 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, concentrated under reduced pressure, and 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] + .

[0210] Step 2

[0211] Compound 10-2 (1.70 g, 7.48 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction system was replaced with nitrogen three times, and then the temperature was lowered to -60 ° C. At this temperature, a tetrahydrofuran solution of isopropylmagnesium bromide (8.13 mL, 18.70 mmol, 2.3 M) was slowly added dropwise to the reaction solution, and the reaction was slowly heated to 25 ° C and stirred for 3 hours. TLC and LCMS monitoring, after the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target product 10-3 (950 mg, 3.50 mmol, white solid, 46%). MS (ESI) m / z: 272.3 [M+H] + .

[0212] Step 3

[0213] Compound 10-3 (0.95 g, 3.50 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.4 mL, 17.5 mmol, 4 M) was added dropwise to the solution. The reaction was stirred at 25 ° C for 1 hour and monitored by TLC and LCMS. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product 10-4 (0.58 g, 3.47 mmol, yellow solid) was directly used for the next step without purification. MS (ESI) m / z: 168.2 [M+H] + .

[0214] Step 4

[0215] Compound 10-4 (0.58 g, 2.86 mmol) was dissolved in dichloromethane (10 mL), and 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 to the solution in sequence. The reaction was stirred at -20 °C for 3 hours and monitored by TLC and LCMS. After the reaction was completed, dichloromethane (50 mL) was added to the reaction solution, and then washed with water once (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 concentrated under reduced pressure by silica gel column chromatography. The obtained crude product was purified by silica gel column chromatography to obtain the product (0.20 g, 0.71 mmol white solid, 20%). MS (ESI) m / z: 281.1 [M+H] + .

[0216] 1 H NMR (400 MHz, DMSO-d 6 )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, 1 H), 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).

[0217] Preparation Example 11 Preparation of Compound 11

[0218]

[0219] first step:

[0220] Compound 11-1 (1.40 g, 10.0 mmol) was dissolved in dichloromethane (20 mL), and compound 5-2 (1.57 g, 13.00 mmol) and cesium carbonate (6.50 g, 20.00 mmol) were added to the reaction solution, stirred at room temperature overnight, monitored by TLC, and after the reaction was completed, filtered, the filter cake was washed with 20 mL of dichloromethane, 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] + .

[0221] Step 2:

[0222] Compound 11-2 (2.14 g, 8.80 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction system was replaced with nitrogen three times, and then the temperature was lowered to below -60 ° C, and a tetrahydrofuran solution of isopropyl magnesium bromide (4.7 mL 2.8 mol / L) was slowly added dropwise. After the addition was complete, the mixture was kept warm for 1 h, and the temperature was slowly raised to room temperature and stirred for 12 hours. The reaction was monitored by TLC to complete. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was slowly added dropwise to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried with anhydrous sodium sulfate, mixed with silica gel, and separated by column chromatography to obtain compound 11-3 (1.50 g, 5.22 mmol, yield: 59%). MS-ESI: M / Z = 288.2 [M+H] + .

[0223] Step 3:

[0224] Compound 11-3 (1.50 g, 5.22 mmol) was added to tetrahydrofuran (15 mL), and 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 a crude hydrochloride product of compound 11-4 (1.03 g, 4.70 mmol, yield: 85%). MS-ESI: M / Z=183.1[M+H] + .

[0225] Step 4:

[0226] Compound 11-4 (224 mg, 1.02 mmol) and N-acetyl-D-alanine (160 mg, 1.22 mmol) were added to a reaction bottle containing dichloromethane (15 mL), cooled to -20 ° C, HATU (463 mg, 1.22 mmol) and N, N-diisopropylethylamine (263 mg, 2.04 mmol) were slowly added, the temperature was maintained, stirring was continued, and the reaction was monitored by TLC and LCMS. After the reaction was completed, water (20 mL) was added, the layers were separated, 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] + .

[0227] 1 H NMR (400 MHz, DMSO-d 6)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).

[0228] Preparation Example 12 Preparation of Compound 12

[0229]

[0230] first step:

[0231] 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, stirred overnight at room temperature, monitored by TLC, and after the reaction was completed, filtered, the filter cake was washed with 20 mL of dichloromethane, 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] + .

[0232] Step 2:

[0233] 12-2 (2.25 g, 9.41 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction system was replaced with nitrogen three times, and then the temperature was lowered to below -60 ° C, and a tetrahydrofuran solution of isopropyl magnesium bromide (5.0 mL, 2.8 mol / L) was slowly added dropwise. After the addition was complete, the mixture was kept warm for 1 h, and the temperature was slowly raised to room temperature and stirred for 12 hours. The reaction was monitored by TLC to complete. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was slowly added dropwise to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL × 3), dried with anhydrous sodium sulfate, mixed with silica gel, and separated by column chromatography to obtain compound 12-3 (0.45 g, 1.59 mmol, yield: 15%). MS-ESI: M / Z = 284.1 [M+H] + .

[0234] Step 3:

[0235] Compound 12-3 (0.45 g, 1.59 mmol) was added to tetrahydrofuran (15 mL), and 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] + .

[0236] Step 4:

[0237] Compound 12-4 (215 mg, 1.00 mmol) and compound 2-6 (179 mg, 1.37 mmol) were added to a reaction bottle containing dichloromethane (15 mL), cooled to -20 ° C, HATU (456 mg, 1.20 mmol) and N, N-diisopropylethylamine (387 mg, 3.00 mmol) were slowly added, the temperature was maintained, stirring was continued, and the reaction was monitored by TLC and LCMS. After the reaction was completed, water (20 mL) was added, the layers were separated, 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] + .

[0238] 1 H NMR (400 MHz, DMSO-d 6 ) 68.17 (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).

[0239] Preparation Example 13 Preparation of Compound 13

[0240]

[0241] first step

[0242] In a 250 mL single-mouth bottle, compound 13-1 (2.00 g, 21.03 mmol) was dissolved in dichloromethane (40 mL), and 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] + .

[0243] Step 2

[0244] 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 replaced with nitrogen three times, and then the temperature was lowered to -60 ° C. At this temperature, a tetrahydrofuran solution of isopropyl magnesium bromide (20 mL, 40 mmol, 2.0 M) was slowly added dropwise to the reaction solution, and the reaction was slowly heated to 25 ° C and stirred for 12 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction was quenched with a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with a 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 13-3 (1.60 g, 6.60 mmol, yield 77.01%). ESI-LCMS: m / z 243.2 [M+H] + .

[0245] Step 3

[0246] In a 100 mL single-mouth bottle, compound 13-3 (400 mg, 1.65 mmol) was dissolved in a hydrochloric acid dioxane solution (4.0 M, 5 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was concentrated under reduced pressure to obtain a crude product, compound 13-4 (250 mg, 1.43 mmol, yield 86.67%), which was directly used for the next step. ESI-LCMS: m / z 139.1 [M+H] + .

[0247] Step 4

[0248] In a 100 mL single-mouth bottle, compound 2-6 (190 mg, 1.45 mmol) and N, N-diisopropylethylamine (562 mg, 4.35 mmol) were added to a DMF (5 mL) solution of compound 13-4 (250 mg, 1.43 mmol), the temperature was lowered to -10 degrees, HATU (825 mg, 2.17 mmol) was added, and the reaction solution was stirred at -10 degrees for 3 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was diluted with ethyl acetate, washed with a saturated sodium chloride solution (30 mL × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and then purified again by reverse MPLC to obtain product 13 (23 mg, 0.09 mmol, yield 6.29%). ESI-LCMS: m / z 252.2 [M+H] + .

[0249] 1 H NMR (400 MHz, DMSO-d 6 )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 (dd, 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).

[0250] Preparation Example 14 Preparation of Compound 14

[0251]

[0252] first step

[0253] In a 250 mL single-mouth bottle, compound 14-1 (2.00 g, 20.81 mmol) was dissolved in dichloromethane (40 mL), and 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] + .

[0254] Step 2

[0255] In a 250mL three-necked flask, compound 14-2 (2.00g, 10.04mmol) was dissolved in anhydrous tetrahydrofuran (20mL), the reaction system was replaced with nitrogen three times, and then the temperature was lowered to -60°C. At this temperature, a tetrahydrofuran solution of isopropylmagnesium bromide (25mL, 50mmol, 2M) was slowly added dropwise to the reaction solution, and the reaction was slowly heated to 25°C and stirred for 12 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction was quenched with a saturated ammonium chloride solution (100mL), extracted with ethyl acetate (100mE×3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL×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 (2.20g, 9.04mmol, yield 90.04%). ESI-LCMS: m / z 244.2[M+H] + .

[0256] Step 3

[0257] In a 100 mL single-mouth bottle, compound 14-3 (1.00 g, 4.11 mmol) was dissolved in a hydrochloric acid dioxane solution (4.0 M, 10 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was concentrated under reduced pressure to obtain a crude product, compound 14-4 (600 mg, 3.42 mmol, yield 83.21%), which was directly used for the next step. ESI-LCMS: m / z 140.1 [M+H] + .

[0258] Step 4

[0259] In a 100 mL single-necked bottle, compound 5-6 (661 mg, 3.42 mmol) and N,N-diisopropylethylamine (884 mg, 6.84 mmol) were added to a DMF (10 mL) solution of compound 14-4 (600 mg, 3.42 mmol). 3 P (3.26 g, 5.13 mmol, 50% DMF solution), the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was diluted with ethyl acetate, washed with a saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified again by reverse MPLC to obtain the product compound 14 (140 mg, 0.45 mmol, yield 13.16%). ESI-LCMS: m / z 315.2 [M+H] + .

[0260] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0261] Preparation Example 15 Preparation of Compound 1SA and Compound 15B

[0262]

[0263] first step:

[0264] 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), 1-hydroxybenzotriazole (4.6 g, 33.8 mmol) were dissolved in dichloromethane (50 mL) solution. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, and the mixture was washed with saturated sodium bicarbonate solution (50 mL × 2), saturated ammonium chloride solution (50 mL × 2), and saturated sodium chloride solution (50 mL × 2) in sequence, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography with an eluent of petroleum ether and ethyl acetate (V / V = 1:1) to obtain a mixture of the product compound 15-2 (4 g, white solid, 38%). MS (ESI) m / z: 373 [M+H] + .

[0265] Step 2:

[0266] Trifluoroacetic acid / dichloromethane (v / v=1:2) (40 mL) solution was added to compound 15-2 (4 g, 10.7 mol) and stirred at 25°C for 2 hours. The reaction solution was rotary evaporated to dryness and freeze-dried to obtain a mixture of the title product compound 15-3 (4 g, white solid). MS (ESI) m / z: 274 [M+H] + .

[0267] Step 3:

[0268] At 0°C, a mixture of compound 15-3 (4 g, 14.6 mmol) and N,N-diisopropylethylamine (11.3 g, 87.6 mmol) were dissolved in a dichloromethane (40 mL) solution, and then compound 9 (1.4 g, 17.5 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour to react. The mixture was purified by reverse column (acetonitrile-water (0.1% trifluoroacetic acid), acetonitrile (30%-70%)), and the obtained residue was freeze-dried and alkalized to obtain compounds 15A and 15B.

[0269] Compound 15A (1 g, white solid, 22%). MS (ESI) m / z: 319 [M+H] + .

[0270] 1 HNMR (400 MHz, DMSO-d 6 )68.79 (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).

[0271] Compound 15B (1 g, white solid, 22%). MS (ESI) m / z: 319 [M+H] + .

[0272] 1 HNMR (400 MHz, DMSO-d 6 )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).

[0273] Preparation Example 16 Preparation of Compound 16

[0274]

[0275] first step:

[0276] 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, 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, and the reaction solution was stirred at -15°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. Purification was performed 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] + .

[0277] Step 2:

[0278] 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, and after stirring at 20°C for 1 hour, a saturated sodium bicarbonate solution was added to the reaction solution, the pH value was adjusted to 8, and extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with a saturated sodium chloride solution, dried with 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] + .

[0279] Step 3:

[0280] Compound 16-3 (1.38 g, 4.5 mmol) was dissolved in dichloromethane (10 mL) solution, and then N, N-diisopropylethylamine (2.68 g, 20.8 mmol) was added to the reaction solution, nitrogen was replaced three times, the reaction temperature was lowered to 0°C, and compound 5 (0.47 g, 5.7 mmol) was added dropwise thereto. After the reaction solution was stirred at 20°C for 1 hour, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V=3:1) to obtain compound 16 (1.14 g, white solid, 70.2%). MS (ESI) m / z: 313 [M+H] + .

[0281] 1 HNMR (400 MHz, CDCl 3 ) 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, 5.2Hz, 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).

[0282] Preparation Example 17 Preparation of Compound 17

[0283]

[0284] first step:

[0285] 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, extract with dichloromethane (20 mL×3), combine the organic phases, wash with sodium bicarbonate solution (50 mL×2) and saturated sodium chloride solution (50 mL×2) in sequence, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with dichloromethane and ethyl acetate (V / V=1:1) to obtain the title product compound 17-2 (2.6 g, light yellow solid, 87%). MS (ESI) m / z: 368.2 [M+H] + .

[0286] Step 2:

[0287] 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 title product, compound 17-3 (2.7 g, yellow oil, crude product) was obtained by concentration under reduced pressure. MS (ESI) m / z: 268.2 [M+H] + .

[0288] Step 3:

[0289] N, N-diisopropylethylamine (4.59 g, 35.5 mmol) was added to a solution of compound 17-3 (2.7 g, 8.9 mmol) in dichloromethane (20 mL), cooled to 0°C with an ice bath, and deuterated acetyl chloride (0.87 g, 10.65 mmol) was slowly added. The reaction solution was stirred at 25°C for 5 hours. 50 mL of water was added for dilution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2) in sequence, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane and ethyl acetate (V / V = 3:1) as eluent to obtain the title product, which was freeze-dried to obtain the title product compound 17 (960 mg, 42%, light yellow solid). MS (ESI) m / z: 312.9 [M+H] + .

[0290] 1 H NMR (400 MHz, CDCl 3 ) 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=14.5, 8.1Hz, 1H), 0.97 (s, 9H), 0.94 (d, J=6.8Hz, 3H), 0.90 (d, J=6.8Hz, 3H).

[0291] Preparation Example 18 Preparation of Compound ZZL-7

[0292]

[0293] first step:

[0294] In a dry single-necked bottle, add (tert-butoxycarbonyl)-L-alanine (4.5 g, 23.78 mmol), dissolve in dichloromethane (50 mL), place in an ice bath and stir for 10 min, then add L-valine methyl ester (3.12 g, 23.78 mmol), N,N-diisopropylethylamine (6.15 g, 47.56 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.01 g, 26.16 mmol) to the bottle in sequence, and stir at room temperature for 2 h. After TLC showed that the reaction was completed, water (50 mL) was added to quench, and 2M hydrochloric acid was used to adjust to acidity, and dichloromethane (50 mL×2) was used to extract, and the organic phases were combined, and the organic phases were adjusted to alkalinity with saturated sodium bicarbonate, and dichloromethane (50 mL×2) was used to extract, and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (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.

[0295] Step 2:

[0296] Add (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol) to a dry single-mouth bottle, dissolve in dichloromethane (30 mL), then add hydrochloric acid-1.4-dioxane (10 mL, 4 M) to the bottle, and stir at room temperature for 2 h. After TLC shows that the reaction is complete, concentrate the organic phase and purify by silica gel column chromatography (DCM: MeOH = 10: 1) to obtain the intermediate L-alanyl-L-valine methyl ester (3.7 g, 18.32 mmol, yield 87.22%). LCMS (M+H + )=203.3.

[0297] 1 HNMR (400 MHz, CDCl 3 ) 68.13 (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).

[0298] Step 3:

[0299] Compound 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), replaced with sufficient nitrogen and stirred at 0 ° C. After 10 min, acetic anhydride (2.8 g, 27.48 mmol) was slowly added dropwise, stirred at this temperature for 10 min, and stirred at room temperature for 2 h. After TLC showed that the reaction was completed, water (50 mL) was added to quench, and 2M hydrochloric acid was used to adjust to acidity, extracted with dichloromethane (50 ml × 4), and the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried with 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 (400 MHz, CDCl 3 )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).

[0300] Preparation Example 19 Preparation of Compound 19

[0301]

[0302] first step

[0303] 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 completed 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%.

[0304] Step 2

[0305] Compound 19-1 (0.10 g, 0.48 mmol) was dissolved in dry dichloromethane (10 mL), stirred thoroughly and cooled to about 0 degrees, then 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 the reaction was complete as monitored by TLC and LCMS, the reaction solution was washed with water, and after separation, the aqueous phase was extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain compound 19 (21 mg, 0.08 mmol, white solid), with a yield of 15%. MSm / z(ESI): 279.2[M+H] + .

[0306] 1 H NMR (400 MHz, DMSO-d 6 ) 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), 4.73 (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).

[0307] Preparation Example 20 Preparation of Compound 20

[0308]

[0309] first step

[0310] In a 100mL three-necked flask, sodium hydride (800mg, 20mmol) was added and replaced with nitrogen three times, then a solution of 4-1 (378mg, 2mmol) in anhydrous tetrahydrofuran (6mL) was added under ice bath. After stirring for 30 minutes, a solution of iodomethane (2.84g, 20mmol) in anhydrous tetrahydrofuran (2mL) was added, and the reaction was continued for 2 hours. After the reaction was complete as monitored by LCMS and TLC, a saturated sodium bicarbonate solution (50mL) was added to quench the reaction, and ethyl acetate (50mL×3) was used for extraction. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography to obtain 20-1 (295mg, 1.45mmol, yield 72.5%). ESI-LCMS: m / z 202.1[MH]-.

[0311] Step 2

[0312] 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 in sequence. The reaction solution was stirred in an ice bath for ten minutes, and then 1-hydroxybenzotriazole (294 mg, 2.18 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (418 mg, 2.18 mmol) were added, and the mixture was slowly heated to room temperature for 3 hours. After the reaction was complete as monitored by LCMS and TLC, saturated brine (50 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography to obtain 20-2 (110 mg, 0.34 mmol, yield 23.4%). ESI-LCMS: m / z 325.2 [M+H] + .

[0313] Step 3

[0314] In a 100 mL three-necked flask, add 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). The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS and TLC, the reaction solution was concentrated, and dichloromethane (50 mL) was added to dilute it. Subsequently, it was concentrated again to remove the residual dioxane hydrochloride solution. The residue was purified by reverse phase silica gel column and freeze-dried to obtain 20-3 (69 mg, 0.31 mmol, yield 91.2%). ESI-LCMS: m / z 225.2 [M+H] + .

[0315] Step 4

[0316] In a 100mL three-necked flask, add 20-3 (69mg, 0.31mmol), anhydrous dichloromethane (6mL), and triethylamine (173mg, 1.71mmol). After stirring for ten minutes under ice bath, slowly add acetyl chloride (73mg, 0.93mmol) in anhydrous dichloromethane (1mL). After the reaction is complete as monitored by LCMS and TLC, add dichloromethane (50mL) to dilute, add an equal volume of saturated sodium bicarbonate aqueous solution to quench, extract the aqueous phase with dichloromethane (50mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by normal phase chromatography to obtain compound 20 (12mg, 0.05mmol, yield 16.1%). MS (ESI) m / z: 267.2[M+H] + .

[0317] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0318] Preparation Example 21 Preparation of Compound 21

[0319]

[0320] first step:

[0321] The intermediate raw material 1-5 (0.40 g, 2.90 mmol) and 2-((tert-butylamino)-2-cyclopropylacetic acid) (0.60 g, 2.80 mmol) were dissolved in DMF (10 mL), cooled to about -10 ° C, and HOBt (0.40 g, 3.00 mmol) and EDCI (0.58 g, 3.00 mmol) were added to the reaction solution. Subsequently, the reaction solution was slowly heated to room temperature and stirred overnight. After the reaction was completed by TLC monitoring, ethyl acetate (50 mL) was added to the reaction solution for dilution and then 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, 21-1 (0.78 g, 2.32 mmol, yield: 80%) was obtained. MS (ESI) m / z: 337.3 [M+H] + .

[0322] Step 2:

[0323] 21-1 (0.78 g, 2.32 mmol) was added to a mixed solution of ethyl acetate (20 mL) and methanol (5 mL), and 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 completed, stirring was continued at room temperature until the reaction was completed as monitored by TLC, and the mixture was concentrated under reduced pressure to obtain a crude hydrochloride of 21-2 (0.62 g, 2.27 mmol, yield: 98%), which was directly used in the next step. MS-ESI: M / Z=237.2[M+H] + .

[0324] Step 3:

[0325] 21-2 hydrochloride (0.62 g, 2.27 mmol) was added to acetic anhydride (10 mL), and then triethylamine (0.69 g, 6.81 mmol) was added and the temperature was raised to 60 ° C for 3 hours. After the reaction was completed by TLC and LCMS monitoring, ethyl acetate (50 mL) was added to the reaction solution for dilution and then the reaction solution was 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] + .

[0326] 1 H NMR (400 MHz, DMSO-d 6 )δ11.84 (s, 1H), 68.28-8.10 (m, 1H), 7.98 (d, J=9.1Hz, 1H), 6.92 (s, 2H), 4.78-4.66 (m, 1H), 3.82-3.74 (m, 1H), 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).

[0327] Activity Test Example 1 Plasma Stability Determination

[0328] After thawing the mouse plasma in a water bath at 37°C, centrifuge to remove the upper clot and record the pH value as 7-8. Take a certain volume of acetonitrile stock solution of the compound to be tested (concentration of 10mM) and dilute it to 1mM with acetonitrile as an intermediate solution. Use Propantheline 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 compound to be tested 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. Draw 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:

[0329]

[0330] 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.

[0331] Table 1 Plasma stability data of some compounds

[0332] Compound <![CDATA[T 1 / 2 (min)]]> ZZL-7 25.29 Compound 1 ＞372.68 Compound 19 ＞372.68 Compound 20 ＞372.68 Compound 21 ＞372.68

[0333] Note: If after 120 minutes, the remaining percentage of the compound is still greater than 80%, then T 1 / 2 Recorded as >372.68min.

[0334] Activity Experiment Example 2 Pharmacokinetics Test

[0335] The pharmacokinetic test of the compound was performed in 6-8 week old CD1 mice. The compound to be tested was dissolved in a 10% hydroxypropyl-β-cyclodextrin aqueous solution containing 10% DMSO and administered by intravenous injection or oral gavage. The compound concentration in the plasma sample will be analyzed by LC-MS / MS method. Pharmacokinetic calculations were performed using WinNonlin (PhoenixTM, version 8.3) or other similar software. The following pharmacokinetic parameters were calculated based on the plasma concentration and time data:

[0336] Oral administration: AUC last , bioavailability (F).

[0337] The above parameter data were statistically calculated.

[0338] Table 2 shows the area under the drug-time curve (AUC) and bioavailability (F) data of the oral administration of the compound of the present application. The results show that the compound of the present application has good pharmacokinetic properties and is significantly better than compound ZZL-7.

[0339] Table 2 Pharmacokinetic data of some compounds

[0340]

[0341]

[0342] Activity Test Example 3

[0343] In vivo efficacy testing1

[0344] 6-8 week old C57 / B6 mice were selected to establish the 28-day animal chronic unpredictable mild stress model (CUMS). The open field test (OFT) was used to evaluate the model successfully and then the efficacy was evaluated. The experiment was divided into a blank control group (Control), a model group (Model), a solvent control group (Vehicle), a fluoxetine control group and a compound group. The test compound was administered by a single intravenous injection (iv) at a dose of 100 mg / kg. After 2 hours, the tail suspension test (TST) and the forced swimming test (FST) were performed to evaluate the depression of the mice. The prolonged immobility time of the mice in TST and FST indicated that the mice were in despair. After the data were summarized and statistically analyzed, SPSS data statistical software was used for analysis, and Graph Pad software was used to draw images based on the SPSS analysis results.

[0345] The test results show that (see Figure 1 and Figure 2 ), compound 1 and compound 5 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in forced swimming and tail suspension tests, proving that the compounds of the present application have a rapid antidepressant effect.

[0346] In vivo efficacy testing2

[0347] 6-8 week old C57 / B6 mice were selected to model the 28d animal chronic unpredictable stress model (CUMS, Chronic Unpredictable Mild Stress), and the open field test (Open Field Test, OFT) was used to evaluate the efficacy after the model was successfully evaluated. The experiment was divided into a blank control group (Control), a model group (Model), a solvent control group (Vehicle), a fluoxetine control group, a ZZL-7 control group, and a compound group. The compound to be tested was orally administered at a dose of 25 mg / kg, and a tail suspension test (TST) was performed 2 hours later to evaluate the depression of the mice. In the TST, the prolonged immobility time of the mice indicated that the mice were desperate. After the data were summarized and statistically analyzed, SPSS data statistical software was used for analysis, and Graph Pad software was used to draw images based on the SPSS analysis results.

[0348] The test results show that (see Figure 3 ), compound 16 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in the tail suspension test, proving that the compounds of the present application have 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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