Lactam ring compound and use thereof

Abstract

Disclosed in the present application are a lactam ring compound and a use thereof. The compound has a rapid antidepressant effect.

Description

Lactam ring compounds and uses thereof Technical Field

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

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

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

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

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

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

[0007] in,

[0008] C * The chiral carbon atom is preferably in S configuration;

[0009] The lactam ring Cy is a 4-16 membered monocyclic, bicyclic or tricyclic ring system optionally containing one or more substitutions; wherein the monocyclic, bicyclic or tricyclic ring each independently contains 0-3 heteroatoms selected from oxygen, sulfur and nitrogen as one or more ring members;

[0010] R1 is selected from R5C(O)-, R5OC(O)-, R5SO2-, (R5)2NC(O)- or (R5)(R6)NC(O)-;

[0011] R5, R6, R8 are -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated cycloalkyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated heterocyclic group, -C 6-10 Monocyclic or bicyclic aryl, -C 5-10 Monocyclic or bicyclic heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated cycloalkyl, -C3-12 Monocyclic or bicyclic saturated or partially unsaturated heterocyclic group, -C 6-10 Monocyclic or bicyclic aryl, -C 5-10 The monocyclic or bicyclic heteroaryl groups are each optionally substituted with 0-3 deuterium, tritium, halogen, hydroxy, amino, nitro, cyano, -C 1-8 Straight-chain or branched alkoxy, -C 1-8 Straight-chain or branched cycloalkyl, -C 3-8 Heterocyclic group, -C 6-10 Aryl, or -C 5-10 Heteroaryl substitution; or

[0012] R5 and R6 together with the nitrogen atom to which they are attached form a 3- to 8-membered monocyclic or polycyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur as one or more ring members, and the ring is optionally substituted with a substituent R7; wherein R7 is independently selected from hydrogen, deuterium, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, -C 3-8 Heterocyclic group, -C 6-10 Aryl and -C 5-10 heteroaryl;

[0013] R2 is independently selected from hydrogen, C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 6-14 Aryl or substituted C 5-14 Heteroaryl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Cycloalkyl, C 6--14 Aryl and C 5-14 The membered heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, carboxyl, amino, nitro, cyano, -C 1-6 Acylamino, -C 1-6 Acyloxy, -C 1-6 Alkoxy, -C 6-14 Aryloxy, -C 1-6 Alkylthio, -C 1-6 Alkyl, -C 1-6 Acyl, -C 6-10 Aryl, -C 3-8 Cycloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl, -C 6-10 Aryl-C 2-6 Alkenyl, -C 6-10 Aryl-C2-6 Alkynyl, heterocyclic, -C 5-14 Heteroaryl, halogenated C 1-6 Alkyl, -C 6-10 Aryl-C 1-6 Alkyl, -C 1-6 Hydroxyalkyl; wherein the heterocyclic group is a saturated or partially saturated 3-7 membered monocyclic ring, or a 7-10 membered bicyclic ring system;

[0014] R3 is selected from -COOR8, -CONR8, -COR8, -OR8, -NR8, -C 3-15 Cycloalkyl, -C 3-15 Heterocycloalkyl, -C 6-15 Aryl, -C 5-15 Heteroaryl; wherein the -C 3-15 Cycloalkyl, -C 3-15 Heterocycloalkyl, -C 6-15 Aryl, -C 5-15 each heteroaryl is optionally substituted with 0-8 R9;

[0015] R9 is optionally selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, -OR 10 、-NR 10 R 11 、-SR 10 、-COR 10 、-SOR 10 、-SO2R 10 、-NR 10 COR 11 、-CONR 10 R 11 、-OCOR 10 、-COOR 10 、-OCOOR 10 、-OCONR 10 R 11 、-NR 10 CONR 11 R 12 、-NR 10 COOR 11 、-NR 10 SO2R 11 、-SO2NR 10 R 11 、-OSO2R 10 、-SO3R 10 , chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently composed of 0-8 R 13 replace;

[0016] R10 、R 11 、R 12 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 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0017] R 13 is selected from hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl.

[0018] In one or more embodiments, C * The chiral carbon atom is in S configuration.

[0019] In one or more embodiments, Cy in the general formula (I) is selected from the group shown in (a):

[0020] X is independently selected from carbon, nitrogen, oxygen, and sulfur atoms; Y is independently selected from carbon and nitrogen atoms; wherein each ring is optionally substituted with one or more R4;

[0021] R4 is independently deuterium, tritium, halogen, hydroxy, amino, nitro, cyano, C 1-6 Alkyl, OR a , SR a 、C(O)R a 、C(O)NR a R b 、C(O)OR a NR a R b NR a C(O)R b 、SO2R a NR a SO2R b 、SO2NR a R b 、-C 6-10 Aryl, -C 3-8 Cycloalkyl, -C 5-10 Heteroaryl, -C 3-8Heterocycloalkyl or heterocycloalkenyl, wherein -C 1- 6 alkyl is optionally substituted by one or more substituents selected from the group consisting of amino, cyano, halogen, hydroxy, -C 1-6 Alkoxy, -C 3-8 Heterocycloalkyl, -C 3-8 Cycloalkyl, -C 5-10 Heteroaryl, -C 6-10 aryl;

[0022] R a and R b independently selected at each occurrence from hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 6-10 Aryl, -C 5-10 Heteroaryl and -C 3-8 Heterocycloalkyl.

[0023] 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:

[0024] in

[0025] Ring A is a 3-15 membered heterocyclyl or a 3-15 membered heteroaryl;

[0026] R1 is -C(O)OR3, -C(O)N(H)R3, -C(O)R3, -OR3, -N(H)R3, -C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 Aryl, or 5-15 membered heteroaryl; optionally, the -C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 Aryl, or 5-15 membered heteroaryl is replaced by one or more selected from C 1-4 Alkyl and halogenated C 1-4 Substitution of alkyl groups;

[0027] R2 is R4C(O)-, R4OC(O)-, R4S(O)2-, (R4)2NC(O)-, -C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 Aryl, or 5-15 membered heteroaryl;

[0028] R3 and R4 are independently -C 1-8 Alkyl, -C 1-8 Deuterated alkyl, -C 2-8 Alkenyl, -C2-8 Alkynyl, -C 3-12 Cycloalkyl, -C 3- 12 Heterocycloalkyl, -C 6-10 aryl, or 5-15 membered heteroaryl.

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

[0030] In one or more embodiments, the A ring is

[0031] In one or more embodiments, the A ring is a 4-13 membered heterocyclyl or a 5-10 membered heteroaryl, and has 1-4 heteroatoms selected from N, O, and S.

[0032] In one or more embodiments, the A ring is wherein n is 1, 2, 3 or 4, m is 1 or 2, p is 1 or 2, X1, X2 and X3 are independently O, S, N or NH, or C, wherein Indicates a single bond or a double bond.

[0033] In one or more embodiments, the A ring is

[0034] In one or more embodiments, R1 is -C(O)OR3, -C(O)N(H)R3, -C 6-15 Aryl, or 5-15 membered heteroaryl; R3 is -C 1-4 Alkyl or -C 1-4 deuterated alkyl; the 5-15 membered heteroaryl has 1 or 2 heteroatoms selected from N, O, and S.

[0035] In one or more embodiments, R1 is

[0036] In one or more embodiments, R2 is R4C(O)- or 5-6 membered heteroaryl; R4 is -C 1-4 Alkyl, -C 1-4 Deuterated alkyl or -C 3-5 cycloalkyl; the 5-6 membered heteroaryl has 1 N heteroatom.

[0037] In one or more embodiments, R2 is

[0038] In one or more embodiments, when Ring A is When R1 is R2 is in Indicates a single bond or a double bond.

[0039] In one or more embodiments, when Ring A is When R1 is R2 is in Indicates a single bond or a double bond.

[0040] In one or more embodiments, when Ring A is When R1 is R2 is in Indicates a single bond or a double bond.

[0041] In one or more embodiments, when Ring A is When R1 is R2 is

[0042] In one or more embodiments, when Ring A is When R1 is R2 is

[0043] In one or more embodiments, when Ring A is When R1 is R2 is

[0044] In one or more embodiments, the compound is selected from:

[0045] 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.

[0046] One or more embodiments of the pharmaceutical preparation of the present application include 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.

[0047] One or more embodiments of the present application provide the use of the compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof in the preparation of a medicament for treating and / or preventing depression.

[0048] One or more embodiments of the present application provide use of the pharmaceutical composition of the present application in preparing a medicament for treating and / or preventing depression.

[0049] One or more embodiments of the present application provide use of the pharmaceutical preparation of the present application in preparing a medicament for treating and / or preventing depression.

[0050] One or more embodiments of the present application provide the use of the compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof in the preparation of a fast-acting drug for treating and / or preventing depression.

[0051] One or more embodiments of the present application provide use of the pharmaceutical composition of the present application in preparing a fast-acting drug for treating and / or preventing depression.

[0052] One or more embodiments of the present application provide use of the pharmaceutical preparation of the present application in preparing a fast-acting drug for treating and / or preventing depression.

[0053] One or more embodiments of the present application provide the use of a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof in the preparation of a medicament for preventing and / or treating 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 and hot flashes.

[0054] In one or more embodiments, the neuropathic pain is chronic pain.

[0055] In one or more embodiments, the chronic pain is fibromyalgia.

[0056] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0057] One or more embodiments of the present application provide a pharmaceutical composition of the present application for use as a medicament.

[0058] One or more embodiments of the present application provide the pharmaceutical preparation of the present application, which is used as a medicament.

[0059] 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.

[0060] 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.

[0061] One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application, which is used as a fast-acting drug for treating and / or preventing depression.

[0062] One or more embodiments of the present application provide a method for preventing and / or treating depression, comprising administering the compound, pharmaceutical composition, or pharmaceutical preparation of the present application to a subject in need thereof.

[0063] One or more embodiments of the present application provide a method for preventing and / or rapidly treating depression, comprising administering the compound, pharmaceutical composition, or pharmaceutical preparation of the present application to a subject in need thereof.

[0064] In one or more embodiments, provided is a method for preventing and / or treating 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, the method comprising administering to a subject in need thereof a compound, pharmaceutical composition, or pharmaceutical formulation of the present application.

[0065] One or more embodiments of the present application also provide pharmaceutical compositions or pharmaceutical preparations comprising the compounds of the present application. For example, the compounds of the present application can be administered in pure form, in combination with other active ingredients, or in combination with pharmaceutically acceptable non-toxic excipients or carriers.

[0066] The following describes the terms used in the technical solutions of this application. As used in the specification and the appended claims, unless otherwise specifically stated, the terms of this application have the following meanings.

[0067] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0068] The term "amino" refers to -NH2.

[0069] The term "hydroxy" refers to -OH.

[0070] "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when an alkyl group is substituted, it may optionally be further substituted with one or more substituents.

[0071] "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.

[0072] "Alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group of 1 to 20 carbon atoms containing one or more triple bonds, preferably an alkynyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkynyl group of 1 to 6 carbon atoms, and even more preferably an alkynyl group of 1 to 4 carbon atoms.

[0073] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated non-aromatic heterocyclic ring, which can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, for example, a 3-8 membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms optionally substituted in the "heterocyclyl" or "heterocycle" ring can be oxidized to various oxidation states; the "heterocyclyl" or "heterocycle" can be attached at a heteroatom or a carbon atom; the "heterocyclyl" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, glycidyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thiazolinyl, pyridinyl, piperidinyl, homopiperidinyl, pyrid ... pyranyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, oxazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be further substituted with one or more substituents.

[0074] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring which may be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, such as a 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms optionally substituted in the heteroaryl ring may be oxidized to various oxidation states. The heteroaryl group may be attached to a heteroatom or a carbon atom, and may be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, and pyrrolopyridinyl. The heteroaryl group may be further substituted with one or more substituents.

[0075] "Cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon group of 1 to 15 carbon atoms, which can be a monocyclic ring of 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10), a bicyclic ring of 4 to 12 carbon atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12), or a polycyclic ring system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15). The ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When a cycloalkyl group is substituted, it may be optionally further substituted by one or more substituents.

[0076] "Heterocycloalkyl" refers to a 3- to 15-membered cyclic saturated aliphatic hydrocarbon group, which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) polycyclic ring system, which can contain one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, or S, and can be monocyclic, fused, bridged, or spirocyclic.

[0077] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring of 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, 8 carbon atoms), a bicyclic ring of 5 to 12 carbon atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms), or a tricyclic ring system of 10 to 15 carbon atoms (e.g., 10, 11, 12, 13, 14, 15 carbon atoms), which can be a bridged ring or a spirocyclic ring, non-limiting examples of which include phenyl and naphthyl. The aryl group can optionally be further substituted with one or more substituents.

[0078] "Alkoxy" refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of "alkyl" is the same as that of "alkyl" described above.

[0079] Unless otherwise indicated, the term "optionally substituted" refers to groups wherein hydrogen atoms are not replaced or one or more hydrogen atoms are replaced by one or more groups independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, and trihalosulfonyl.

[0080] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0081] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0082] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0083] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0084] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0085] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0086] The term "compound" includes all stereoisomers, geometric isomers, and tautomers. The "compound" described herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms or mixtures thereof. The compounds herein containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. The "compound" described herein also includes geometric isomers, which refer to forms in which the substituents on the double bonds or rings of the compound have different cis-trans isomers and are not chiral. The "compound" described herein also includes tautomeric forms. Tautomeric forms can arise from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0087] The compounds herein, whether intermediates or compounds of formula (I), may also be isotopically labeled by replacing one or more atoms thereof with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds are considered to be within the scope of this invention. Examples of isotopes in the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, each having the same number of protons but different mass numbers.

[0088] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0089] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc.

[0090] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, other than the active ingredient. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0091] "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.

[0092] In one or more embodiments, the compounds of the present application are more active than existing rapid antidepressant compounds. For example, compared to an existing compound (compound ZZL-7), the compounds of the present application have excellent rapid in vivo antidepressant activity and significantly better drugability (metabolic stability, AUC, bioavailability, etc.). BRIEF DESCRIPTION OF THE DRAWINGS

[0093] FIG1 shows the results of the forced swimming test of in vivo efficacy test 1 of active example 3.

[0094] FIG2 is the result of the tail suspension experiment of in vivo efficacy test 1 of active example 3.

[0095] FIG3 shows the results of the tail suspension experiment of in vivo efficacy test 2 of active example 3. DETAILED DESCRIPTION

[0096] The present application will be further described below in conjunction with the examples, and the implementation details of the present application are provided. However, it should be noted that the examples described below are exemplary and are only used to explain the present application, and should not be construed as limiting the present application. It is still within the scope of protection of the present application for those skilled in the art to modify or replace them according to the prior art. The reagents used in the examples of the present application can all be commercially available.

[0097] The following compounds were prepared in the examples of this application:

[0098] Table 1: Series A compounds

[0099] Table 2: B series compounds

[0100] Table 3: C-series compounds

[0101] Preparation Example

[0102] Preparation Example 1 Preparation of Compound A1-2

[0103] first step

[0104] Acetylmethionine 1-1 (3.0 g, 15.7 mmol) was dissolved in N,N-dimethylformamide (30 mL), and L-valine methyl ester hydrochloride (3.16 g, 18.9 mmol), 1-hydroxybenzotriazole (3.18 g, 23.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.51 g, 23.6 mmol) and N,N-diisopropylethylamine (6.09 g, 47.1 mmol) were added thereto. The reaction mixture was allowed to react at room temperature for 4 hours. After completion of the reaction as monitored by TLC and LCMS, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel flash column chromatography (dichloromethane / methanol = 20 / 1) to obtain acetylmethionyl-L-valine methyl ester 1-2 (3.3 g, light yellow solid) in a 67% yield. MS m / z (ESI): 304.9 [M+H] + .

[0105] Step 2

[0106] Acetylmethionyl-L-valine methyl ester 1-2 (2.8 g, 9.2 mmol) was dissolved in acetone (30 mL) and iodomethane (13.1 g, 92 mmol) was added. The mixture was allowed to react at room temperature for 4 hours. After completion of the reaction as monitored by TLC and LCMS, the solution was rotary evaporated to dryness. The solution was then dissolved in acetonitrile (30 mL) and cesium carbonate (6.0 g, 18.4 mmol) was added. The reaction was continued at 60°C for 6 hours. After completion of the reaction, the solvent was rotary evaporated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the crude target product. Preparative HPLC analysis yielded compound A1-2 (332 mg, white solid) in a 14% yield. MS m / z (ESI): 257.0 [M+H] + .

[0107] 1H NMR (400MHz, DMSO-d6) δ8.19 (d, J=8.4Hz, 1H), 4.56-4.33 (m, 1H), 4.28-4.21 (m, 1H), 3.66-3.65 (d, J=3.2Hz, 3H), 3.50-3.46 (m, 1H), 3.36-3.33(m, 1H), 2.33-2.24(m, 1H), 2.20-2.07(m, 1H), 1.84-1.83(m, 3H), 1.79-1.67(m, 1H), 0.92-0.88(m, 3H), 0.84-0.81(m, 3H).

[0108] Preparation Example 2 Preparation of Compound B1-1

[0109] first step

[0110] Methyl (R)-2-hydroxy-3-methylbutanoate 2-1 (2.0 g, 15 mmol) was dissolved in dichloromethane (50 mL) at 0°C, and trifluoromethanesulfonic anhydride (5.5 g, 20 mmol) and 2,6-lutidine (2.1 g, 20 mmol) were added. The reaction mixture was allowed to react at 25°C for 3 hours. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was concentrated, and the residue was extracted with petroleum ether (30 mL × 3) and concentrated under reduced pressure to give compound 2-2 (3.1 g, colorless liquid) in a yield of 73%.

[0111] 1 H NMR (400MHz, CDCl3) δ4.98 (d, J=4.0Hz, 1H), 3.85 (s, 3H), 2.36-2.43 (m, 1H), 1.10 (d, J=6.8Hz, 3H), 1.01 (d, J=6.8Hz, 3H).

[0112] Step 2

[0113] 3-Amino-1H-pyridin-2-one 2-3 (2.5 g, 23 mmol) was added to toluene (50 mL), and acetic anhydride (2.8 g, 27.4 mmol) was added thereto. The reaction solution was reacted at 110°C for 3 hours. After the reaction was complete as monitored by TLC and LCMS, the reaction solution was concentrated, and the residue was washed with ethyl acetate (10 mL), filtered under reduced pressure, and the filter cake was recrystallized from methanol to obtain compound 2-4 (2.0 g, black solid) in a yield of 55%.

[0114] 1H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 9.19 (s, 1H), 8.21 (dd, J=7.2, 1.2Hz, 1H), 7.07 (dd, J=6.4, 1.6Hz, 1H), 6.19 (t, J=6.8Hz, 1H), 2.11 (s, 3H).

[0115] Step 3

[0116] Compound 2-4 (700 mg, 4.6 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (202 mg, 5.1 mmol) was added. After reacting at room temperature for 30 minutes, compound 2-2 (1.46 g, 5.5 mmol) was added. The reaction solution was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC and LCMS, water (5 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined and washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to obtain compound B1-1 (970 mg, white solid) in a yield of 75%. MS m / z (ESI): 267.1 [M+H] + .

[0117] 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.21 (dd, J=7.4, 1.6Hz, 1H), 7.40 (dd, J=7.0, 1.8Hz, 1H), 6.30 (t, J=7.2Hz, 1H) , 4.95 (d, J = 10.0Hz, 1H), 3.64 (s, 3H), 2.51-2.59 (m, 1H), 2.10 (s, 3H), 1.08 (d, J = 6.8Hz, 3H), 0.67 (d, J = 6.8Hz, 3H).

[0118] Preparation Example 3 Preparation of Compound A1-3

[0119] Compound B1-1 (1.0 g, 3.8 mmol) was dissolved in methanol (10 mL), and palladium carbon (0.4 g) and palladium hydroxide (0.4 g) were added thereto. The reaction solution was reacted at 40°C under a hydrogen atmosphere for 48 hours. After the reaction was complete as monitored by TLC and LCMS, the reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure. The resulting residue was separated and purified using a reverse separation column (0.1% TFA in H2O:CH3CN) to obtain compound A1-3 (0.45 g, yellow oil) with a yield of 42%. MSm / z (ESI): 271.2 [M+H] +.

[0120] 1 H NMR (400MHz, CDCl3) δ6.60 (s, 1H), 4.81 (dd, J=28.2, 10.2Hz, 1H), 4.36 (ddt, J=27.2, 11.8, 6.0Hz, 1H), 3.72 (m, 3H), 3.45 (m, 2H), 2. 60 (td, J=12.8, 7.0Hz, 1H), 2.23 (m, 1H), 2.03 (s, 3H), 1.90 (m, 2H), 1.43 (m, 1H), 1.01 (t, J=6.4Hz, 3H), 0.90 (dd, J=14.4, 6.6Hz, 3H).

[0121] Preparation Example 4 Preparation of Compound B1-5

[0122] first step

[0123] To ethyl nitroacetate (20.28 g, 152.4 mmol) and 1,1,3,3-tetramethoxypropane (50.04 g, 304.8 mmol) was added concentrated sulfuric acid (140 mg, 1.4 mmol) dropwise and stirred at 130°C for 45 minutes. The reaction mixture was cooled to room temperature, and L-valine methyl ester hydrochloride 4-1 (20.0 g, 152.4 mmol), N,N-diisopropylethylamine (19.70 g, 152.4 mmol), and methanol (140 mL) were added. The mixture was stirred at room temperature for 1 minute, then raised to 80°C and stirred for 16 hours. The reaction mixture was slowly cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 1:1) as eluent to yield the title product 4-2 (11.5 g, brown oil, 30%). MS (ESI) m / z: 255.2 [M+H] + .

[0124] Step 2

[0125] Compound 4-2 (9.0 g, 35 mmol) was dissolved in a solution of methanol and water (V / V = 5:1, 54 mL). Lithium hydroxide monohydrate (5.94 g, 141.6 mmol) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and diluted with water (50 mL). The pH was adjusted to 1-2 with dilute hydrochloric acid (1.0 M), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4-3 (1.5 g, brown oil, 16%). MS (ESI) m / z: 241 [M+H] + .

[0126] Step 3

[0127] Compound 4-3 (1.5 g, 6.2 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (2.57 g, 18.6 mmol) and deuterated iodomethane (1.8 g, 12.4 mmol) were then added to the reaction solution. The reaction solution was stirred at 25°C for 1 hour. The reaction system was concentrated under reduced pressure to obtain product 4-4 (1.5 g, brown oil, 84%). MS (ESI) m / z: 258 [M+H] + .

[0128] Step 4

[0129] Compound 4-4 (1.5 g, 5.8 mmol) was dissolved in N,N-dimethylformamide and acetic acid (V / V = 25:6, 31 mL). Zinc powder (2.28 g, 34.8 mmol) was then added to the reaction solution. The reaction solution was stirred at 25°C for 2 hours, then placed in an ice bath, diluted with water (80 mL), and adjusted to pH 8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4-5 (1.05 g, yellow oil, 77%). MS (ESI) m / z: 228 [M+H] + .

[0130] Step 5

[0131] To a solution of compound 4-5 (0.6 g, 2.64 mmol) in dichloromethane (15 mL) was added triethylamine (1.07 g, 10.56 mmol). The reaction temperature was lowered to 0°C, and acetyl chloride (414 mg, 5.28 mmol) was slowly added dropwise to the reaction solution. The temperature was slowly raised to 25°C, and the reaction was stirred at 25°C for 1 hour. The solution was concentrated under reduced pressure and purified by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 3:1) as eluents to obtain the title product B1-5 (415 mg, brown solid, 58%). MS (ESI) m / z: 270.1 [M+H] + .

[0132] 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.21 (dd, J=7.4, 1.4Hz, 1H), 7.40 (dd, J=7.0, 1.7Hz, 1H), 6.30 (t, J=7.2 Hz, 1H), 4.94 (d, J=9.7Hz, 1H), 2.60-2.52 (m, 1H), 2.10 (s, 3H), 1.08 (d, J=6.5Hz, 3H), 0.67 (d, J=6.8Hz, 3H).

[0133] Preparation Example 5 Preparation of Compound B1-6

[0134] first step

[0135] Zinc powder (921 mg, 14.17 mmol) was added to a solution of compound 4-2 (3.0 g, 11.81 mmol) in methanol (30 mL). Glacial acetic acid (72 mg, 1.2 mmol) was then slowly added dropwise to the reaction solution, and the reaction was stirred at room temperature for 2 hours. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 7:3) as eluents to afford compound 5-1 (1.32 g, white solid, 49.9%). MS (ESI) m / z: 225 [M+H] + .

[0136] Step 2

[0137] Compound 5-1 (1.32 g, 5.89 mmol) was dissolved in dichloromethane (15 mL). Deuterated acetyl chloride (477 mg, 5.89 mmol) and N,N-diisopropylethylamine (912 mg, 7.06 mmol) were then added sequentially to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After dilution with water (15 mL), the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 74:26) as eluents to afford compound B1-6 (500 mg, gray-green solid, 31.5%). MS (ESI) m / z: 270.1 [M+H] + .

[0138] 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.22 (dd, J=7.4, 1.3Hz, 1H), 7.41 (dd, J=7.0, 1.7Hz, 1H), 6.30 (t, J=7.2 Hz, 1H), 4.94 (d, J=9.7Hz, 1H), 3.64 (s, 3H), 2.61-2.52 (m, 1H), 1.08 (d, J=6.5Hz, 3H), 0.67 (d, J=6.8Hz, 3H).

[0139] Preparation Example 6 Preparation of Compound C1-6

[0140] To a solution of compound 4-5 (450 mg, 1.98 mmol) in dichloromethane (20 mL) was added triethylamine (1.07 g, 10.56 mmol). The reaction temperature was lowered to 0°C, and cyclopropylcarboxylic acid chloride (414 mg, 3.96 mmol) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 25°C and the reaction was stirred at 25°C for 1 hour. The solution was concentrated under reduced pressure and purified by silica gel column chromatography using petroleum ether and ethyl acetate (V / V = 3:1) as eluents to obtain compound C1-6 (420 mg, brown solid, 71%). MS (ESI) m / z: 296.2 [M+H] + .

[0141] 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 8.19 (dd, J=7.4, 1.6Hz, 1H), 7.40 (dd, J=7.4, 1.6Hz, 1H), 6.29 (t, J=7.2Hz, 1H), 4.9 5 (d, J=9.7Hz, 1H), 2.62-2.52 (m, 1H), 2.28-2.16 (m, 1H), 1.09 (d, J=6.5Hz, 3H), 0.81-0.72 (m, 4H), 0.68 (d, J=6.8Hz, 3H).

[0142] Preparation Example 7 Preparation of Compound B1-4

[0143] first step

[0144] 7-1 (0.80 g, 7.20 mmol) was added to toluene (5 mL), and acetic anhydride (0.81 g, 7.92 mmol) was added. The reaction mixture was reacted at 110°C for 3 hours. After completion of the reaction as monitored by TLC and LCMS, the reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 7-2 (1.00 g, white solid, 90%).

[0145] Step 2

[0146] Compound 7-2 (0.20 g, 1.31 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (35 mg, 1.44 mmol) was added thereto. After reacting at room temperature for 30 minutes, compound 2-2 (0.40 g, 1.57 mmol) was added. The reaction solution was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC and LCMS, water (5 mL) was added to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate, and the residue obtained by concentration under reduced pressure was separated and purified by silica gel column to obtain compound B1-4 (45 mg, 0.17 mmol, white solid, 12%). MS m / z (ESI): 268.2 [M+H] + .

[0147] 1 H NMR (400MHz, CDCl3) δ8.83 (s, 1H), 7.15 (d, J=4.7Hz, 1H), 7.09 (d, J=4.8Hz, 1H), 5.30 (d, J=10. 3Hz, 1H), 3.77 (s, 3H), 2.42 (s, 3H), 2.37 (m, 1H), 1.10 (d, J=6.6Hz, 3H), 0.85 (d, J=6.7Hz, 3H).

[0148] Preparation Example 8 Preparation of Compound C1-7

[0149] first step

[0150] In a 250 mL three-necked flask, compound 8-1 (1.0 g, 9.08 mmol), anhydrous 1,4-dioxane (40 mL), 2-bromopyridine (1.58 g, 9.99 mmol), sodium tert-butoxide (2.62 g, 27.24 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2′, 4′, 6′-triisopropyl-1,1′-biphenyl) (2′-amino-1,1′-biphenyl-2 -yl)palladium (381 mg, 0.45 mmol), nitrogen replacement protection, reaction at 90 ° C for 3 hours. After LCMS and TLC monitoring showed that the reaction was complete, it was concentrated under reduced pressure. The crude product was dissolved in saturated sodium bicarbonate aqueous solution (150 mL) and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with dichloromethane (30 mL) and filtered. The filter cake was the product. Compound 8-2 (900 mg, 4.81 mmol, yield 52.97%) was obtained. ESI-LCMS: m / z 188.2 [M+H] + .

[0151] Step 2

[0152] In a 100 mL single-necked flask, compound 8-2 (810 mg, 4.33 mmol), anhydrous tetrahydrofuran (30 mL), and sodium hydride (190 mg, 4.76 mmol) were added sequentially. The mixture was purged with nitrogen and reacted at 25°C for 30 minutes. Compound 2-2 (1.37 g, 5.20 mmol) was then added and allowed to react at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, methanol (10 mL) was added for quenching. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound C1-7 (1.0 g, 3.32 mmol, yield 76.67%). ESI-LCMS: m / z 302.4 [M+H] + .

[0153] 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.54 (dd, J=7.5, 1.6Hz, 1H), 8.20 (dd, J=5.0, 1.5Hz, 1H), 7.57 (ddd, J=8.8, 7.2, 1.9Hz, 1H), 7.22 (dd, J=10.4, 5.0 Hz, 2H), 6.83-6.77 (m, 1H), 6.32 (t, J=7.2Hz, 1H), 4.97 (d, J=9.8Hz, 1H), 3. 64 (s, 3H), 2.63-2.52 (m, 1H), 1.09 (d, J = 6.5Hz, 3H), 0.69 (d, J = 6.8Hz, 3H).

[0154] Preparation Example 9 Preparation of Compound C1-8

[0155] first step

[0156] In a 100 mL single-necked flask, compound C1-7 (800 mg, 2.65 mmol), tetrahydrofuran (16 mL), and aqueous lithium hydroxide solution (0.5 M, 16 mL) were added sequentially and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the mixture was diluted with water (100 mL), the pH was adjusted to 4-5 with 1.0 M hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product 9-1 (750 mg, 2.61 mmol, 98.49% yield) was used directly in the next reaction. ESI-LCMS: m / z 288.3 [M+H] + .

[0157] Step 2

[0158] In a 100 mL single-necked flask, compound 9-1 (500 mg, 1.74 mmol), dichloromethane (20 mL), and thionyl chloride (414 mg, 3.48 mmol) were added sequentially and reacted at 25°C for 30 minutes. Deuterated methanol (2 mL) was added and the reaction was continued at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the mixture was concentrated under reduced pressure. The crude product was redissolved in ethyl acetate (100 mL) and washed once with saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound C1-8 (350 mg, 1.15 mmol, yield 66.09%). ESI-LCMS: m / z 305.4 [M+H] + .

[0159] 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.54 (dd, J=7.5, 1.6Hz, 1H), 8.20 (dd, J=5.0, 1.5Hz, 1H), 7.57 (ddd, J=8.8, 7.2, 2.0Hz, 1H), 7.22 (dd, J=10.6, 5. 0Hz, 2H), 6.82-6.77 (m, 1H), 6.32 (t, J=7.2Hz, 1H), 4.97 (d, J=9.8Hz, 1H), 2.57 (dq, J=20.4, 6.8Hz, 1H), 1.09 (d, J=6.5Hz, 3H), 0.69 (d, J=6.8Hz, 3H).

[0160] Preparation Example 10 Preparation of Compound C1-3

[0161] first step

[0162] In a 100 mL single-necked flask, compound B1-1 (620 mg, 2.33 mmol), tetrahydrofuran (15 mL), and aqueous lithium hydroxide solution (0.5 M, 15 mL) were added sequentially and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, 1.0 M hydrochloric acid (100 mL) was added for dilution, the pH was adjusted to 1-2, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next reaction. Compound 10-1 (550 mg, 2.18 mmol, yield 93.56%) was obtained. ESI-LCMS: m / z 253.3 [M+H] + .

[0163] Step 2

[0164] In a 100 mL single-necked bottle, compound 10-1 (550 mg, 2.18 mmol), dichloromethane (20 mL), methylamine hydrochloride (736 mg, 10.9 mmol), N,N-diisopropylethylamine (1.69 g, 13.08 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (2.49 g, 6.54 mmol) were added in sequence and reacted at 25 ° C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, dilute hydrochloric acid (1.0 M) was added to quench the mixture, and the mixture was diluted with dichloromethane (100 mL). The organic phase was washed with dilute hydrochloric acid (1.0 M) (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate yielded the product) to give compound C1-3 (400 mg, 1.51 mmol, yield 69.27%). ESI-LCMS: m / z 266.3 [M+H] + .

[0165] 1 H NMR (400MHz, DMSO-d6) 69.17 (s, 1H), 8.43 (d, J=4.5Hz, 1H), 8.16 (dd, J=7.2, 1.1Hz, 1H), 7.57 (dd, J=7.1, 1.6Hz, 1H), 6.27 (t, J=7.2Hz, 1H ), 5.19 (d, J=11.0Hz, 1H), 2.58 (d, J=4.6Hz, 3H), 2.27 (tt, J=13.1, 6.5Hz, 1H), 2.11 (s, 3H), 0.97 (d, J=6.5Hz, 3H), 0.65 (d, J=6.6Hz, 3H).

[0166] Preparation Example 11 Preparation of Compound C1-5

[0167] first step

[0168] In a 100 mL single-necked flask, compound 2-3 (3.0 g, 27.24 mmol) and triethylamine (8.27 g, 81.75 mmol) were added, the temperature was lowered to 0°C, and cyclopropylcarbonyl chloride (4.27 g, 40.88 mmol) was slowly added. After addition, the temperature was returned to 25°C and the reaction was allowed to proceed for 2 hours. After LCMS and TLC monitoring indicated the reaction was complete, methanol was added to quench the reaction, the mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 11-2 (2.7 g, 15.15 mmol, yield 55.62%). ESI-LCMS: m / z 179.2 [M+H] + .

[0169] Step 2

[0170] In a 100 mL three-necked flask, compound 11-1 (600 mg, 3.37 mmol), anhydrous tetrahydrofuran (30 mL), and sodium hydride (148 mg, 3.71 mmol) were added sequentially. The mixture was purged with nitrogen and reacted at 25°C for 30 minutes. Compound 2-2 (1.33 g, 5.05 mmol) was then added and reacted at 25°C for 2 hours. After LCMS and TLC monitoring indicated the reaction was complete, methanol was added for quenching, the mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound C1-5 (850 mg, 2.91 mmol, 86.35% yield).

[0171] ESI-LCMS: m / z 293.4 [M+H] + .

[0172] 1 H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 8.18 (dd, J=7.4, 1.7Hz, 1H), 7.40 (dd, J=7.0, 1.7Hz, 1H), 6.29 (t, J=7.2Hz, 1H), 4.94 (d, J=9.7H z, 1H), 3.64 (s, 3H), 2.61-2.52 (m, 1H), 2.20 (tt, J=7.5, 5.0Hz, 1H), 1.08 (d, J=6.5Hz, 3H), 0.79-0.72 (m, 4H), 0.67 (d, J=6.8Hz, 3H).

[0173] Preparation Example 12 Preparation of Compound C1-4

[0174] first step

[0175] In a 100 mL single-necked flask, compound C1-5 (600 mg, 2.05 mmol), tetrahydrofuran (13 mL), and aqueous lithium hydroxide solution (0.5 M, 13 mL) were added sequentially and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, the mixture was diluted with 1.0 M hydrochloric acid (100 mL), the pH was adjusted to 1-2, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product 12-1 (560 mg, 2.01 mmol, 98.05% yield) was used directly in the next reaction.

[0176] ESI-LCMS: m / z 279.4 [M+H] + .

[0177] Step 2

[0178] In a 100 mL single-necked bottle, compound 12-1 (500 mg, 1.80 mmol), dichloromethane (20 mL), methylamine hydrochloride (608 mg, 9.00 mmol), N,N-diisopropylethylamine (1.40 g, 10.80 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.74 g, 7.20 mmol) were added in sequence and reacted at 25°C for 2 hours. After LCMS and TLC monitoring showed the reaction was complete, dilute hydrochloric acid (1.0 M) was added to quench the reaction, dilute with dichloromethane (100 mL), separate the layers, and wash the organic phase with dilute hydrochloric acid (1.0 M) (50 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain compound C1-4 (300 mg, 1.03 mmol, yield 57.22%). ESI-LCMS: m / z 292.4 [M+H] + .

[0179] 1 H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 8.44 (d, J=4.5Hz, 1H), 8.12 (dd, J=7.3, 1.4Hz, 1H), 7.57 (dd, J=7.1, 1.5Hz, 1H), 6.27 (t, J=7.2Hz, 1H), 5.21 (d, J =11.0Hz, 1H), 2.58 (d, J = 4.5Hz, 3H), 2.27 (qd, J = 13.2, 6.6Hz, 1H), 2.21-2. 12 (m, 1H), 0.97 (d, J = 6.5Hz, 3H), 0.79-0.73 (m, 4H), 0.66 (d, J = 6.6Hz, 3H).

[0180] Preparation Example 13 Preparation of Compound B1-3

[0181] first step

[0182] In a 100 mL single-necked flask, compound 13-1 (1.0 g, 9.00 mmol) and triethylamine (2.73 g, 27.00 mmol) were added, the temperature was lowered to 0°C, and acetyl chloride (1.06 g, 13.5 mmol) was slowly added. After addition, the temperature was returned to 25°C and the reaction was allowed to proceed for 2 hours. After LCMS and TLC monitoring indicated the reaction was complete, methanol was added to quench the reaction, the mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 13-2 (500 mg, 3.26 mmol, yield 36.22%). ESI-LCMS: m / z 154.2 [M+H] + .

[0183] Step 2

[0184] In a 100 mL single-necked flask, compound 13-2 (375 mg, 2.45 mmol), anhydrous N,N-dimethylformamide (20 mL), and sodium hydride (108 mg, 2.70 mmol) were added sequentially. The atmosphere was purged with nitrogen and the mixture was reacted at 25°C for 30 minutes. Compound 2-2 (777 mg, 2.94 mmol) was then added and the mixture was reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, saturated aqueous sodium bicarbonate solution (150 mL) was added for quenching. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (50 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B1-3 (110 mg, 0.41 mmol, yield 16.73%). ESI-LCMS: m / z 268.3 [M+H] + .

[0185] 1 H NMR (400MHz, DMSO-d6) δ9.53 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 4.90 (d, J=9.3Hz, 1H), 3. 65 (s, 3H), 2.66-2.57 (m, 1H), 2.11 (s, 3H), 1.11 (d, J = 6.6Hz, 3H), 0.70 (d, J = 6.8Hz, 3H).

[0186] Example 14 Synthesis of Compound A1-4

[0187] first step

[0188] To a 100 mL three-necked flask, compound A1-4a (1.0 g, 7.8 mmol) and triethylamine (2.37 g, 23.4 mmol) were added sequentially. The temperature was lowered to 0°C, and acetyl chloride (918 mg, 11.7 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly warmed to 25°C and reacted for 2 hours. After LCMS and TLC monitoring indicated completion of the reaction, methanol (50 mL) was added for quenching. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to afford compound A1-4b (950 mg, 5.58 mmol, 71.5% yield).

[0189] ESI-LCMS: m / z 171.2 [M+H] + .

[0190] Step 2

[0191] In a 100 mL three-necked flask, compound A1-4b (500 mg, 2.94 mmol), anhydrous N,N-dimethylformamide (20 mL), and sodium hydride (78 mg, 3.23 mmol) were added sequentially. Under nitrogen, the mixture was reacted at 25°C for 30 minutes, followed by the addition of compound 2-2 (932 mg, 3.53 mmol), and the reaction was stirred for 2 hours. After LCMS and TLC monitoring indicated the reaction was complete, dilute hydrochloric acid (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain compound A1-4 (98 mg, 0.34 mmol, 11.6% yield).

[0192] ESI-LCMS: m / z 285.4 [M+H] + .

[0193] 1 H NMR (400MHz, DMSO-d6) δ8.02-7.90 (m, 1H), 4.76 (d, J=10.7Hz, 0.83H), 4.62-4.53 (m, 1H), 4.23 ( d, J=9.4Hz, 0.19H), 3.64 (s, 2.45H), 3.59 (s, 0.55H), 3.57-3.36 (m, 2H), 2.28-2.04 (m, 1H), 1.8 5(s, 2.35H), 1.84(s, 0.62H), 1.80-1.56(m, 4H), 1.43-1.31(m, 1H), 1.21-1.01(m, 1H), 0.96(d, J=6.5Hz, 0.57H), 0.89 (d, J=6.5Hz, 2.46H), 0.84 (d, J=6.7Hz, 0.61H), 0.73 (d, J=6.7Hz, 2.41H).

[0194] Example 15 Synthesis of Compound C1-2

[0195] first step

[0196] In a 100 mL three-necked flask, compound C1-3 (150 mg, 0.57 mmol), methanol (20 mL), palladium on carbon (75 mg), and palladium hydroxide on carbon (75 mg) were added in sequence. The reaction was allowed to proceed at 60°C under hydrogen atmosphere for 48 hours. After LCMS and TLC monitoring indicated the reaction was complete, the mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain compound C1-2 (60 mg, 0.22 mmol, 39.1% yield).

[0197] ESI-LCMS: m / z 270.3 [M+H] + .

[0198] 1 H NMR (400MHz, DMSO-d6) δ8.16-8.03 (m, 1H), 7.93 (d, J=4.5Hz, 0.65H), 7.86 (d, J=4.5Hz, 0.35H) , 4.57 (d, J = 10.9Hz, 0.67H), 4.50 (d, J = 11.0Hz, 0.33H), 4.34-4.18 (m, 1H), 3.54-3.43 (m, 1H), 3 .31-3.18(m,1H),2.58-2.52(m,1H),2.16-2.03(m,1H),2.00-1.89(m,1H),1.83(s,3H),1.80-1 .66 (m, 2H), 1.62-1.46 (m, 1H), 0.88-0.83 (m, 3H), 0.81 (d, J = 6.6Hz, 2H), 0.75 (d, J = 6.6Hz, 1H).

[0199] Example 16 Synthesis of Compound C1-18

[0200] first step

[0201] In a 250 mL three-necked flask, compound C1-18a (4 g, 35.35 mmol) and anhydrous tetrahydrofuran (100 mL) were added sequentially. The mixture was purged with nitrogen and cooled to -10°C. Isopropylmagnesium chloride·lithium chloride (35 mL, 70 mmol, 2.0 M tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the reaction solution was slowly returned to room temperature and stirred for 4 hours. After LCMS and TLC monitoring indicated the reaction was complete, quenched with saturated aqueous ammonium chloride (200 mL) under ice-bath conditions, and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound C1-18b (2.5 g, 15.9 mmol, 45.0% yield).

[0202] ESI-LCMS: m / z 158.1 [M+H] + .

[0203] Step 2

[0204] In a 250 mL three-necked flask, compound C1-18b (1.5 g, 9.54 mmol), anhydrous dichloromethane (100 mL), triethylamine (2.89 g, 28.62 mmol), and pyridine (490 mg, 6.21 mmol) were added sequentially. The reaction solution was stirred at room temperature for 10 minutes, and then phosphorus tribromide (7.7 g, 28.62 mmol) was slowly added dropwise. After the addition was complete, stirring was continued for 16 hours. After LCMS and TLC monitoring showed that the reaction was complete, saturated aqueous sodium carbonate solution (200 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound C1-18c (170 mg, 0.77 mmol, 8.1% yield).

[0205] ESI-LCMS: m / z 221.9 [M+H] + .

[0206] 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=3.3Hz, 1H), 7.36 (d, J=3.3Hz, 1H), 5.16 (d, J =6.7Hz, 1H), 2.52-2.42 (m, 1H), 1.15 (d, J = 6.6Hz, 3H), 1.04 (d, J = 6.7Hz, 3H).

[0207] Step 3

[0208] In a 100 mL three-necked flask, compound C1-18c (140 mg, 0.64 mmol), anhydrous N,N'-dimethylformamide (10 mL), compound 2-4 (195 mg, 1.28 mmol), and potassium carbonate (265 mg, 1.92 mmol) were added sequentially and reacted at 80°C for 8 hours. After LCMS and TLC monitoring showed the reaction was complete, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound C1-18 (40 mg, 0.13 mmol, yield 20.3%).

[0209] ESI-LCMS: m / z 292.2 [M+H] + .

[0210] 1H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 8.16 (d, J = 7.0Hz, 1H), 7.86 (d, J = 3.0Hz, 1H), 7.75 (d, J = 3.0Hz, 1H), 7.56 (d, J = 6.5Hz, 1H ), 6.31 (t, J=7.1Hz, 1H), 6.04 (d, J=10.6Hz, 1H), 2.89-2.76 (m, 1H), 2.11 (s, 3H), 0.94 (d, J=6.4Hz, 3H), 0.79 (d, J=6.5Hz, 3H).

[0211] Preparation Example 17 Preparation of Comparative Compound ZZL-7

[0212] first step

[0213] In a dry single-necked flask, (tert-butoxycarbonyl)-L-alanine (4.5 g, 23.78 mmol) was added, dissolved in dichloromethane (50 mL), and stirred in an ice bath for 10 min. Then, 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) were added to the flask in sequence and stirred at room temperature for 2 h. After TLC showed that the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was adjusted to acidity with 2M hydrochloric acid and extracted with dichloromethane (50 mL × 2). The organic phases were combined and adjusted to alkalinity with saturated sodium bicarbonate and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE: EA = 2: 1) to obtain the intermediate (tert-butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol, yield 90.39%). LCMS (M+H + )=303.1.

[0214] Step 2

[0215] (tert-Butyloxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol) was added to a dry single-necked flask and dissolved in dichloromethane (30 mL). 1.4-Dioxane hydrochloride (10 mL, 4 M) was then added to the flask and stirred at room temperature for 2 h. After TLC showed the reaction was complete, the organic phase was concentrated and purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain the intermediate L-alanyl-L-valine methyl ester (3.7 g, 18.32 mmol, yield 87.22%). LCMS (M+H+ )=203.3; 1 HNMR (400MHz, CDCl3) δ 8.13 (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).

[0216] Step 3

[0217] L-Alanyl-L-valine methyl ester (3.7 g, 18.32 mmol) and N,N-diisopropylethylamine (4.72 g, 36.64 mmol) were dissolved in tetrahydrofuran (50 mL), the atmosphere was thoroughly purged with nitrogen, and the mixture was stirred at 0°C. After 10 minutes, acetic anhydride (2.8 g, 27.48 mmol) was slowly added dropwise. The mixture was stirred at this temperature for 10 minutes and then moved to room temperature and stirred for 2 hours. After TLC indicated the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was acidified with 2M hydrochloric acid. The mixture was extracted with dichloromethane (50 mL x 4). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1). Compound ZZL-7 (acetyl-L-alanyl-L-valine methyl ester, 2.6 g, 10.67 mmol, yield 58.23%) was obtained. LCMS (M+H + )=245.3; 1 HNMR (400MHz, CDCl3) δ6.68 (d, J=8.5Hz, 1H), 6.21 (d, J=7.1Hz, 1H), 4.57-4.47 (m, 1H), 4.44 (dd, J=8.7, 4. 9Hz, 1H), 3.68 (s, 3H), 2.18-2.04 (m, 1H), 1.94 (s, 3H), 1.31 (d, J=7.0Hz, 3H), 0.85 (dd, J=10.1, 6.9Hz, 6H).

[0218] Activity Test Example 1 Plasma Stability Determination

[0219] After thawing the mouse plasma in a water bath at 37°C, centrifuge to remove the upper clot and record the pH at 7-8. Take a certain volume of acetonitrile stock solution of the test compound (concentration of 10mM) and dilute it to 1mM with acetonitrile as an intermediate solution. Propantheline is used as a positive control. Take a certain volume of the compound intermediate solution, add the corresponding volume of plasma and mix evenly so that the concentration of the test compound in the incubation system is 5μM and the content of organic solvent acetonitrile is 0.5%. Take 50μL of mixed plasma in a 96-well plate (N=2), incubate in a 37°C water bath for a certain period of time, add 300μL of methanol solution containing the internal standard to terminate the reaction, vortex centrifuge and take the supernatant for LC-MS / MS analysis. Make a curve based on the remaining percentage of the compound and the incubation time to obtain the k value and calculate the half-life of each compound. The formula is as follows:

[0220] 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.

[0221] Table 1 Plasma stability data of some compounds Note: If the remaining percentage of the compound is still greater than 80% after 120 minutes, then T 1 / 2 Recorded as >372.68min.

[0222] Activity Experiment Example 2 Pharmacokinetics Test

[0223] Compound pharmacokinetic testing was performed in 6-8 week old CD1 mice. Test compounds were dissolved in a 10% hydroxypropyl-β-cyclodextrin aqueous solution containing 10% DMSO and administered intravenously or orally. Compound concentrations in plasma samples were analyzed using LC-MS / MS. Pharmacokinetic calculations were performed using WinNonlin (Phoenix™, version 8.3) or other similar software. The following pharmacokinetic parameters were calculated based on plasma concentration versus time data:

[0224] Oral administration: AUC last , bioavailability (F).

[0225] The above parameter data were statistically calculated.

[0226] Table 2 shows the area under the concentration-time curve (AUC) and bioavailability (F) data of some compounds after oral administration. The results show that the compounds of the present application have good pharmacokinetic properties and are significantly better than ZZL-7.

[0227] Table 2 Pharmacokinetic data of some compounds

[0228] Activity Experiment Example 3

[0229] In vivo efficacy testing 1

[0230] 6-8 week old C57 / B6 mice were induced with a 28-day chronic unpredictable mild stress (CUMS) model. The open field test (OFT) was used to assess the model's success before evaluating drug efficacy. The experiment consisted of a blank control group, a model group, a vehicle control group, a fluoxetine control group, and a compound group. The test compound was administered intravenously (IV) at a dose of 100 mg / kg. Two hours later, the tail suspension test (TST) and forced swimming test (FST) were performed to assess depression in the mice. Prolonged immobility in the TST and FST indicated behavioral despair. Data were aggregated and analyzed using SPSS statistical software, and graphs were plotted using Graph Pad software based on the SPSS analysis results.

[0231] The test results show (see Figures 1 and 2) that compounds B1-1, B1-5 and B1-6 can quickly reverse the prolonged immobility time in the forced swimming and tail suspension tests in mice with chronic unpredictable stress, demonstrating that the embodiments of the present invention have a rapid antidepressant effect.

[0232] In vivo efficacy testing 2

[0233] 6-8 week old C57 / B6 mice were used to establish a 28-day chronic unpredictable mild stress (CUMS) model. The open field test (OFT) was used to evaluate the model's success before evaluating the drug's efficacy. The experiment was divided into a blank control group, a model group, a solvent control group, a fluoxetine control group, a ZZL-7 control group, and a compound group. The test compound was administered orally at a single dose of 25 mg / kg. Two hours later, the tail suspension test (TST) was performed to assess depression in the mice. Prolonged immobility in the TST indicated despair in the mice. Data were aggregated and analyzed using SPSS statistical software, and graphs were plotted using Graph Pad software based on the SPSS analysis results.

[0234] The test results showed (see FIG3 ) that compound B1-6 could quickly reverse the prolonged immobility time in the tail suspension test in the chronic unpredictable stress model mice, demonstrating that the embodiments of the present invention have a rapid antidepressant effect.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof: in, C * The chiral carbon atom is preferably in S configuration; The lactam ring Cy is a 4-16 membered monocyclic, bicyclic or tricyclic ring system optionally containing one or more substitutions; wherein the monocyclic, bicyclic or tricyclic ring each independently contains 0-3 heteroatoms selected from oxygen, sulfur and nitrogen as one or more ring members; R1 is selected from R5C(O)-, R5OC(O)-, R5SO2-, (R5)2NC(O)- or (R5)(R6)NC(O)-; R5, R6, R8 are -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated cycloalkyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated heterocyclic group, -C 6-10 Monocyclic or bicyclic aryl, -C 5-10 Monocyclic or bicyclic heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated cycloalkyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated heterocyclic group, -C 6-10 Monocyclic or bicyclic aryl, -C 5-10 The monocyclic or bicyclic heteroaryl groups are each optionally substituted with 0-3 deuterium, tritium, halogen, hydroxy, amino, nitro, cyano, -C 1-8 Straight chain or branched alkoxy, -C 1-8 Straight or branched cycloalkyl, -C 3-8 Heterocyclic group, -C 6-10 Aryl, or -C 5-10 Heteroaryl substitution; or R5 and R6 together with the nitrogen atom to which they are attached form a 3- to 8-membered monocyclic or polycyclic ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur as one or more ring members, the ring being optionally substituted with a substituent R7; wherein R7 is independently selected from hydrogen, deuterium, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, -C 3-8 Heterocyclic group, -C 6-10 Aryl and -C 5-10 heteroaryl; R2 is independently selected from hydrogen, C 1-8 Alkyl, substituted C 2-8 Alkenyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 6-14 Aryl or substituted C 5-14 Heteroaryl, wherein the substituted C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Cycloalkyl, C 6-14 Aryl and C 5-14 The heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, carboxyl, amino, nitro, cyano, -C 1-6 Acylamino, -C 1-6 Acyloxy, -C 1-6 Alkoxy, -C 6-14 Aryloxy, -C 1-6 Alkylthio, -C 1-6 Alkyl, -C 1-6 Acyl, -C 6-10 Aryl, -C 3-8 Cycloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl, -C 6-10 Aryl-C 2-6 Alkenyl, -C 6-10 Aryl-C 2-6 Alkynyl, heterocyclic, -C 5-14 Heteroaryl, halogenated C 1-6 Alkyl, -C 6-10 Aryl-C 1-6 Alkyl, -C 1-6 Hydroxyalkyl; wherein the heterocyclic group is a saturated or partially saturated 3-7 membered monocyclic ring, or a 7-10 membered bicyclic ring system; R3 is selected from -COOR8, -CONHR8, -COR8, -OR8, -NR8, -C 3-15 Cycloalkyl, -C 3-15 Heterocycloalkyl, -C 6-15 Aryl, -C 5-15 Heteroaryl; wherein the -C 3-15 Cycloalkyl, -C 3-15 Heterocycloalkyl, -C 6-15 Aryl, -C 5-15 each heteroaryl is optionally substituted with 0-8 R9; R9 is selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, -OR 10 、-NR 10 R 11 、-SR 10 、-COR 10 、-SOR 10 、-SO2R 10 、-NR 10 COR 11 、-CONR 10 R 11 、-OCOR 10 、-COOR 10 、-OCOOR 10 、-OCONR 10 R 11 、-NR 10 CONR 11 R 12 、-NR 10 COOR 11 、-NR 10 S02R 11 、-SO2NR 10 R 11 、-OSO2R 10 、-SO3R 10 , 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 0-8 R 13 replace; R 10 , R 11 , R 12 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 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl; R 13 is selected from hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each chain alkyl, heterochain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof, characterized in that: In the general formula (I): Cy is selected from the group shown in (a): X is independently selected from carbon, nitrogen, oxygen, and sulfur atoms; Y is independently selected from carbon and nitrogen atoms; wherein each ring is optionally substituted with one or more R4; R4 is independently, at each occurrence, deuterium, tritium, halogen, hydroxy, amino, nitro, cyano, C 1-6 Alkyl, OR a , SR a 、C(O)R a 、C(O)NR a R b 、C(O)OR a NR a R b NR a C(O)R b 、SO2R a NR a S02R b 、SO2NR a R b , -C 6-10 Aryl, -C 3-8 Cycloalkyl, -C 5-10 Heteroaryl, -C 3-8 Heterocycloalkyl or heterocycloalkenyl, wherein -C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of amino, cyano, halogen, hydroxy, -C 1-6 Alkoxy, -C 3-8 Heterocycloalkyl, -C 3-8 Cycloalkyl, -C 5-10 Heteroaryl, -C 6-10 Aryl; R a and R b is independently selected at each occurrence from hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 6-10 Aryl, -C 5-10 Heteroaryl and -C 3-8 Heterocycloalkyl.

3. A compound of formula (II), or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof: in Ring A is a 3-15 membered heterocyclyl or a 3-15 membered heteroaryl; R1 is -C(O)OR3, -C(O)N(H)R3, -C(O)R3, -OR3, -N(H)R3, -C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 Aryl, or 5-15 membered heteroaryl; optionally, the -C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 Aryl, or 5-15 membered heteroaryl is replaced by one or more selected from C 1-4 Alkyl and halogenated C 1-4 Substitution of alkyl groups; R2 is R4C(O)-, R4OC(O)-, R4S(O)2-, (R4)2NC(O)-, -C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 Aryl, or 5-15 membered heteroaryl; R3 and R4 are independently -C 1-8 Alkyl, -C 1-8 Deuterated alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-12 Cycloalkyl, -C 3- 12 Heterocycloalkyl, -C 6-10 Aryl, or 5-15 membered heteroaryl; Preferably, C * The carbon atom is in S configuration.

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 the A ring is 5. The compound of claim 4, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein the A ring is a 4-13 membered heterocyclyl or a 5-10 membered heteroaryl, and has 1-4 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 the A ring is wherein n is 1, 2, 3 or 4, m is 1 or 2, p is 1 or 2, X1, X2 and X3 are independently O, S, N or NH, or C, wherein Indicates a single bond or a double bond.

7. The compound of claim 6, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein the A ring is 8. 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 -C(O)OR3, -C(O)N(H)R3, -C 6-15 Aryl, or 5-15 membered heteroaryl; R3 is -C 1-4 Alkyl or -C 1-4 deuterated alkyl; the 5-15 membered heteroaryl has 1-2 heteroatoms selected from N, O, and S.

9. The compound of claim 8, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R1 is 10. The compound of claim 3, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein R2 is R4C(O)- or a 5-6 membered heteroaryl; R4 is -C 1-4 Alkyl, -C 1-4 Deuterated alkyl or -C 3-5 Cycloalkyl; the 5-6 membered heteroaryl has 1 N heteroatom.

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 R2 is 12. The compound of claim 6, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein when ring A is When R1 is R2 is in Indicates a single bond or a double bond.

13. The compound of claim 6, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein when ring A is When R1 is R2 is in Indicates a single bond or a double bond.

14. The compound of claim 6, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein when ring A is When R1 is R2 is in Indicates a single bond or a double bond.

15. The compound of claim 12, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein when ring A is When R1 is R2 is 16. The compound of claim 13, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein when ring A is When R1 is R2 is 17. The compound of claim 14, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein when ring A is When R1 is R2 is 18. A compound, or a pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, wherein the compound is selected from:

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 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.

20. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 18 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.

21. Use of the compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, the pharmaceutical composition of claim 19, or the pharmaceutical preparation of claim 20 in the preparation of a medicament for treating and / or preventing depression.

22. Use of the compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, the pharmaceutical composition of claim 19, or the pharmaceutical preparation of claim 20 in the preparation of a fast-acting drug for treating and / or preventing depression.

23. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, a pharmaceutical composition according to claim 19, or a pharmaceutical preparation according to claim 20 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 and hot flashes.

24. The use according to claim 23, wherein the neuropathic pain is chronic pain.

25. The use according to claim 24, wherein the chronic pain is fibromyalgia.

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