Lactam ring compounds and uses thereof

Abstract

The present application discloses lactam ring compounds and uses thereof, which have a rapid antidepressant effect.

Description

TECHNICAL FIELD

[0001] The present application generally belongs to the field of medicine. Specifically, the present application relates to compounds with rapid anti-depression effect and applications thereof. BACKGROUND

[0002] Depression is a common mental disorder characterized by significant and persistent low mood, and is a common mental illness. The clinical mood is out of touch with the situation, and the emotional depression can be from gloomy to desperate, self-deprecating and depressed, even pessimistic and world-weary, and can have suicidal attempts or behaviors. Severe cases can have hallucinations, delusions and other psychotic symptoms. Globally, more than 350 million people suffer from depression, with an increase of 18% in the past decade. As of 2017, there are more than 54 million depression patients in China. The recurrence rate of major depressive disorder is as high as 50%-85%, and the suicide rate is 4.0%-10.6%, which has become the most common mental illness.

[0003] The imbalance 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. Antidepressants are mainly divided into the following four categories according to their effects and mechanisms of action: 1) Monoamine oxidase inhibitors: such as isopropylhydrazine, isocarboxazid, which has been basically discontinued due to the presence of ingredients with greater side effects; 2) Tricyclic antidepressants: this class of drugs has a good effect on depression relief, but has a greater adverse effect on patients with other body conditions, including clomipramine, imipramine hydrochloride, etc.; 3) Selective 5-HT reuptake inhibitors: this drug can make up for the symptoms of 5-hydroxytryptamine deficiency in depression patients, mainly including fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine; 4) 5-HT and norepinephrine reuptake inhibitors: this class of drugs has a dual antidepressant mechanism and relatively high safety, such as venlafaxine, duloxetine, etc. Among them, the 3rd and 4th categories are the main drugs, and the 1st and 2nd categories are basically discontinued.

[0004] Since the advent of the 5-hydroxytryptamine reuptake inhibitor (SSRi), there have been dozens of generations of iterative upgrades. There are currently more than a hundred kinds of research projects, mainly focusing on SSRi, selective 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI), norepinephrine and specific 5-hydroxytryptamine antidepressants (NaSSA), 5-HT receptor antagonists and reuptake inhibitors (SARIs), NMDA receptor antagonists, etc. The market for antidepressants is also very concentrated. To date, there have been more than 30 SSRi varieties in global application, and the TOP10 are escitalopram, sertraline, venlafaxine, paroxetine, duloxetine, flupentixol + mirtazapine, fluoxetine, citalopram and fluvoxamine, with a combined market share of over 90%.

[0005] However, the currently used antidepressants in clinic have serious limitations, mainly slow onset, lag, and need 3-4 weeks of continuous medication to take effect, and many patients give up treatment because they cannot achieve the desired effect; for patients with suicidal tendencies, their lives may not be saved in time. The (S) enantiomer of ketamine (Esketamine) in the form of nasal spray was listed in the United States in 2019. It can quickly (within hours) relieve depressive symptoms and can last for 3-4 days. Although esketamine can quickly take effect, it has serious side effects, including severe drowsiness, dissociative hallucinations, potential addiction, and must be used 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 that can be quickly and effectively taken orally. SUMMARY

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

[0007]

[0008] wherein,

[0009] C * The chiral carbon atom is preferably in the 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 each of the monocyclic, bicyclic or tricyclic ring independently contains 0-3 heteroatoms selected from oxygen, sulfur, nitrogen as one or more ring members;

[0011] R1is selected from R5C(O)-, R5OC(O)-, R5SO2-, (R5)2NC(O)- or (R5)(R6)NC(O)-;

[0012] R5, R6, R8are -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 heterocyclyl, -C 6-10 monocyclic or bicyclic aryl, -C 5-10 monocyclic or bicyclic heteroaryl, said -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 groups, -C 6-10 Monocyclic or bicyclic aryl, -C 5-10 Monocyclic or bicyclic heteroaryl groups are each optionally surrounded by 0-3 deuterium, tritium, halogen, hydroxyl, amino, nitro, cyano, or -C groups. 1-8 Straight-chain or branched alkoxy groups, -C 1-8 Straight-chain or branched cycloalkyl, -C 3-8 Heterocyclic group, -C 6-10 aryl, or -C 5-10 heteroaryl substitution; or

[0013] R5 and R6, together with the nitrogen atom to which they are attached, form a 3- to 8-membered monocyclic or polycyclic ring, wherein the ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur as one or more ring members, and the ring is optionally substituted by a substituent R7; wherein R7 is independently selected from hydrogen, deuterium, halogen, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 3-8 cycloalkyl, -C 3-8 Heterocyclic group, -C 6-10 Aryl and -C 5-10 Mixed aromatics;

[0014] R2 is independently selected from hydrogen and substituted C. 1-8 Alkyl groups, substituted C 2-8 Alkenyl, substituted C 3-8 cycloalkyl, 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 may be optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, carboxyl, amino, nitro, cyano, -C 1-6 Acylamino, -C 1-6 Acyloxy group, -C 1-6 Alkoxy, -C 6-14 aryloxy group, -C 1-6 Alkylthio, -C 1-6 Alkyl, -C 1-6 Acyl group, -C 6-10 Aryl, -C 3-8 cycloalkyl, -C 2-6 Alkenyl, C 2-6 alkynyl group, -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 system;

[0015] R3 is selected from -COOR8, -CONR8, -COR8, -OR8, -NR8, -C 3-15 cycloalkyl, -C 3-15 Heterocyclic alkyl, -C 6-15 Aryl, -C 5-15 Heteroaryl; wherein the -C 3-15 cycloalkyl, -C 3-15 Heterocyclic alkyl, -C 6-15 Aryl, -C 5-15 Each of the heteroaryl groups may be optionally replaced by 0-8 R9s;

[0016] R9 can be selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, or -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;

[0017] R10 R 11 R 12 Each of the following groups is 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 group is independently substituted by 0-8 halogens, cyano, hydroxyl, mercapto, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl groups;

[0018] R 13 It is selected from hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, mercapto, 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, mercapto, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl.

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

[0020] In one or more embodiments, Cy in 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 by one or more R4 atoms;

[0023] R4 is independently of deuterium, tritium, halogen, hydroxyl, amino, nitro, cyano, or C each time it appears. 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 SO2R a NR a SO2R b SO2NR a R b -C 6-10 Aryl, -C 3-8 cycloalkyl, -C 5-10heteroaryl, -C 3-8 Heterocyclic alkyl or heterocyclic alkenyl, wherein -C 1-6 The alkyl group may optionally be substituted by one or more substituents selected from the following: amino, cyano, halogen, hydroxyl, -C 1-6 Alkoxy, -C 3-8 Heterocyclic alkyl, -C 3-8 cycloalkyl, -C 5-10 heteroaryl, -C 6-10 Aryl;

[0024] R a and R b Each time it appears, it is independently selected 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 Heterocyclic alkyl groups.

[0025] One or more embodiments of this application provide compounds of formula (II), or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, enantiomers, diastereomers, racemates, polymorphs, cocrystals, or metabolites thereof:

[0026]

[0027] in

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

[0029] 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 heteroaryl; optionally, the -C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 aryl, or 5-15 heteroaryl, is selected from one or more C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents;

[0030] 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 heteroaryl;

[0031] R3 and R4 are independently -C 1-8 Alkyl, -C1-8 Deuterated alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 3-12 cycloalkyl, -C 3-12 Heterocyclic alkyl, -C 6-10 Aryl, or 5-15 heteroaryl.

[0032] In one or more embodiments, C * The carbon atom has an 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 heterocyclic group or a 5-10 membered heteroaryl group, 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, and X1, X2, and X3 are independently O, S, N, NH, or C. 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, R1 is -C(O)OR3, -C(O)N(H)R3, -C 6-15 Aryl, or 5-15 heteroaryl; R3 is -C 1-4 Alkyl or -C 1-4 Deuterated alkyl; the 5-15-membered heteroaryl group has one or two heteroatoms selected from N, O, and S.

[0039] In one or more embodiments, R1 is

[0040] In one or more embodiments, R2 is R4C(O)- or a 5-6 heteroaryl group; R4 is -C 1-4 Alkyl, -C 1-4 Deuterated alkyl or -C 3-5 Cycloalkyl; the 5-6 membered heteroaryl group has one N heteroatom.

[0041] In one or more embodiments, R2 is

[0042] In one or more embodiments, when ring A is When R1 is in Indicates a single bond or a double bond.

[0043] In one or more embodiments, when ring A is When R1 is R2 is in Indicates a single bond or a double bond.

[0044] In one or more embodiments, when ring A is When R1 is R2 is in Indicates a single bond or a double bond.

[0045] In one or more embodiments, when ring A is When R1 is R2 is

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

[0047] When R1 is R2 is

[0048] In one or more embodiments, when ring A is When R1 is R2 is In one or more embodiments, the compound is selected from:

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055] One or more embodiments of this application provide pharmaceutical compositions comprising the compounds of this application or their pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, enantiomers, diastereomers, racemates, polymorphs, cocrystals, or metabolites, and pharmaceutically acceptable carriers, excipients, or excipients.

[0056] One or more embodiments of this application may be pharmaceutical formulations comprising the compounds of this application or their pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, enantiomers, diastereomers, racemates, polymorphs, cocrystals, or metabolites, as well as pharmaceutically acceptable carriers, excipients, or excipients.

[0057] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, prodrug, deuterated product, hydrate, solvate, enantiomer, diastereomer, racemic mixture, polymorph, cocrystal, or metabolite in the preparation of a medicament for the treatment and / or prevention of depression.

[0058] One or more embodiments of this application provide the use of the pharmaceutical composition of this application in the preparation of a medicament for treating and / or preventing depression.

[0059] One or more embodiments of this application provide the use of the pharmaceutical formulation of this application in the preparation of a medicament for treating and / or preventing depression.

[0060] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, prodrug, deuterated product, hydrate, solvate, enantiomer, diastereomer, racemic mixture, polymorph, cocrystal, or metabolite in the preparation of a fast-acting medicament for the treatment and / or prevention of depression.

[0061] One or more embodiments of this application provide the use of the pharmaceutical composition of this application in the preparation of a fast-acting medicament for the treatment and / or prevention of depression.

[0062] One or more embodiments of this application provide the use of the pharmaceutical formulation of this application in the preparation of a fast-acting medicament for the treatment and / or prevention of depression.

[0063] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, prodrug, deuterated product, hydrate, solvate, enantiomer, diastereomer, racemic mixture, polymorph, cocrystal, or metabolite in the preparation of a medicament for the prevention and / or treatment of irritability, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, traumatic brain injury, memory loss, appetite disorders, bulimia, obesity, substance 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 this application provide compounds of this application that can be used as pharmaceuticals.

[0067] One or more embodiments of this application provide pharmaceutical compositions of this application, which are used as pharmaceuticals.

[0068] One or more embodiments of this application provide pharmaceutical formulations of this application, which are used as drugs.

[0069] One or more embodiments of this application provide compounds, pharmaceutical compositions, or pharmaceutical preparations of this application for the prevention and / or treatment of depression.

[0070] One or more embodiments of this application provide compounds, pharmaceutical compositions, or pharmaceutical preparations of this application for the prevention and / or rapid treatment of depression.

[0071] One or more embodiments of this application provide compounds, pharmaceutical compositions, or pharmaceutical preparations of this application that can be used as fast-acting remedies for treating and / or preventing depression.

[0072] One or more embodiments of this application provide methods for preventing and / or treating depression, the methods comprising administering a compound, pharmaceutical composition, or pharmaceutical preparation of this application to a subject in need of such treatment.

[0073] One or more embodiments of this application provide methods for preventing and / or rapidly treating depression, the method comprising administering a compound, pharmaceutical composition, or pharmaceutical preparation of this application to a subject in need of such treatment.

[0074] In one or more embodiments, methods are provided for preventing and / or treating irritability, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, traumatic brain injury, memory loss, appetite disorders, bulimia, obesity, substance 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 methods comprising administering the compounds, pharmaceutical compositions, or pharmaceutical preparations of the present application to a subject in need of such treatment.

[0075] One or more embodiments of this application also provide pharmaceutical compositions or pharmaceutical formulations comprising the compounds of this application. For example, the compounds of this application may be administered in pure form, in combination with other active ingredients, or in combination with pharmaceutically acceptable nontoxic excipients or carriers.

[0076] The terminology used in the technical solutions of this application is explained below. As used in the specification and appended claims, unless otherwise specified, the terminology of this application has the following meanings.

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

[0078] The term "amino" refers to -NH2.

[0079] The term "hydroxyl group" refers to -OH.

[0080] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 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 substituented, it may optionally be further substituted by one or more substituents.

[0081] "Alkenyl" refers to an aliphatic hydrocarbon group with a straight or branched chain of 1 to 20 carbon atoms containing one or more double bonds, preferably an alkenyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkenyl group with 1 to 6 carbon atoms, and even more preferably an alkenyl group with 1 to 4 carbon atoms.

[0082] "Alynyl" refers to an aliphatic hydrocarbon group with a straight or branched chain of 1 to 20 carbon atoms containing one or more triple bonds, preferably an alkynyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkynyl group with 1 to 6 carbon atoms, and even more preferably an alkynyl group with 1 to 4 carbon atoms.

[0083] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated non-aromatic heterocycle, which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, for example, a 3- to 8-membered heterocyclic group. The 1 to 4 (e.g., 1, 2, 3, 4) N or S atoms selectively substituted in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclic group" or "heterocycle" include epoxyethyl, epoxypropyl, azirropropyl, oxacyclobutyl, azirrobutyl, thioheterobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, oxacycloheptyl, thioheterobutyl, oxazorphinyl, diazorphinyl, thioazorphinyl, pyridinyl, piperidinyl, homopiperidinyl, furfural, etc. nylonyl, thiophenyl, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylalkyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentanecycloyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidyl Azolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3] [1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. The “heterocyclic group” or “heterocycle” may optionally be further substituted with one or more substituents.

[0084] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can 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 system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, such as 5- to 8-membered heteroaryls. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the heteroaryl ring can be oxidized to various oxidation states. The heteroaryl group can be attached to a heteroatom or a carbon atom. The heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furanyl, thiophenyl, pyranyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted with one or more substituents.

[0085] "Cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon group with 1 to 15 carbon atoms, which can be a monocyclic ring with 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10), a bicyclic ring with 4 to 12 carbon atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12), or a polycyclic system with 10 to 15 carbon atoms (e.g., 10, 11, 12, 13, 14, 15). Preferably, the cyclic carbon atoms are 3 to 10, more preferably 3 to 8. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0086] "Heterocyclic alkyl" 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, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) polycyclic system, which may 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.

[0087] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring with 3 to 8 carbons (e.g., 3, 4, 5, 6, 7, 8 carbons), a bicyclic ring with 5 to 12 carbons (e.g., 5, 6, 7, 8, 9, 10, 11, 12 carbons), or a tricyclic system with 10 to 15 carbons (e.g., 10, 11, 12, 13, 14, 15 carbons). It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl and naphthyl groups. The aryl group may optionally be 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-hexoxy, cyclopropoxy, and cyclobutoxy. The definition of alkyl is the same as that of "alkyl" as described above.

[0089] Unless otherwise stated, the term "optionally substituted" means that a hydrogen atom is not substituted, or one or more hydrogen atoms are substituted by one or more groups independently selected from the following groups: alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalosulfonyl.

[0090] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0091] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this 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.

[0092] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0093] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0094] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0095] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0096] The term "compound" includes all stereoisomers, geometric isomers, and tautomers. A "compound" as used herein can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms, or mixtures thereof. Compounds containing asymmetric carbon atoms as used herein can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. A "compound" as used herein also includes geometric isomers, which are chiral forms of compounds where the substituents on the double bonds or rings have different cis-trans isomers. A "compound" as used herein also includes tautomers. Tautomers can arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0097] The compounds described herein, whether intermediates or compounds of formula (I), may 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 document. Examples of isotopes in the compounds described 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 a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0099] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers.

[0100] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0101] "Pharmaceutically acceptable excipients" refers to inert substances added to a pharmaceutical composition to facilitate administration of the 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 this application exhibit stronger activity compared to existing rapid-acting antidepressant compounds. For example, compared to existing compounds (compound ZZL-7), the compounds of this application demonstrate superior rapid-acting antidepressant activity in vivo and significantly better druggability (metabolic stability, AUC, bioavailability, etc.). Attached Figure Description

[0103] Figure 1 The results are from the forced swimming experiment used in the in vivo efficacy test of Example 3.

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

[0105] Figure 3 The results of the in vivo efficacy test 2 for Example 3 are shown in the tail suspension experiment. Detailed Implementation

[0106] The present application is further described below with reference to embodiments, providing implementation details. However, it should be noted that the embodiments described below are exemplary and are only used to explain the present application, and should not be construed as limiting the present application. Modifications or substitutions made by those skilled in the art based on existing technology still fall within the protection scope of the present application. The reagents used in the embodiments of this application are all commercially available.

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

[0108] Table 1: Compounds of Series A

[0109]

[0110]

[0111]

[0112] Table 2: B-series compounds

[0113]

[0114]

[0115]

[0116]

[0117] Table 3: C-series compounds

[0118]

[0119]

[0120] Preparation Examples

[0121] Preparation of compound A1-2 in Example 1

[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 to the solution. The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete as monitored by TLC and LCMS, water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel rapid column chromatography (dichloromethane / methanol = 20 / 1) to obtain acetylmethionine-L-valine methyl ester 1-2 (3.3 g, pale yellow solid), yield: 67%. MS m / z (ESI): 304.9 [M+H] + .

[0125] Step 2

[0126] Acetylmethionine-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 reaction was carried out at room temperature for 4 hours. After the reaction was monitored by rLC and LCMS, the solution was dried by rotary evaporation. The solution was then dissolved in acetonitrile (30 mL), and cesium carbonate (6.0 g, 18.4 mmol) was added. The reaction was carried out at 60 °C for 6 hours. After the reaction was completed, the solvent was dried by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the crude target product. Compound A1-2 (332 mg, white solid) was then obtained by preparative HPLC, yielding 14%. MS m / z (ESI): 257.0 [M+H] + .

[0127] 1 H NMR (400MHz, DMSO-d6) 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 of compound B1-1 in Example 2

[0129]

[0130] first step

[0131] (R)-2-hydroxy-3-methylbutyrate methyl ester 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-dimethylpyridine (2.1 g, 20 mmol) were added. The reaction mixture was reacted at 25 °C for 3 hours. After the reaction was monitored by TLC and LCMS until complete, 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), yield: 73%.

[0132] 1H 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).

[0133] Step 2

[0134] 2.5 g (23 mmol) of 3-amino-1H-pyridin-2-one 2-3 was added to toluene (50 mL), followed by the addition of acetic anhydride (2.8 g, 27.4 mmol). The reaction mixture was reacted at 110 °C for 3 hours. After the reaction was completed as monitored by TLC and LCMS, the reaction mixture 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 give compound 2-4 (2.0 g, black solid), yield: 55%.

[0135] 1 H 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).

[0136] Step 3

[0137] 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 mixture was stirred at room temperature for 5 hours. After the reaction was monitored by TLC and LCMS until complete, 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give compound B1-1 (970 mg, white solid), yield: 75%. MS m / z (ESI): 267.1 [M+H] + .

[0138] 1H 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).

[0139] Preparation of compound A1-3 in Example 3

[0140]

[0141] Compound B1-1 (1.0 g, 3.8 mmol) was dissolved in methanol (10 mL), and palladium on carbon (0.4 g) and palladium hydroxide (0.4 g) were added. The reaction solution was reacted at 40 °C for 48 hours under a hydrogen atmosphere. After the reaction was completed 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 residue obtained was purified by reverse separation column (0.1% TFA in H2O: CH3CN) to give compound A1-3 (0.45 g, yellow oil), yield: 42%. MS m / z (ESI): 271.2 [M+H] + .

[0142] 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).

[0143] Preparation of compound B1-5 in Example 4

[0144]

[0145] first step

[0146] Concentrated sulfuric acid (140 mg, 1.4 mmol) was added dropwise to ethyl nitroacetate (20.28 g, 152.4 mmol) and 1,1,3,3-tetramethoxypropane (50.04 g, 304.8 mmol), and the mixture was stirred at 130 °C for 45 min. The reaction 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 min, then heated to 80 °C and stirred for 16 h. The reaction was slowly cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V = 1:1) as eluents to give 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 methanol and water (V / V = 5:1, 54 mL). Lithium hydroxide monohydrate (5.94 g, 141.6 mmol) was then added to the reaction mixture, and the mixture 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). The mixture was 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 give 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), followed by the addition of potassium carbonate (2.57 g, 18.6 mmol) and deuterated iodomethane (1.8 g, 12.4 mmol) to the reaction solution. The reaction mixture was stirred at 25 °C for 1 hour. The reaction system was concentrated under reduced pressure to give 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). Zinc powder (2.28 g, 34.8 mmol) was then added to the reaction mixture. After stirring at 25 °C for 2 hours, the reaction mixture was placed in an ice bath, diluted with water (80 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 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 was cooled to 0 °C, and acetyl chloride (414 mg, 5.28 mmol) was slowly added dropwise. The reaction was then slowly heated to 25 °C and stirred at 25 °C for 1 hour. The solution was concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V = 3:1) as eluent to give the title product B1-5 (415 mg, brown solid, 58%). MS (ESI) m / z: 270.1 [M+H] + .

[0155] 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).

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

[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). Then, glacial acetic acid (72 mg, 1.2 mmol) was slowly added dropwise to the reaction mixture, and the reaction was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V = 7:3) as eluents to give 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). Then, deuterated acetyl chloride (477 mg, 5.89 mmol) and N,N-diisopropylethylamine (912 mg, 7.06 mmol) were added sequentially to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. After dilution with water (15 mL), the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to elute petroleum ether and ethyl acetate (V / V = 74:26), yielding compound B1-6 (500 mg, grayish-green solid, 31.5%). MS (ESI) m / z: 270.1 [M+H] + .

[0162] 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).

[0163] Preparation of compound C1-6 in Example 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 was cooled to 0 °C, and cyclopropyl chloride (414 mg, 3.96 mmol) was slowly added dropwise. After the addition was complete, the reaction was slowly raised to 25 °C and stirred at 25 °C for 1 hour. The solution was concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether and ethyl acetate (V / V = 3:1) as eluent to give compound C1-6 (420 mg, brown solid, 71%). MS (ESI) m / z: 296.2 [M+H] + .

[0166] 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).

[0167] Preparation of compound B1-4 in Example 7

[0168]

[0169] first step

[0170] Compound 7-1 (0.80 g, 7.20 mmol) was added to toluene (5 mL), followed by the addition of acetic anhydride (0.81 g, 7.92 mmol). The reaction mixture was incubated at 110 °C for 3 hours. After the reaction was completed 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%).

[0171] Step 2

[0172] 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. After reacting at room temperature for 30 minutes, compound 2-2 (0.40 g, 1.57 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was monitored by TLC and LCMS to be complete, water (5 mL) was added to quench the reaction, followed by extraction 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 vacuum concentration was purified by silica gel column chromatography to give compound B1-4 (45 mg, 0.17 mmol, white solid, 12%). MS m / z (ESI): 268.2 [M+H] + .

[0173] 1 H NMR (400MHz, CDCl3) 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 of compound C1-7 in Example 8

[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), and methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2′-2′-2′-3′-3′-3′-3′-4′-6 ... β-Palpaline (381 mg, 0.45 mmol) was reacted under nitrogen purging protection at 90 °C for 3 hours. After the reaction was confirmed to be complete by LCMS and TLC, the mixture was concentrated under reduced pressure. The crude product was dissolved in saturated sodium bicarbonate aqueous solution (150 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was slurried with dichloromethane (30 mL), filtered, and the filter cake was the product. Compound 8-2 was given (900 mg, 4.81 mmol, yield 52.97%). ESI-LCMS: m / z 188.2 [M+H] + .

[0178] Step 2

[0179] 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 then purged with nitrogen and reacted at 25 °C for 30 minutes. Compound 2-2 (1.37 g, 5.20 mmol) was then added, and the reaction was continued at 25 °C for 2 hours. After the reaction was confirmed to be complete by LCMS and TLC, methanol (10 mL) was added to quench the reaction. The mixture was then concentrated under reduced pressure and purified by silica gel column chromatography to give compound C1-7 (1.0 g, 3.32 mmol, yield 76.67%). ESI-LCMS: m / z 302.4 [M+H] + .

[0180] 1 H NMR (400MHz, DMSO-d6) 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, 5.0 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).

[0181] Preparation of compound C1-8 in Example 9

[0182]

[0183] first step

[0184] In a 100 mL single-necked flask, compound C1-7 (800 mg, 2.65 mmol), tetrahydrofuran (16 mL), and lithium hydroxide aqueous solution (0.5 M, 16 mL) were added sequentially, and the reaction was carried out at 25 °C for 2 hours. After the reaction was confirmed to be complete 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 × 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 used directly in the next step of the reaction. ESI-LCMS: m / z 288.3 [M+H] + .

[0185] Step 2

[0186] 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. The mixture was reacted at 25 °C for 30 min, followed by the addition of deuterated methanol (2 mL), and the reaction was continued at 25 °C for 2 h. After the reaction was confirmed to be complete by LCMS and TLC, the mixture 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), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound C1-8 (350 mg, 1.15 mmol, yield 66.09%). ESI-LCMS: m / z 305.4 [M+H] + .

[0187] 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).

[0188] Preparation of compound C1-3 in Example 10

[0189]

[0190] first step

[0191] In a 100 mL single-necked flask, compound B1-1 (620 mg, 2.33 mmol), tetrahydrofuran (15 mL), and lithium hydroxide aqueous solution (0.5 M, 15 mL) were added sequentially, and the reaction was carried out at 25 °C for 2 hours. After the reaction was confirmed to be complete 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, concentrated under reduced pressure, and 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] + .

[0192] Step 2

[0193] In a 100 mL single-necked flask, 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), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (2.49 g, 6.54 mmol) were added sequentially, and the mixture was reacted at 25 °C for 2 hours. After the reaction was confirmed to be complete by LCMS and TLC, it was quenched with dilute hydrochloric acid (1.0 M), diluted with dichloromethane (100 mL), separated, and the organic phase was washed with dilute hydrochloric acid (1.0 M) (50 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate yield) to give compound C1-3 (400 mg, 1.51 mmol, yield 69.27%). ESI-LCMS: m / z 266.3 [M+H] + .

[0194] 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).

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

[0196]

[0197] first step

[0198] 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 mixture was cooled to 0 °C, and cyclopropylformyl chloride (4.27 g, 40.88 mmol) was slowly added. After the addition was complete, the mixture was restored to 25 °C and reacted for 2 hours. After the reaction was confirmed to be complete by LCMS and TLC, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 11-2 (2.7 g, 15.15 mmol, 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), 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 the reaction was continued at 25 °C for 2 hours. After the reaction was confirmed to be complete by LCMS and TLC, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound C1-5 (850 mg, 2.91 mmol, yield 86.35%).

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

[0202] 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).

[0203] Preparation of compound C1-4 in Example 12

[0204]

[0205] first step

[0206] In a 100 mL single-necked flask, compound C1-5 (600 mg, 2.05 mmol), tetrahydrofuran (13 mL), and lithium hydroxide aqueous solution (0.5 M, 13 mL) were added sequentially, and the reaction was carried out at 25 °C for 2 hours. After the reaction was confirmed to be complete 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, yield 98.05%) was used directly in the next step of the reaction.

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

[0208] Step 2

[0209] In a 100 mL single-necked flask, 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)hexafluorophosphate urea (2.74 g, 7.20 mmol) were added sequentially, and the mixture was reacted at 25 °C for 2 hours. After the reaction was confirmed to be complete by LCMS and TLC, the mixture was quenched with dilute hydrochloric acid (1.0 M), diluted with dichloromethane (100 mL), separated, and the organic phase was washed with dilute hydrochloric acid (1.0 M) (50 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound C1-4 (300 mg, 1.03 mmol, yield 57.22%). ESI-LCMS: m / z 292.4 [M+H] + .

[0210] 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=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 of compound B1-3 in Example 13

[0212]

[0213] first step

[0214] 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 mixture was cooled to 0 °C, and acetyl chloride (1.06 g, 13.5 mmol) was slowly added. After the addition was complete, the mixture was restored to 25 °C and reacted for 2 hours. After the reaction was confirmed to be complete by LCMS and TLC, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 13-2 (500 mg, 3.26 mmol, yield 36.22%). ESI-LCMS: m / z 154.2 [M+H] + .

[0215] Step 2

[0216] 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 mixture was purged with nitrogen and reacted at 25 °C for 30 min. Compound 2-2 (777 mg, 2.94 mmol) was then added, and the reaction was continued at 25 °C for 2 h. After the reaction was confirmed to be complete by LCMS and TLC, the reaction was quenched with saturated sodium bicarbonate aqueous solution (150 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound B1-3 (110 mg, 0.41 mmol, yield 16.73%). ESI-LCMS: m / z 268.3 [M+H] + .

[0217] 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).

[0218] Example 14 Synthesis of compound A1-4

[0219]

[0220] first step

[0221] In 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 mixture was cooled to 0 °C, and acetyl chloride (918 mg, 11.7 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was slowly heated to 25 °C and reacted for 2 hours. After LCMS and TLC monitoring showed that the reaction was complete, methanol (50 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure and subjected to silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound A1-4b (950 mg, 5.58 mmol, yield 71.5%).

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

[0223] Step 2

[0224] 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. The mixture was reacted at 25 °C for 30 minutes under nitrogen protection. Then, compound 2-2 (932 mg, 3.53 mmol) was added, and the reaction was continued with stirring for 2 hours. After LC-MS and TLC monitoring showed complete reaction, the mixture was quenched with dilute hydrochloric acid (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography to give compound A1-4 (98 mg, 0.34 mmol, yield 11.6%).

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

[0226] 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).

[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 on carbon (75 mg), and palladium hydroxide on carbon (75 mg) were added sequentially. The reaction was carried out at 60 °C for 48 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS and TLC, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was performed to give compound C1-2 (60 mg, 0.22 mmol, yield 39.1%).

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

[0232] 1 H NMR (400MHz, DMSO-d6) 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 = 10.9Hz, 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).

[0233] Example 16 Synthesis of compound C1-18

[0234]

[0235] first step

[0236] In a 250 mL three-necked flask, compound C1-18a (4 g, 35.35 mmol) and anhydrous tetrahydrofuran (100 mL) were added sequentially. Under nitrogen purging protection, the mixture was cooled to -10 °C, and isopropyl magnesium chloride·lithium chloride (35 mL, 70 mmol, 2.0 M tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the reaction mixture was slowly brought back to room temperature and stirred for 4 hours. After LCMS and TLC monitoring showed that the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (200 mL) under ice bath conditions. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound C1-18b (2.5 g, 15.9 mmol, yield 45.0%).

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

[0238] Step 2

[0239] 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 mixture 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 LC-MS and TLC monitoring showed that the reaction was complete, the mixture was quenched with saturated sodium carbonate aqueous solution (200 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound C1-18c (170 mg, 0.77 mmol, yield 8.1%).

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

[0241] 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).

[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), and potassium carbonate (265 mg, 1.92 mmol) were added sequentially, and the mixture was reacted at 80 °C for 8 hours. After the reaction was confirmed to be complete by LCMS and TLC, the mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 3), 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 purified by silica gel column chromatography to give compound C1-18 (40 mg, 0.13 mmol, yield 20.3%).

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

[0245] 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).

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

[0247]

[0248] first step

[0249] Add (tert-butyloxycarbonyl)-L-alanine (4.5 g, 23.78 mmol) to a dry single-necked flask, dissolve in dichloromethane (50 mL), and stir in an ice bath for 10 min. Then add L-valine methyl ester (3.12 g, 23.78 mmol), N,N-diisopropylethylamine (6.15 g, 47.56 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.01 g, 26.16 mmol) to the flask in sequence, and stir at room temperature for 2 h. After the reaction was confirmed by TLC, water (50 mL) was added to quench the reaction, and the solution was adjusted to acidity with 2 M hydrochloric acid. The mixture was then extracted with dichloromethane (50 mL × 2), and the organic phases were combined. The organic phases were then adjusted to alkalinity with saturated sodium bicarbonate, extracted with dichloromethane (50 mL × 2), 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 give the intermediate (tert-butoxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol, yield 90.39%). LCMS (M+H) + =303.1.

[0250] Step 2

[0251] (tert-Butoxycarbonyl)-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). Then, 1,4-dioxane hydrochloride (10 mL, 4 M) was added to the flask, and the mixture was stirred at room temperature for 2 h. After the reaction was complete as indicated by TLC, the organic phase was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give 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).

[0252] Step 3

[0253] 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), purged with nitrogen, and stirred at 0 °C. After 10 min, acetic anhydride (2.8 g, 27.48 mmol) was slowly added dropwise, and the mixture was stirred at this temperature for 10 min. The mixture was then moved to room temperature and stirred for 2 h. After the reaction was confirmed by TLC, water (50 mL) was added to quench the reaction, and the solution was adjusted to acidity with 2 M hydrochloric acid. The mixture was extracted with dichloromethane (50 mL × 4), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 5:1). The 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).

[0254] Activity Experiment Example 1: Plasma Stability Determination

[0255] After thawing mouse plasma in a water bath at 37°C, the supernatant was removed by centrifugation, and the pH was recorded as 7-8. A certain volume of acetonitrile stock solution (concentration 10 mM) of the test compound was taken and diluted to 1 mM with acetonitrile as an intermediate solution. Propantheline was used as a positive control. A certain volume of the intermediate solution was taken and mixed with an corresponding volume of plasma to make the concentration of the test compound in the incubation system 5 μM and the content of acetonitrile organic solvent 0.5%. 50 μL of the mixed plasma was placed in a 96-well plate (N=2), incubated in a water bath at 37°C for a certain time, and then 300 μL of methanol solution containing internal standard was added to terminate the reaction. The supernatant was collected by vortex centrifugation and analyzed by LC-MS / MS. A curve was plotted between the remaining percentage of the compound and the incubation time to obtain the k value, and the half-life of each compound was calculated. The formula is as follows:

[0256]

[0257] Table 1 shows the plasma stability data of some compounds. The results show that the compounds of this application exhibit excellent plasma stability, which is significantly better than ZZL-7.

[0258] Table 1. Plasma stability data for some compounds.

[0259] Compound 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 the remaining percentage of the compound is still greater than 80% after 120 minutes, then T 1 / 2 Recorded as >372.68min.

[0261] Activity Experiment Example 2: Pharmacokinetic Detection

[0262] Pharmacokinetic assays were performed in 6-8 week old CD1 mice. The test compound was dissolved in a 10% aqueous solution of hydroxypropyl-β-cyclodextrin containing 10% DMSO and administered intravenously or by gavage. Plasma concentrations were analyzed using LC-MS / MS. Pharmacokinetic calculations were performed using WinNonlin (Phoenix™, version 8.3) or similar software. The following pharmacokinetic parameters were calculated based on plasma concentration versus time data:

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

[0264] Perform statistical calculations on the above parameter data.

[0265] Table 2 shows the area under the curve (AUC) and bioavailability (F) data of some compounds administered orally. The results show that the compounds in this application have good pharmacokinetic properties, which are significantly better than ZZL-7.

[0266] Table 2 shows the pharmacokinetic data of some compounds.

[0267] Compound AUC last (h*ng / 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 Experiment Example 3

[0269] In vivo drug efficacy test 1

[0270] A 28-day chronic unpredictable mild stress (CUMS) model was established using 6-8 week old C57 / B6 mice. The efficacy of the drug was evaluated after successful model establishment using the open field test (OFT). The experiment included a blank control group, a model group, a solvent 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 evaluate mouse depression. Prolonged immobility time in both TST and FST indicated behavioral despair. Data were collected and analyzed using SPSS statistical software, and graphs were generated using GraphPad software based on the SPSS analysis results.

[0271] Test results show (see) Figure 1 and Figure 2 Compounds B1-1, B1-5, and B1-6 can rapidly reverse the prolonged immobility time in 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.

[0272] In vivo drug efficacy test 2

[0273] A 28-day chronic unpredictable mild stress (CUMS) model was established using 6-8 week old C57 / B6 mice. The efficacy was evaluated after successful model establishment using the open field test (OFT). The experiment included 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 dose of 25 mg / kg. Two hours later, the tail suspension test (TST) was performed to assess mouse depression. Prolonged immobility in the TST indicated behavioral despair. Data were collected and analyzed using SPSS statistical software, and graphs were generated using GraphPad software based on the SPSS analysis results.

[0274] Test results show (see) Figure 3 Compound B1-6 can rapidly reverse the prolonged immobility time in the tail suspension test in mice with chronic unpredictable stress, demonstrating that the embodiments of the present invention have a rapid antidepressant effect.

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, C * The chiral carbon atom is preferably in the S configuration; The lactam ring Cy is selected from R1is R5C(O)-, R5is -C 1-6 alkyl; R2 bonded to the N atom is hydrogen; with C * R2is isopropyl attached to the chiral carbon atom; R3is selected from -COOR8, R8is -C 1-6 alkyl.

2. Compounds of formula (II) or pharmaceutically acceptable salts thereof: in A ring is R1is -C(O)OR3, R3is -C 1-6 alkyl or -C 1-6 deuteroalkyl; R2is R4C(O)-, R4is -C 1-6 alkyl or -C 1-6 deuteroalkyl; C * The carbon atom is in the S configuration.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R3is -C 1-4 alkyl or -C 1-4 deuteroalkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is 5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 is -C 1-4 alkyl or -C 1-4 deuteroalkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is 7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is R2 is 8. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from:

9. A pharmaceutical composition comprising a compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or excipient.

10. A pharmaceutical preparation comprising a compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or excipient.

11. Use of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 9, or the pharmaceutical preparation of claim 10 in the preparation of a medicament for the treatment and / or prevention of depression.

12. Use of any compound of claims 1-8 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 9, or the pharmaceutical preparation of claim 10 in the preparation of a fast-acting medicament for the treatment and / or prevention of depression.

13. Use of any compound of claims 1-8 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 9, or the pharmaceutical preparation of claim 10 in the preparation of a medicament for the treatment and / or prevention of irritability, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, traumatic brain injury, memory loss, appetite disorders, obesity, substance abuse, alcoholism, tobacco addiction, obsessive-compulsive disorder, panic disorder, premenstrual syndrome, bipolar disorder, neuropathic pain, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, and vasomotor symptoms.

14. The use as described in claim 13, wherein the neuropathic pain is chronic pain or migraine.

15. The use as described in claim 14, wherein the chronic pain is fibromyalgia.

16. The use as claimed in claim 13, wherein the appetite disorder is bulimia.

17. The use as described in claim 13, wherein the vasomotor symptom is hot flashes.

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