Lactam ring 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 characterized by significant and persistent low mood. Clinically, it can be seen that the mood is low and disproportionate to the situation. The depression can range from melancholy to grief, inferiority and depression, and even pessimism and world-weariness. There may be suicidal attempts or behaviors; severe cases may have psychotic symptoms such as hallucinations and delusions. More than 350 million people suffer from depression worldwide, an increase of 18% in the past decade. As of 2017, there were more than 54 million depression patients in China alone. The recurrence rate of major depressive disorder is as high as 50%-85%, and the suicide rate is 4.0%-10.6%. It has become the most common mental illness.

[0003] The disorder of neurotransmitters such as norepinephrine, dopamine, and 5-HT (5-hydroxytryptamine) 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 iprohydrazine and isocarboxazid. Since these drugs contain ingredients with greater side effects, they are now basically discontinued; 2) Tricyclic antidepressants: This type of drug has a good effect on relieving depression, but has a greater adverse effect on patients with other diseases. This drug includes clomipramine, imipramine hydrochloride, etc.; 3) Selective 5-HT reuptake inhibitors: This drug can make up for the symptoms of insufficient 5-hydroxytryptamine in depressed patients, mainly fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine; 4) 5-HT and norepinephrine reuptake inhibitors: This type of drug has a dual antidepressant mechanism and is relatively safe, such as venlafaxine, duloxetine, etc. 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 formula (I), or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof:

[0007]

[0008] in,

[0009] C * The chiral carbon atom is preferably in S configuration;

[0010] 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;

[0011] R 1 Selected from R 5 C(O)-、R 5 OC(O)-、R 5 SO 2 -、(R 5 ) 2 NC(O)-or(R 5 )(R 6 )NC(O)-;

[0012] R 5 , R 6 , R 8 Yes-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-12 Monocyclic or bicyclic saturated or partially unsaturated cycloalkyl, -C 3-12Monocyclic 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

[0013] R 5 and R 6 Together with the nitrogen atom to which they are attached, they 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 by a substituent R7; wherein R 7 are 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;

[0014] R 2 independently selected from hydrogen, substituted 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 1-6Alkoxy, -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;

[0015] R 3 Selected from -COOR 8 、-CONR 8 、-COR 8 、-OR 8 、-NR 8 , -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 The heteroaryl group is each optionally substituted by 0-8 R 9 replace;

[0016] R 9 Selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, -OR 10 、-NR 10 R 11 、-SR 10 、-COR 10 、-SOR 10 、-SO 2 R 10 、-NR 10 COR 11 、-CONR 10 R 11 、-OCOR 10 、-COOR 10 、-OCOOR 10 、-OCONR 10R 11 、-NR 10 CONR 11 R 12 、-NR 10 COOR 11 、-NR 10 SO 2 R 11 、-SO 2 NR 10 R 11 、-OSO 2 R 10 、-SO 3 R 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;

[0017] 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;

[0018] 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.

[0019] In one or more embodiments, C * The chiral carbon atom is in S configuration.

[0020] In one or more embodiments, Cy in the general formula (I) is selected from the group shown in (a):

[0021]

[0022] 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 R 4replace;

[0023] R 4 is independently at each occurrence deuterium, tritium, halogen, hydroxy, amino, nitro, cyano, C 1-6 Alkyl, ORa, 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 、SO 2 R a NR a SO 2 R b 、SO 2 NR 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;

[0024] 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.

[0025] 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:

[0026]

[0027] in

[0028] Ring A is a 3-15 membered heterocyclyl or a 3-15 membered heteroaryl;

[0029] R 1 -C(O)OR 3 、-C(O)N(H)R 3 、-C(O)R 3 、-OR 3 、-N(H)R 3 , -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;

[0030] R 2 For R 4 C(O)-、R 4 OC(O)-、R 4 S(O) 2 -、(R 4 ) 2 NC(O)-、-C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 Aryl, or 5-15 membered heteroaryl;

[0031] R 3 and R 4 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.

[0032] In one or more embodiments, C * The carbon atom is in S configuration.

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

[0034] 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.

[0035] In one or more embodiments, the A ring is Where n is 1, 2, 3 or 4, m is 1 or 2, p is 1 or 2, X 1 , X 2 and X 3 are independently O, S, N or NH, or C, wherein Indicates a single bond or a double bond.

[0036] In one or more embodiments, the A ring is

[0037]

[0038] In one or more embodiments, R 1 -C(O)OR 3 、-C(O)N(H)R 3 , -C 6-15 Aryl, or 5-15 membered heteroaryl; R 3 For -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.

[0039] In one or more embodiments, R 1 for

[0040] In one or more embodiments, R 2 For R 4 C(O)- or 5-6 membered heteroaryl; R 4 For -C 1-4 Alkyl, -C 1-4 Deuterated alkyl or -C 3-5 Cycloalkyl; the 5-6 membered heteroaryl has 1 N heteroatom.

[0041] In one or more embodiments, R 2 for

[0042] In one or more embodiments, when the A ring is When R 1 for in Indicates a single bond or a double bond.

[0043] In one or more embodiments, when the A ring is When R 1 for R 2 for in Indicates a single bond or a double bond.

[0044] In one or more embodiments, when the A ring is When R 1 for R 2 for in Indicates a single bond or a double bond.

[0045] In one or more embodiments, when the A ring is When R 1 for R 2 for

[0046] In one or more embodiments, when the A ring is

[0047] When R 1 for R 2 for

[0048] In one or more embodiments, when the A ring is When R 1 for R 2 for In one or more embodiments, the compound is selected from:

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055] 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.

[0056] One or more embodiments of the pharmaceutical preparation of the present application include the 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.

[0057] 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 in the preparation of a medicament for treating and / or preventing depression.

[0058] 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.

[0059] One or more embodiments of the present application provide use of the pharmaceutical preparation of the present application in preparing a drug for treating and / or preventing depression.

[0060] 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 in the preparation of a fast-acting drug for treating and / or preventing depression.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] In one or more embodiments, the neuropathic pain is chronic pain.

[0065] In one or more embodiments, the chronic pain is fibromyalgia.

[0066] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0067] One or more embodiments of the present application provide the pharmaceutical composition of the present application, which is used as a medicament.

[0068] One or more embodiments of the present application provide the pharmaceutical preparation of the present application, which is used as a medicament.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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, a pharmaceutical composition, or a pharmaceutical formulation of the present application.

[0075] 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.

[0076] 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.

[0077] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0078] The term "amino" refers to -NH 2 .

[0079] The term "hydroxy" refers to -OH.

[0080] "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.

[0081] "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.

[0082] "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.

[0083] "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.

[0084] "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.

[0085] "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.

[0086] "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.

[0087] "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.

[0088] "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.

[0089] 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.

[0090] "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.

[0091] "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.

[0092] "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.

[0093] "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 state 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 binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0094] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0095] "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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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).

[0101] "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.

[0102] 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

[0103] Figure 1 The results of the forced swimming test of in vivo efficacy test 1 of active example 3 are shown.

[0104] Figure 2 The results of the tail suspension experiment of in vivo efficacy test 1 of active example 3 are shown in FIG.

[0105] Figure 3 The results of the tail suspension experiment of in vivo efficacy test 2 of active example 3 are shown. DETAILED DESCRIPTION

[0106] 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.

[0107] The following compounds were prepared in the examples of this application:

[0108] Table 1: Series A compounds

[0109]

[0110]

[0111]

[0112] Table 2: B series compounds

[0113]

[0114]

[0115]

[0116]

[0117] Table 3: C series compounds

[0118]

[0119]

[0120] Preparation Example

[0121] Preparation Example 1 Preparation of Compound A1-2

[0122]

[0123] first step

[0124] 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 solution was reacted at room temperature for 4 hours. After the reaction was completed as monitored by TLC and LCMS, water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue, which 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), with a yield of 67%. MSm / z(ESI): 304.9[M+H] + .

[0125] Step 2

[0126] 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 thereto, and the mixture was reacted at room temperature for 4 hours. After the reaction was complete as monitored by rLC and LCMS, the solution was rotary evaporated to dryness, and then dissolved in acetonitrile (30 mL), and cesium carbonate (6.0 g, 18.4 mmol) was added thereto, and the mixture was reacted at 60°C for 6 hours. After the reaction was completed, the solvent was rotary evaporated to dryness under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane / methanol=10 / 1) to obtain the crude target product, and then compound A1-2 (332 mg, white solid) was obtained by preparative HPLC, with a yield of 14%. MS m / z (ESI): 257.0 [M+H] + .

[0127] 1 H NMR (400 MHz, DMSO-d 6 )68.19 (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).

[0128] Preparation Example 2 Preparation of Compound B1-1

[0129]

[0130] first step

[0131] At 0°C, (R)-2-hydroxy-3-methylbutyric acid methyl ester 2-1 (2.0 g, 15 mmol) was dissolved in dichloromethane (50 mL), and trifluoromethanesulfonic anhydride (5.5 g, 20 mmol) and 2,6-dimethylpyridine (2.1 g, 20 mmol) were added thereto. The reaction solution was reacted at 25°C for 3 hours. After the reaction was complete as monitored by TLC and LCMS, the reaction solution was concentrated, and the residue was extracted with petroleum ether (30 mL×3) and concentrated under reduced pressure to obtain compound 2-2 (3.1 g, colorless liquid), with a yield of 73%.

[0132] 1 H NMR (400 MHz, CDCl 3) 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).

[0133] Step 2

[0134] 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, the residue was washed with ethyl acetate (10 mL), filtered under reduced pressure, and the filter cake was recrystallized with methanol to obtain compound 2-4 (2.0 g, black solid), with a yield of 55%.

[0135] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0136] Step 3

[0137] Compound 2-4 (700 mg, 4.6 mmol) was dissolved in tetrahydrofuran (20 mL), sodium hydride (202 mg, 5.1 mmol) was added thereto, and 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, and then extracted with ethyl acetate (50 mL×3), the organic phases were combined and washed with brine (20 mL×3), dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column (petroleum ether / ethyl acetate=4 / 1~1 / 1) to obtain compound B1-1 (970 mg, white solid), yield: 75%. MS m / z(ESI): 267.1[M+H] + .

[0138] 1 H NMR (400 MHz, DMSO-d 6)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).

[0139] Preparation Example 3 Preparation of Compound A1-3

[0140]

[0141] 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 for 48 hours under a hydrogen atmosphere. After the reaction was complete as monitored by TLC and LCMS, the reaction solution was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure. The obtained residue was separated by a reverse separation column (0.1% TFA in H 2 O:CH 3 CN) after separation and purification to obtain compound A1-3 (0.45 g, yellow oil), yield: 42%. MSm / z(ESI): 271.2[M+H] + .

[0142] 1 H NMR (400 MHz, CDCl 3 )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).

[0143] Preparation Example 4 Preparation of Compound B1-5

[0144]

[0145] first step

[0146] Concentrated sulfuric acid (140 mg, 1.4 mmol) was added dropwise to the compound ethyl nitroacetate (20.28 g, 152.4 mmol) and 1,1,3,3-tetramethoxypropane (50.04 g, 304.8 mmol), 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 with an eluent of petroleum ether and ethyl acetate (V / V=1:1) to obtain the title product 4-2 (11.5 g, brown oil, 30%). MS (ESI) m / z: 255.2 [M+H] + .

[0147] Step 2

[0148] Compound 4-2 (9.0 g, 35 mmol) was dissolved in a solution of methanol and water (V / V=5:1, 54 mL), and then lithium hydroxide monohydrate (5.94 g, 141.6 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. The reaction was concentrated under reduced pressure and diluted with water (50 mL), and the pH was adjusted to 1-2 with dilute hydrochloric acid (1.0 M), extracted with ethyl acetate (50 mL×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] + .

[0149] Step 3

[0150] Compound 4-3 (1.5 g, 6.2 mmol) was dissolved in N, N-dimethylformamide (25 mL), and potassium carbonate (2.57 g, 18.6 mmol) and deuterated iodomethane (1.8 g, 12.4 mmol) were added to the reaction solution in sequence. 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] + .

[0151] Step 4

[0152] Compound 4-4 (1.5 g, 5.8 mmol) was dissolved in N, N-dimethylformamide and acetic acid (V / V=25:6, 31 mL), and then zinc powder (2.28 g, 34.8 mmol) was added to the reaction solution. After the reaction solution was stirred at 25°C for 2 hours, the reaction system was placed in an ice bath, diluted with water (80 mL), adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3), dried with 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] + .

[0153] Step 5

[0154] Triethylamine (1.07 g, 10.56 mmol) was added to a solution of compound 4-5 (0.6 g, 2.64 mmol) in dichloromethane (15 mL), the reaction temperature was lowered to 0°C, acetyl chloride (414 mg, 5.28 mmol) was slowly added dropwise to the reaction solution, the reaction temperature was slowly raised to 25°C, and the reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V=3:1) to obtain the title product B1-5 (415 mg, brown solid, 58%). MS (ESI) m / z: 270.1 [M+H] + .

[0155] 1 H NMR (400 MHz, DMSO-d 6 )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=7.2Hz, 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).

[0156] Preparation Example 5 Preparation of Compound B1-6

[0157]

[0158] first step

[0159] Zinc powder (921 mg, 14.17 mmol) was added to a methanol (30 mL) solution of compound 4-2 (3.0 g, 11.81 mmol). Subsequently, glacial acetic acid (72 mg, 1.2 mmol) was slowly added dropwise to the reaction solution, and the reaction was stirred at room temperature for 2 hours. Filter, concentrate the filtrate under reduced pressure, and purify it by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V=7:3) to obtain compound 5-1 (1.32 g, white solid, 49.9%). MS (ESI) m / z: 225 [M+H] + .

[0160] Step 2

[0161] Compound 5-1 (1.32 g, 5.89 mmol) was dissolved in dichloromethane (15 mL) solution, and then deuterated acetyl chloride (477 mg, 5.89 mmol) and N, N-diisopropylethylamine (912 mg, 7.06 mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at room temperature for 2 hours. After dilution with water (15 mL), it was extracted with dichloromethane (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to elute petroleum ether and ethyl acetate (V / V=74:26) to obtain compound B1-6 (500 mg, gray-green solid, 31.5%). MS (ESI) m / z: 270.1 [M+H] + .

[0162] 1 H NMR (400 MHz, DMSO-d 6 )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=7.2Hz, 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).

[0163] Preparation Example 6 Preparation of Compound C1-6

[0164]

[0165] Triethylamine (1.07 g, 10.56 mmol) was added to a solution of compound 4-5 (450 mg, 1.98 mmol) in dichloromethane (20 mL), the reaction temperature was lowered to 0°C, cyclopropylacyl chloride (414 mg, 3.96 mmol) was slowly added dropwise to the reaction solution, and the temperature was slowly raised to 25°C after the addition was complete. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with an eluent of petroleum ether and ethyl acetate (V / V=3:1) to obtain compound C1-6 (420 mg, brown solid, 71%). MS (ESI) m / z: 296.2 [M+H] + .

[0166] 1 H NMR (400 MHz, DMSO-d 6 )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), 4.95 (d, J=9.7 Hz, 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).

[0167] Preparation Example 7 Preparation of Compound B1-4

[0168]

[0169] first step

[0170] 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 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 crude product was separated and purified by silica gel column to obtain compound 7-2 (1.00 g, white solid, 90%).

[0171] Step 2

[0172] Compound 7-2 (0.20 g, 1.31 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (35 mg, 1.44 mmol) was added thereto, and 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, and then 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] + .

[0173] 1 H NMR (400 MHz, CDCl 3 ) 68.83 (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).

[0174] Preparation Example 8 Preparation of Compound C1-7

[0175]

[0176] first step

[0177] 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, react at 90 ° C for 3 hours, LCMS and TLC monitoring show that the reaction is complete, and then concentrate under reduced pressure. The crude product is dissolved in saturated sodium bicarbonate aqueous solution (150 mL), and then extracted with ethyl acetate (50 mL×3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is slurried with dichloromethane (30 mL) and filtered. The filter cake is the product. Compound 8-2 (900 mg, 4.81 mmol, yield 52.97%) is obtained. ESI-LCMS: m / z 188.2 [M+H] + .

[0178] Step 2

[0179] In a 100 mL single-mouth bottle, compound 8-2 (810 mg, 4.33 mmol), anhydrous tetrahydrofuran (30 mL), sodium hydride (190 mg, 4.76 mmol) were added in sequence, nitrogen replacement protection was used, and the mixture was reacted at 25°C for 30 minutes. Compound 2-2 (1.37 g, 5.20 mmol) was added and the mixture was reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, methanol (10 mL) was added to quench the mixture, 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] + .

[0180] 1 H NMR (400 MHz, DMSO-d 6 ) 68.58 (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, 5.0Hz, 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).

[0181] Preparation Example 9 Preparation of Compound C1-8

[0182]

[0183] first step

[0184] In a 100 mL single-mouth bottle, compound C1-7 (800 mg, 2.65 mmol), tetrahydrofuran (16 mL), and aqueous lithium hydroxide solution (0.5 M, 16 mL) were added in sequence and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, water (100 mL) was added for dilution, the pH was adjusted to 4-5 with 1.0 M hydrochloric acid, and 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 9-1 (750 mg, 2.61 mmol, yield 98.49%) was directly used for the next step. ESI-LCMS: m / z 288.3 [M+H] + .

[0185] Step 2

[0186] In a 100 mL single-mouth bottle, compound 9-1 (500 mg, 1.74 mmol), dichloromethane (20 mL), thionyl chloride (414 mg, 3.48 mmol) were added in sequence, reacted at 25°C for 30 minutes, deuterated methanol (2 mL) was added, and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, it was concentrated under reduced pressure, the crude product was redissolved in ethyl acetate (100 mL), washed once with saturated sodium bicarbonate aqueous 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] + .

[0187] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0188] Preparation Example 10 Preparation of Compound C1-3

[0189]

[0190] first step

[0191] In a 100mL single-mouth bottle, compound B1-1 (620mg, 2.33mmol), tetrahydrofuran (15mL), and lithium hydroxide aqueous solution (0.5M, 15mL) were added in sequence and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, 1.0M hydrochloric acid was added for dilution (100mL), the pH was adjusted to 1-2, and the mixture was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was directly used for the next step. Compound 10-1 (550mg, 2.18mmol, yield 93.56%) was obtained. ESI-LCMS: m / z 253.3[M+H] + .

[0192] Step 2

[0193] 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, dilute with dichloromethane (100 mL), separate the layers, wash the organic phase with dilute hydrochloric acid (1.0 M) (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform silica gel column chromatography (ethyl acetate gives the product) to obtain compound C1-3 (400 mg, 1.51 mmol, yield 69.27%). ESI-LCMS: m / z 266.3 [M+H] + .

[0194] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0195] Preparation Example 11 Preparation of Compound C1-5

[0196]

[0197] first step

[0198] In a 100mL single-mouth bottle, add compound 2-3 (3.0g, 27.24mmol), triethylamine (8.27g, 81.75mmol), cool to 0℃, slowly add cyclopropylcarbonyl chloride (4.27g, 40.88mmol), return to 25℃ and react for 2 hours. After LCMS and TLC monitoring show that the reaction is complete, add methanol to quench, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain compound 11-2 (2.7g, 15.15mmol, yield 55.62%). ESI-LCMS: m / z 179.2[M+H]+ .

[0199] Step 2

[0200] In a 100 mL three-necked flask, compound 11-1 (600 mg, 3.37 mmol), anhydrous tetrahydrofuran (30 mL), sodium hydride (148 mg, 3.71 mmol) were added in sequence, replaced with nitrogen for protection, reacted at 25°C for 30 minutes, and compound 2-2 (1.33 g, 5.05 mmol) was added, and reacted at 25°C for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, methanol was added for quenching, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound C1-5 (850 mg, 2.91 mmol. Yield 86.35%).

[0201] ESI-LCMS: m / z 293.4 [M+H] + .

[0202] 1 H NMR (400 MHz, DMSO-d 6 )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=9.7Hz, 1H), 3.6 4 (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).

[0203] Preparation Example 12 Preparation of Compound C1-4

[0204]

[0205] first step

[0206] In a 100 mL single-mouth bottle, compound C1-5 (600 mg, 2.05 mmol), tetrahydrofuran (13 mL), and lithium hydroxide aqueous solution (0.5 M, 13 mL) were added in sequence 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 12-1 (560 mg, 2.01 mmol, yield 98.05%) was directly used for the next step reaction.

[0207] ESI-LCMS: m / z 279.4 [M+H]+ .

[0208] Step 2

[0209] In a 100 mL single-mouth 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), N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (2.74 g, 7.20 mmol) were added in sequence, and the mixture was 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, dilute with dichloromethane (100 mL), separate the mixture, wash the organic phase (50 mL×3) with dilute hydrochloric acid (1.0 M), dry with 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] + .

[0210] 1 H NMR (400 MHz, DMSO-d 6 )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=1 1.0 Hz, 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).

[0211] Preparation Example 13 Preparation of Compound B1-3

[0212]

[0213] first step

[0214] In a 100mL single-mouth bottle, add compound 13-1 (1.0g, 9.00mmol), triethylamine (2.73g, 27.00mmol), cool to 0℃, slowly add acetyl chloride (1.06g, 13.5mmol), return to 25℃ and react for 2 hours. After LCMS and TLC monitoring show that the reaction is complete, add methanol to quench, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain compound 13-2 (500mg, 3.26mmol, yield 36.22%). ESI-LCMS: m / z 154.2[M+H] + .

[0215] Step 2

[0216] In a 100 mL single-mouth bottle, compound 13-2 (375 mg, 2.45 mmol), anhydrous N, N-dimethylformamide (20 mL), sodium hydride (108 mg, 2.70 mmol) were added in sequence, nitrogen replacement protection was used, and the mixture was reacted at 25°C for 30 minutes. Compound 2-2 (777 mg, 2.94 mmol) was added and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, saturated sodium bicarbonate aqueous solution (150 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined and washed with saturated sodium chloride aqueous 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] + .

[0217] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0218] Example 14 Synthesis of Compound A1-4

[0219]

[0220] first step

[0221] In a 100mL three-necked flask, compound A1-4a (1.0g, 7.8mmol) and triethylamine (2.37g, 23.4mmol) were added in sequence, the temperature was lowered to 0°C, acetyl chloride (918mg, 11.7mmol) was slowly added dropwise, and after the addition was complete, the reaction solution was slowly heated to 25°C and reacted for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, methanol (50mL) was added to quench, the mixture was concentrated under reduced pressure, and silica gel column chromatography (dichloromethane: methanol = 15: 1) was performed to obtain compound A1-4b (950mg, 5.58mmol, yield 71.5%).

[0222] ESI-LCMS: m / z 171.2 [M+H] + .

[0223] Step 2

[0224] In a 100mL three-necked flask, compound A1-4b (500mg, 2.94mmol), anhydrous N, N-dimethylformamide (20mL), sodium hydride (78mg, 3.23mmol) were added in sequence, and under nitrogen protection, the reaction was continued at 25°C for 30 minutes, and compound 2-2 (932mg, 3.53mmol) was added, and the reaction was continued for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, dilute hydrochloric acid (100mL) was added to quench, and the mixture was extracted with ethyl acetate (50mL×3), and the organic phases were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and chromatographed on a silica gel column to obtain compound A1-4 (98mg, 0.34mmol, yield 11.6%).

[0225] ESI-LCMS: m / z 285.4 [M+H] + .

[0226] 1 H NMR (400 MHz, DMSO-d 6 )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, 0.1 9H), 3.64(s, 2.45H), 3.59(s, 0.55H), 3.57-3.36(m, 2H), 2.28-2.04(m, 1H), 1.85(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=6.5 Hz, 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).

[0227] Example 15 Synthesis of Compound C1-2

[0228]

[0229] first step

[0230] In a 100 mL three-necked flask, compound C1-3 (150 mg, 0.57 mmol), methanol (20 mL), palladium carbon (75 mg), palladium hydroxide carbon (75 mg) were added in sequence. The mixture was reacted at 60 ° C for 48 hours under hydrogen conditions. After LCMS and TLC monitoring showed that the reaction was completed, the mixture was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was performed to obtain compound C1-2 (60 mg, 0.22 mmol, yield 39.1%).

[0231] ESI-LCMS: m / z 270.3 [M+H] + .

[0232] 1 H NMR (400 MHz, DMSO-d 6 ) 68.16-8.03 (m, 1H), 7.93 (d, J = 4.5Hz, 0.65H), 7.86 (d, J = 4.5Hz, 0.35H), 4.57 (d, J = 10.9 Hz, 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).

[0233] Example 16 Synthesis of Compound C1-18

[0234]

[0235] first step

[0236] In a 250mL three-necked flask, compound C1-18a (4g, 35.35mmol), anhydrous tetrahydrofuran (100mL), nitrogen replacement protection, cooling to -10°C, slowly adding isopropylmagnesium chloride·lithium chloride (35mL, 70mmol, 2.0M tetrahydrofuran solution), after the addition is complete, the reaction solution slowly returns to room temperature and continues to stir for 4 hours. After LCMS and TLC monitoring show that the reaction is complete, add saturated ammonium chloride aqueous solution (200mL) to quench under ice bath, extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and silica gel column chromatography to obtain compound C1-18b (2.5g, 15.9mmol, yield 45.0%).

[0237] ESI-LCMS: m / z 158.1 [M+H] + .

[0238] Step 2

[0239] In a 250mL three-necked flask, compound C1-18b (1.5g, 9.54mmol), anhydrous dichloromethane (100mL), triethylamine (2.89g, 28.62mmol), pyridine (490mg, 6.21mmol) were added in sequence. After the reaction solution was stirred at room temperature for 10 minutes, phosphorus tribromide (7.7g, 28.62mmol) was slowly added dropwise, and stirring was continued for 16 hours after the addition was complete. After LCMS and TLC monitoring showed that the reaction was complete, saturated sodium carbonate aqueous solution (200mL) was added to quench, and extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and silica gel column chromatography was performed to obtain compound C1-18c (170mg, 0.77mmol, yield 8.1%).

[0240] ESI-LCMS: m / z 221.9 [M+H] + .

[0241] 1 H NMR (400 MHz, CDCl 3 )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).

[0242] Step 3

[0243] 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), potassium carbonate (265 mg, 1.92 mmol) were added in sequence and reacted at 80°C for 8 hours. After LCMS and TLC monitoring showed that the reaction was complete, water (100 mL) was added for dilution, and ethyl acetate (50 mL × 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound C1-18 (40 mg, 0.13 mmol, yield 20.3%).

[0244] ESI-LCMS: m / z 292.2 [M+H] + .

[0245] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0246] Preparation Example 17 Preparation of Comparative Compound ZZL-7

[0247]

[0248] first step

[0249] 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.

[0250] Step 2

[0251] 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, the organic phase is 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 (400 MHz, CDCl 3 ) 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).

[0252] Step 3

[0253] 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).

[0254] Activity Test Example 1 Plasma Stability Determination

[0255] 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:

[0256]

[0257] 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.

[0258] Table 1 Plasma stability data of some compounds

[0259] Compound <![CDATA[T 1 / 2 (min)]]> ZZL-7 25.29 A1-3 ＞372.68 B1-1 214.17 A1-4 ＞372.68 C1-2 ＞372.68 C1-18 ＞372.68

[0260] Note: If after 120 minutes, the remaining percentage of the compound is still greater than 80%, then T 1 / 2 Recorded as >372.68min.

[0261] Activity Experiment Example 2 Pharmacokinetics Test

[0262] The pharmacokinetic test of the compound was carried out 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:

[0263] Oral administration: AUC last , bioavailability (F).

[0264] The above parameter data were statistically calculated.

[0265] Table 2 shows the area under the concentration-time curve (AUC) and bioavailability (F) data of some compounds for oral administration. The results show that the compounds of the present application have good pharmacokinetic properties and are significantly better than ZZL-7.

[0266] Table 2 Pharmacokinetic data of some compounds

[0267] Compound <![CDATA[AUC last (mg / mL)]]> F(％) ZZL-7 138.5 7.5 A1-3 287.7 24.0 B1-5 432.8 32.3 B1-6 567.1 41.9

[0268] Activity Test Example 3

[0269] In vivo efficacy testing1

[0270] 6-8 week old C57 / B6 mice were selected to establish the 28-day animal chronic unpredictable 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, a model group, a solvent control group, 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.

[0271] The test results show that (see Figure 1 and Figure 2 ), compounds B1-1, B1-5 and B1-6 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in forced swimming and tail suspension tests, proving that the embodiments of the present invention have a rapid antidepressant effect.

[0272] In vivo efficacy testing2

[0273] 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, a model group, a solvent control group, 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 the tail suspension test (TST) was performed 2h 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 GraphPad software was used to draw images based on the SPSS analysis results.

[0274] The test results show that (see Figure 3 ), compound B1-6 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in the tail suspension test, proving 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 - C3-8 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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