Amide compounds and uses thereof

Abstract

The present application discloses amide 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 major clinical feature. It is characterized by mood depression that is not commensurate with the situation, and emotional depression can range from gloom to despair, self-depression, and even pessimism and nihilism. In severe cases, psychotic symptoms such as hallucinations and delusions can occur.

[0003] Disorders of neurotransmitters such as norepinephrine, dopamine, and 5-HT in the brain are considered to be the main biological factors 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 isopropyl hydrazine and isocarboxazid. Due to the presence of components with significant side effects, these drugs have been basically discontinued; 2) tricyclic antidepressants: this class of drugs has a good effect on relieving depression, but has a greater adverse effect on patients with other conditions. This drug includes clomipramine and imipramine hydrochloride; 3) selective 5-HT (5-hydroxytryptamine) reuptake inhibitors: this drug can compensate for the symptoms of 5-hydroxytryptamine deficiency in depressed patients. The main ones are fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine; 4) 5-HT and norepinephrine reuptake inhibitors: this class of drugs has a dual antidepressant mechanism and relatively high safety, such as venlafaxine and duloxetine. Among them, the third and fourth categories are the main drugs, and the first and second categories have been basically discontinued.

[0004] Since the advent of 5-hydroxytryptamine reuptake inhibitors (SSRis), there have been dozens of generations of iterative upgrades. There are currently more than a hundred in- development projects, mainly focusing on SSRis, selective 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and specific 5-hydroxytryptamine antidepressants (NaSSAs), 5-HT receptor antagonists and reuptake inhibitors (SARIs), and NMDA receptor antagonists. The antidepressant market is also very concentrated. To date, more than 30 SSRi varieties have been used globally, with the top 10 being escitalopram, sertraline, venlafaxine, paroxetine, duloxetine, flupentixol + melitracen, 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 and delayed onset of action, 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 with fast onset of action, good efficacy, and oral administration in clinic. SUMMARY

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

[0007]

[0008] wherein,

[0009] R1, R2 are each independently selected from hydrogen, R8-(CO)-, R8-(SO)-, R8-(SO2)-, R8-O(CO)-, R8R9-N(CO)-, or C1-C 15 chain alkyl, C1-C 15 hetero chain alkyl, C3-C 15 cycloalkyl, C3-C 15 heterocycloalkyl, C5-C 15 aryl, C5-C 15 heteroaryl;

[0010] or R1, R2 together with the nitrogen atom adjacent thereto form a C3-C 15 heterocycloalkyl or C5-C 15 heteroaryl;

[0011] R3, R4 are each independently selected from hydrogen, deuterium, tritium, or C1-C 15 chain alkyl, C1-C 15 hetero chain alkyl, C3-C 15 cycloalkyl, C3-C 15 heterocycloalkyl, C5-C 15 aryl, C5-C 15 heteroaryl;

[0012] or R3, R4 together with the carbon atom to which they are attached form a C3-C10 cycloalkyl group substituted with n R8 groups; 10 cycloalkyl group or C3-C10 10 heterocycloalkyl group;

[0013] X is optionally -CO-, -SO-, -SO2-, -CHR8-, or

[0014] R5, R6 are each independently optionally hydrogen or C1-C10 alkyl substituted with n R8 groups; 15 alkyl group, C1-C10 15 heteroalkyl group, C3-C10 15 cycloalkyl group, C3-C10 15 heterocycloalkyl group, C5-C10 15 aryl group, C5-C10 15 heteroaryl group;

[0015] R7 is optionally C3-C10 cycloalkyl substituted with n R8 groups; 15 cycloalkyl group, C3-C10 15 heterocycloalkyl group, C5-C10 15 aryl group, C5-C10 15 heteroaryl group;

[0016] R8 is optionally hydrogen, deuterium, tritium, halogen, oxyl, -CN, -NO2, -OR9, -NR9R 10 , -SR9, -COR9, -SOR9, -SO2R9, -NR9COR 10 , -CONR9R 10 , -OCOR9, -COOR9, -OCOOR9, -OCONR9R 10 , -NR9CONR 10 R 11 , -NR9COOR 10 , -NR9SO2R 10 , -SO2NR9R 10 , -OSO2R9, -SO3R9, alkyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group; wherein each alkyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group is independently substituted with n R 12 groups;

[0017] R9, R 10 , R 11each independently selected from hydrogen, deuterium, tritium, a linear alkyl, a hetero-linear alkyl, a cyclic alkyl, a hetero-cyclic alkyl, an aryl, or a hetero-aryl, wherein each linear alkyl, hetero-linear alkyl, cyclic alkyl, hetero-cyclic alkyl, aryl, or hetero-aryl is independently substituted with n halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate ester, sulfonamide, alkyl, or haloalkyl;

[0018] R 12 selected from hydrogen, deuterium, tritium, a linear alkyl, a hetero-linear alkyl, a cyclic alkyl, a hetero-cyclic alkyl, an aryl, or a hetero-aryl, wherein each linear alkyl, hetero-linear alkyl, cyclic alkyl, hetero-cyclic alkyl, aryl, or hetero-aryl is independently substituted with n halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate ester, sulfonamide, alkyl, or haloalkyl;

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

[0020] One or more embodiments of the present application provide a compound of Formula (II), or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof:

[0021]

[0022] wherein

[0023] R1is C3-C 15 aryl, 3-15 membered heteroaryl, C3-C 15 cycloalkyl, or 3-15 membered heterocycloalkyl; optionally, the C3-C 15 aryl, 3-15 membered heteroaryl, C3-C 15 cycloalkyl, or 3-15 membered heterocycloalkyl is substituted with a substituent selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, and carbonyl; the 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl comprises 1-4 heteroatoms selected from N, O, and S;

[0024] R2is C1-C6alkyl, hydroxyC1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C 15 aryl, 3-15 membered heteroaryl, C3-C 15cycloalkyl, or 3-15 membered heterocycloalkyl; said 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl comprises 1-4 heteroatoms selected from N, O, and S;

[0025] R3 is C1-C6 alkyl or C1-C6 deuterated alkyl;

[0026] when R2 is methyl, R1 is not unsubstituted phenyl;

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

[0028] C ** the carbon atom is in the R or S configuration.

[0029] In one or more embodiments, R3 is methyl or deuterated methyl.

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

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

[0032] In one or more embodiments, R1 is C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, said C5-C6 aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl is substituted with a substituent selected from halogen, C1-C4 alkyl, haloC1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and carbonyl; said 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl comprises 1 or 2 heteroatoms selected from N, O, and S.

[0033] In one or more embodiments, wherein R1 is

[0034] In one or more embodiments, R2 is C1-C4 alkyl, hydroxyC1-C4 alkyl, haloC1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; said 5-6 membered heteroaryl comprises 1 or 2 heteroatoms selected from N, O, and S.

[0035] In one or more embodiments, R2 is methyl,

[0036] In one or more embodiments, R1is C5-C6aryl, 5-6 membered heteroaryl, C5-C6cycloalkyl, or 5-6 membered heterocycloalkyl; optionally, said C5-C6aryl, 5-6 membered heteroaryl, C5-C6cycloalkyl, or 5-6 membered heterocycloalkyl is substituted with a substituent selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, C1-C4alkylamino, and carbonyl; said 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl comprises 1 or 2 heteroatoms selected from N, O, and S;

[0037] R2is C1-C4alkyl, hydroxyC1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, C1-C4alkylamino, C3-C6cycloalkyl, C5-C6aryl, or 5-6 membered heteroaryl; said 5-6 membered heteroaryl comprises 1 or 2 heteroatoms selected from N, O, and S.

[0038] In one or more embodiments, R1is R2is methyl,

[0039] One or more embodiments of the present application provide a compound of Formula (III), or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof:

[0040]

[0041] wherein

[0042] R1is C3-C 15 aryl, or 3-15 membered heteroaryl; said 3-15 membered heteroaryl comprises 1-4 heteroatoms selected from N, O, and S;

[0043] R2is C1-C6alkyl, hydroxyC1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C 15 aryl, 3-15 membered heteroaryl, C3-C 15 cycloalkyl, or 3-15 membered heterocycloalkyl; said 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl comprises 1-4 heteroatoms selected from N, O, and S;

[0044] R3is C3-C 15 aryl, 3-15 membered heteroaryl, C3-C 15 cycloalkyl, or 3-15 membered heterocycloalkyl; said 3-15 membered heteroaryl or 3-15 membered heterocycloalkyl comprises 1-4 heteroatoms selected from N, O, and S; optionally, said 3-15 membered heterocycloalkyl is substituted with carbonyl.

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

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

[0047] In one or more embodiments, C ** The carbon atom is in the R or S configuration.

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

[0049] In one or more embodiments, R1is C5-C6aryl or 5-6 membered heteroaryl; the 5-6 membered heteroaryl comprises 1 or 2 N heteroatoms; R2is C1-C4alkyl; R3is C5-C6aryl, 5-6 membered heteroaryl, C3-C6cycloalkyl, or 5-6 membered heterocycloalkyl; the 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl comprises 1 or 2 heteroatoms selected from N, O, and S.

[0050] In one or more embodiments, wherein R1is R2is methyl; R3is

[0051] One or more embodiments of the present application provide a compound of Formula (IV), or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof:

[0052]

[0053] wherein

[0054] R1is C5-C6aryl or 5-6 membered heteroaryl; the 5-6 membered heteroaryl comprises 1 or 2 N heteroatoms;

[0055] R2, R3are each independently H or C1-C6alkyl and are not simultaneously H or C1-C6alkyl; or R2, R3and the carbon atom to which they are attached form a C3-C6cycloalkyl or 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and S;

[0056] X1is C or S;

[0057] R4, R5and the X1atom to which they are attached form a 1 carbonyl or 1 sulfone group, C3-C6cycloalkyl, or 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and S;

[0058] R6is H or C1-C6alkyl.

[0059] In one or more embodiments, C * the carbon atom is in the R or S configuration.

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

[0061] In one or more embodiments, C ** the carbon atom is in the R or S configuration.

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

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

[0064]

[0065] wherein,

[0066] R1is a 5-6 membered heteroaryl; the 5-6 membered heteroaryl comprises 1 or 2 N heteroatoms;

[0067] R2, R3are each independently H or C1-C6alkyl and are not simultaneously H or C1-C6alkyl; or R2, R3and the carbon atom to which they are attached form a C3-C4cycloalkyl;

[0068] R4, R5and the carbon atom to which they are attached form a carbonyl or a 3-5 membered heterocycloalkyl; the 3-5 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from O and S.

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

[0070]

[0071] wherein

[0072] R1is a 5-6 membered heteroaryl; the 5-6 membered heteroaryl comprises 1 or 2 N heteroatoms;

[0073] R2is C1-C4alkyl.

[0074] One or more embodiments of the present application provide a compound, or a pharmaceutically acceptable salt, prodrug, deuterated analog, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof, selected from:

[0075]

[0076] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof, and a pharmaceutically acceptable carrier, adjuvant, or excipient.

[0077] One or more embodiments of the present application provide a pharmaceutical formulation comprising a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof, and a pharmaceutically acceptable carrier, adjuvant, or excipient.

[0078] One or more embodiments of the present application provide use of a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof, a pharmaceutical composition of the present application, or a pharmaceutical formulation of the present application in the manufacture of a medicament for treating and / or preventing depression.

[0079] One or more embodiments of the present application provide use of a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof, a pharmaceutical composition of the present application, or a pharmaceutical formulation of the present application in the manufacture of a fast-acting medicament for treating and / or preventing depression.

[0080] One or more embodiments of the present application provide use of a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated metabolite, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, co-crystal, or metabolite thereof, a pharmaceutical composition of the present application, or a pharmaceutical formulation of the present application in the manufacture of a medicament for treating and / or preventing restlessness, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, bulimia, obesity, drug abuse, alcoholism, tobacco addiction, obsessive-compulsive disorder, panic disorder, premenstrual syndrome, migraine, bipolar disorder, neuropathic pain, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, and vasomotor symptoms or hot flushes.

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

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

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

[0084] One or more embodiments of the present application provide the pharmaceutical composition of the present application for use as a medicament.

[0085] One or more embodiments of the present application provide the pharmaceutical preparation of the present application for use as a medicament.

[0086] One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application for use in the prevention and / or treatment of depression.

[0087] One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application for use in the prevention and / or rapid treatment of depression.

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

[0089] One or more embodiments of the present application provide a method of preventing and / or rapid treatment of depression, the method comprising administering to a subject in need thereof the compound, pharmaceutical composition or pharmaceutical preparation of the present application.

[0090] One or more embodiments of the present application provide the use of the compound, pharmaceutical composition or pharmaceutical preparation of the present application in the manufacture of a medicament for the treatment and / or prevention of restlessness, 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, e.g., fibromyalgia), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, and vasomotor symptoms or hot flushes.

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

[0092] The following explanations are provided for the terms used in the technical solutions of the present application. As used in the specification and the appended claims, unless otherwise indicated, the terms in the present application have the following meanings.

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

[0094] The term "amino" means -NH2.

[0095] The term "hydroxy" means -OH.

[0096] "Alkyl" means a straight or branched chain saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to eight (e.g., one, two, three, four, five, six, seven, eight) carbon atoms, more preferably one to six carbon atoms, and even more preferably one to four carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, neopentyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and the various branched isomers thereof; when substituted, alkyl groups can be optionally further substituted with one or more substituents.

[0097] "Alkenyl" means a straight or branched chain aliphatic hydrocarbon radical of one to twenty carbon atoms containing one or more double bonds, preferably one to eight (e.g., one, two, three, four, five, six, seven, eight) carbon atoms, more preferably one to six carbon atoms, and even more preferably one to four carbon atoms.

[0098] "Alkynyl" means a straight or branched chain aliphatic hydrocarbon radical of one to twenty carbon atoms containing one or more triple bonds, preferably one to eight (e.g., one, two, three, four, five, six, seven, eight) carbon atoms, more preferably one to six carbon atoms, and even more preferably one to four carbon atoms.

[0099] "Heterocyclyl" or "heterocycle" means a saturated or unsaturated non-aromatic ring which can be a 3 to 10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 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, e.g., 3 to 8 membered heterocyclyl. Optionally 1 to 4 (e.g., 1, 2, 3, 4) of the N, S in the ring of the "heterocyclyl" or "heterocycle" can be oxidized into various oxidation states; the "heterocyclyl" or "heterocycle" can be attached at a heteroatom or carbon atom; the "heterocyclyl" or "heterocycle" can be bridged or spiro. Non-limiting examples of "heterocyclyl" or "heterocycle" include epoxyl, propoxyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidyl, homopiperidyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thioxazanyl, 1,3-dithianyl, dihydrofuranyl, dihydrothienyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, 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-indolizinyl, quinolizinyl, N-pyridinylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantyl, and oxaspiro[3.3]heptyl. The "heterocyclyl" or "heterocycle" can be optionally further substituted with one or more substituents.

[0100] "Heteroaryl" means a substituted or unsubstituted aromatic ring which can be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, for example, 5 to 8 membered heteroaryl. Optionally substituted 1 to 4 (e.g., 1, 2, 3, 4) N, S in the ring of the heteroaryl can be oxidized into various oxidation states. The heteroaryl can be attached at a heteroatom or carbon atom, the heteroaryl can be fused or spiro, non-limiting examples include, cinnolinyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridyl. The heteroaryl is optionally further substituted with one or more substituents.

[0101] "Cycloalkyl" means a cyclic saturated aliphatic hydrocarbon group of 1 to 15 carbon atoms which can be a 3 to 10 carbon (e.g., 3, 4, 5, 6, 7, 8, 9, 10) membered monocyclic, 4 to 12 carbon (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12) membered bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15) membered polycyclic ring system, preferably 3 to 10 carbon atoms in the ring carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. When the cycloalkyl is substituted, it can be optionally further substituted with one or more substituents.

[0102] "Heterocycloalkyl" means a cyclic saturated aliphatic hydrocarbon group of 3 to 15 members which can be a 3 to 10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) polycyclic ring system which can contain one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, or S, and can be monocyclic, fused, bridged, and spiro.

[0103] "Aryl" means a substituted or unsubstituted aromatic ring which can be a 3 to 8 carbon (e.g., 3, 4, 5, 6, 7, 8 carbon) membered monocyclic, 5 to 12 carbon (e.g., 5, 6, 7, 8, 9, 10, 11, 12 carbon) membered bicyclic, or 10 to 15 carbon (e.g., 10, 11, 12, 13, 14, 15 carbon) membered tricyclic ring system which can be fused or spiro, non-limiting examples include phenyl, naphthyl. The aryl can be optionally further substituted with one or more substituents.

[0104] "Alkoxy" refers to a group in which at least one carbon atom of an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The alkyl definition is the same as that described above for "alkyl."

[0105] Unless otherwise indicated, the term "optionally substituted" means that a hydrogen atom is not substituted, or one or more hydrogen atoms are replaced by one or more groups independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocyclo, hydroxy, alkoxy, aryloxy, thiohydroxy, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalo silyl.

[0106] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or bases and is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0107] "Pharmaceutical composition" means a mixture of one or more of the compounds of the present application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic or active agents.

[0108] "Prodrug" means a compound of the present application which is metabolized in vivo to form a biologically active compound of the present application. Prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application in such a way that the modifications can be easily removed in vivo to form the parent compound. When a prodrug of the present application is administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0109] "Cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of API and CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystals are a kind of multi-component crystals, including binary cocrystals formed between two neutral solids, and multi-component cocrystals formed between neutral solids and salts or solvates.

[0110] "stereoisomers" refer to isomers that differ only in the arrangement of atoms in space, and include enantiomeric, diastereomeric, and conformational isomers.

[0111] "optionally" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance can or can not occur, and this description encompasses the situation where it does occur and the situation where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group can or can not be present, and this description encompasses the situation where the heterocyclyl is substituted with alkyl, and the situation where the heterocyclyl is not substituted with alkyl.

[0112] The term "compound" includes all stereoisomers, geometric isomers, tautomers. The "compounds" described herein can be asymmetric, e.g., having one or more stereocenters. Unless otherwise specified, all stereoisomers are included, such as enantiomeric, diastereomeric, or other stereoisomeric forms or mixtures thereof. Compounds described herein that contain an asymmetric carbon atom can be isolated in optically active form or as racemates. Optically active forms can be resolved from racemic mixtures or synthesized from chiral starting materials or chiral reagents. The "compounds" described herein also include geometric isomeric forms, which refer to the different spatial orientations of substituents around a double bond or ring and do not possess an asymmetric carbon. The "compounds" described herein also include tautomeric forms. Tautomeric forms can result from the exchange of a single bond and an adjacent proton.

[0113] The compounds herein, whether intermediates or compounds of Formula (I), can also be isotopically-labeled by having one or more atoms replaced by an atom having the same atomic number but a different atomic mass than the atom which it replaces. Such isotopically-labeled (i.e., radiolabeled) compounds are within the scope of the present application. Examples of isotopes that can be suitably substituted into the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, each of which has the same number of protons but a different number of neutrons than the atoms which it replaces.

[0114] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, prepared from a compound of the present application having specific substituents discovered to be useful with a pharmaceutically acceptable acid or base.

[0115] The term "pharmaceutically acceptable carrier" refers to any formulation vehicle or medium that can deliver an effective amount of an active substance of the present application, does not interfere with the biological activity of the active substance, and is nontoxic to the host or patient. Representative carriers include water, oil, vegetable and mineral, ointment bases, lotion bases, ointment bases, and the like. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, and the like.

[0116] The term "pharmaceutically acceptable excipient" refers to an inert substance used in drug formulation or in the compounding of a pharmaceutical preparation that does not produce an adverse, allergic or other untoward reaction with the active ingredient. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrating agents.

[0117] The term "pharmaceutically acceptable excipient" refers to an inert substance used in drug formulation or in the compounding of a pharmaceutical preparation that does not produce an adverse, allergic or other untoward reaction with the active ingredient. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrating agents.

[0118] In one or more embodiments, the compounds of the present application are more active than existing fast-acting antidepressant compounds. For example, the compounds of the present application have superior in vivo fast-acting antidepressant activity and significantly better drugability (metabolic stability, AUC, bioavailability, etc.) than existing compounds (Compound ZZL-7). BRIEF DESCRIPTION OF DRAWINGS

[0119] Figure 1 Forced swimming test results of active example 3 in vivo pharmacodynamic test 1.

[0120] Figure 2 Forced swimming test results of active example 3 in vivo pharmacodynamic test 1.

[0121] Figure 3 Forced swimming test results of active example 3 in vivo pharmacodynamic test 1. DETAILED DESCRIPTION

[0122] The present application is further illustrated by the following examples, which give details of the working of the application. It should be noted, however, that the following examples are illustrative only and are not intended to limit the scope of the present application. Any modification or alternative to the present application made by those skilled in the art based on the prior art is still within the scope of the present application. The reagents used in the examples of the present application are commercially available.

[0123] Preparation examples

[0124] Preparation of compound 1 of Preparation Example 1

[0125]

[0126] First step

[0127] (S)-2-amino-3-methylbutan-1-ol 1-1 (5.0 g, 48 mmol) was dissolved in 1,4-dioxane / water (50 mL / 10 mL) and a solution of benzyl oxycarbonyl succinimidyl ester (12.0 g, 48 mmol) in 1,4-dioxane (50 mL) / water (10 mL) was added slowly. The reaction was allowed to react at 25 °C for 16 h. After the reaction was completed, ethyl acetate was added to dilute (200 mL), then washed with 5% sodium bicarbonate solution and 5% citric acid solution respectively, the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude (S)-(1-hydroxy-3-methylbutan-2-yl)benzylcarbamate 1-2 (10.4 g, white solid, yield 87%). The crude was used directly in the next step without further purification. MS m / z (ESI): 238.1 [M+H] + .

[0128] Second Step

[0129] (S)-(1-hydroxy-3-methylbutan-2-yl)benzylcarbamate 1-2 (7.0 g, 29 mmol) was dissolved in ethyl acetate (140 mL) and 2-iodoxybenzoic acid (20.6 g, 74 mmol) was added. The reaction was refluxed at 80 °C for 4 h. After the reaction was completed, the reaction was filtered with celite and the filtrate was concentrated to give crude (S)-(3-methyl-1-oxobutan-2-yl)benzylcarbamate 1-3 (7.0 g, white solid), yield: 91%. The crude was used directly in the next step without further purification. MS m / z (ESI): 236.1 [M+H] + .

[0130] Third Step

[0131] (S)-(3-methyl-1-oxobutan-2-yl)benzylcarbamate 1-3 (7.0 g, 30.0 mmol) and glyoxal solution (15.4 mL, 120 mmol) were dissolved in methanol (70 mL) and ammonia water (18.9 mL, 150 mmol) was added slowly, the temperature was maintained below 10 °C during the dropping process. The reaction was stirred at 25 °C for 16 h. After the reaction was completed, the reaction was poured into ice water and the precipitated solid was collected by filtration, the obtained filter cake was washed with water and dried to give crude (S)-(1-(1H-imidazol-2-yl)-2-methylpropyl)benzylcarbamate 1-4 (5.0 g, white solid), yield 60%. The crude was used directly in the next step without further purification. MS m / z (ESI): 274.1 [M+H] + .

[0132] Fourth Step

[0133] Benzyl (S)-(1-(1H-imidazol-2-yl)-2-methylpropyl)carbamate 1-4 (3.0 g, 11 mmol) was dissolved in methanol (75 mL), followed by the addition of palladium on carbon (0.3 g, 10 wt.%). The mixture was purged with hydrogen gas three times, and the reaction was stirred at 25 °C under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction was filtered through celite, and the filtrate was concentrated to give crude (S)-1-(1H-imidazol-2-yl)-2-methylpropan-1-amine 1-5 (1.2 g, white solid) in 71% yield. MS m / z (ESI): 140.1 [M+H] + .

[0134] Fifth step

[0135] (S)-1-(1H-Imidazol-2-yl)-2-methylpropan-1-amine 1-5 (1.2 g, 9 mmol) and N-acetyl-D-alanine (1.2 g, 9 mmol) were dissolved in N,N-dimethylformamide (12 mL), and 1-hydroxybenzotriazole (1.3 g, 9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9 mmol) were added at -20 °C. The reaction was stirred at 0 °C for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, and the organic phase was combined and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column (dichloromethane / methanol = 15 / 1) and then by reverse phase preparative purification to give (R)-N-((S)-1-(1H-imidazol-2-yl)-2-methylpropyl)-2-acetylamino propanamide 1 (0.6 g, white solid) in 32% yield. MS m / z (ESI): 253.0 [M+H] + .

[0136] 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.08 (m, 2H), 7.00 (s, 1H), 6.82 (s, 1H), 4.72 (dd, J = 9.1, 7.4 Hz, 1H), 4.36 (t, J = 7.2 Hz, 1H), 2.11 (m, 1H), 1.82 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).

[0137] Preparation of the compound 2 of Preparation Example 2

[0138]

[0139] First step

[0140] Compound 2-1 (4.18 g, 38.0 mmol) was dissolved in dichloromethane (40 mL), compound 2-2 (4.74 g, 39.1 mmol) and cesium carbonate (14.86 g, 45.5 mmol) were added to the solution, the reaction was stirred at 25 °C for 12 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (petroleum ether and ethyl acetate (V / V = 1:1) as mobile phase) to obtain the target product 2-3 (7.61 g, white solid, 84.47%). MS (ESI) m / z: 214.0 [M+H] + .

[0141] Second step

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

[0143] Third step

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

[0145] Fourth step

[0146] Compound 2-6 (1.33 g, 10.1 mmol) was dissolved in dichloromethane (10 mL), 1-hydroxybenzotriazole (2.05 g, 15.1 mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (3.87 g, 20.2 mmol) and NMM (3.06 g, 30.3 mmol) were added to the solution successively, the reaction was stirred at 25 °C for 1 h, then compound 2-5 (1.33 g, 8.1 mmol) was added to the reaction solution, the reaction was stirred for another 2 h. The reaction solution was concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether and ethyl acetate (V / V = 1:1)) and SFC (CHIRALPAK AD-H 250 mm x 20 mm, 5 μm, 40% MeOH (NH4OH 0.2%): 60% CO2) to obtain 2. MS (ESI) m / z: 267.0 [M+H] + .

[0147] 1 H NMR (400 MHz, CD3OD) 66.95 (d, J = 1.1 Hz, 1H), 6.88 (d, J = 1.1 Hz, 1H), 4.76 (d, J = 9.7 Hz, 1H), 4.26 (q, J = 7.2 Hz, 1H), 3.66 (s, 3H), 2.27-2.24 (m, 1H), 1.94 (s, 3H), 1.31 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H).

[0148] Preparation of compound 3 of Preparation Example 3

[0149]

[0150] First step

[0151] To a solution of compound 3-1 (1.50 g, 12.00 mmol) in dichloromethane (30 mL) was added 2-2 (1.45 g, 12 mmol), cesium carbonate (4.69 g, 14.4 mmol) successively. The reaction was stirred at room temperature overnight. The reaction solution was filtered, the filtrate was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent of petroleum ether and ethyl acetate (V / V = 5:1) to obtain the target product 3-2 (2 g, colorless liquid, 73.0%). MS (ESI) m / z: 229.1 [M+H] + .

[0152] Second step

[0153] To a solution of compound 3-2 (1.80 g, 7.89 mmol) in tetrahydrofuran (15 mL) was added dropwise isopropyl magnesium bromide in tetrahydrofuran (11.80 mL, 1 N, 11.80 mmol) at -78 °C under nitrogen protection. The reaction was stirred at -78 °C for 1 h. After quenching with saturated ammonium chloride solution, the reaction was allowed to warm to room temperature, diluted with ethyl acetate (60 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of petroleum ether and ethyl acetate (V / V = 4:1) to give the target product 3-3 (650 mg, colorless liquid, 30.4%). MS (ESI) m / z: 273.0 [M+H] + .

[0154] Third step

[0155] To a solution of compound 3-3 (650 mg, 2.39 mmol) in tetrahydrofuran (40 mL) was added HCl / dioxane (3 mL, 4 N, 12 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h. The reaction was rotary evaporated to dryness, then slurry with petroleum ether (10 mL) and filtered. The filter cake was air-dried to give the target product 3-4 (500 mg, off-white solid, 100%). MS (ESI) m / z: 169.1 [M+H] + .

[0156] Fourth step

[0157] To a solution of compound 2-6 (388 mg, 2.97 mmol) in dichloromethane (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (854 mg, 4.46 mmol), 1-hydroxybenzotriazole (602 mg, 4.46 mmol), N,N-diisopropylethylamine (1153 mg, 8.92 mmol), and 3-4 (500 mg, 2.97 mmol) sequentially at 0 °C. The reaction was stirred at 0 °C for 2 h. The reaction was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of dichloromethane and methanol (V / V = 20:1), and lyophilized to give the target product (585 mg, white solid, 70.0%). MS (ESI) m / z: 282.0 [M+H] + .

[0158] 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J = 2.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.44-7.38 (m, 1H), 4.78-4.75 (m, 1H), 4.46-4.40 (m, 1H), 2.30-2.15 (m, 1H), 2.01-1.94 (m, 3H), 1.40-1.25 (m, 3H), 1.02-0.90 (m, 3H), 0.86-0.76 (m, 3H).

[0159] Preparation of compound 4 of Preparation Example 4

[0160]

[0161] First step

[0162] Compound 1-5 (2.45 g, 17.6 mmol), compound 4-1 (3.33 g, 17.6 mmol) and N-methylmorpholine (5.33 g, 52.8 mmol) were added into dichloromethane (20 mL), the reaction was lowered to 0°C, 1-hydroxybenzotriazole (3.56 g, 26.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.04 g, 26.4 mmol) were slowly added into the reaction, after the reaction was stirred at 20°C for 2 hours, dichloromethane extraction (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 1:1) to obtain the target product 4-2 (3.45 g, colorless oil, 63.1%). MS (ESI) m / z: 311.0 [M+H] + .

[0163] Second step

[0164] Compound 4-2 (3.45 g, 11.1 mmol) and triethylamine (2.24 g, 22.2 mmol) were added into dichloromethane (30 mL), the reaction was lowered to 0°C, benzyl oxycarbonyl succinimide (3.04 g, 12.2 mmol) was slowly added into the reaction, after the reaction was stirred at 20°C for 2 hours, dichloromethane extraction (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 2:1) to obtain the target product 4-3 (3.61 g, colorless oil, 72.9%). MS (ESI) m / z: 445.2 [M+H] + .

[0165] Third step

[0166] Compound 4-3 (3.61 g, 8.1 mmol) was added to dichloromethane (30 mL), the reaction was reduced to 0 °C, trifluoroacetic acid (10 mL) was slowly added to the reaction, after the reaction was stirred at 20 °C for 1 hour, saturated sodium bicarbonate solution was added to the reaction, the pH value was adjusted to 9, dichloromethane was extracted (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 4-4 (2.3 g, colorless oil, 81.4 %). MS (ESI) m / z: 345 [M+H] + .

[0167] Fourth step

[0168] Compound 4-4 (2.3 g, 6.6 mmol), compound 4-5 (0.63 g, 6.6 mmol), tripyrridyl phosphonium hexafluorophosphate bromide (9.22 g, 19.8 mmol) and N, N-diisopropyl ethylamine (3.45 g, 26.4 mmol) were added to dichloroethane (20 mL), after the reaction was stirred at 20 °C for 16 hours, dichloromethane was extracted (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent dichloromethane and methanol (V / V = 15:1) to obtain the target product 4-6 (350 mg, colorless oil, 12.4 %). MS (ESI) m / z: 422.1 [M+H] + .

[0169] Fifth step

[0170] Compound 4-6 (350 mg, 0.82 mmol) was dissolved in tert-butyl alcohol (20 mL), then Pd / C (120 mg) was added to the reaction, hydrogen was replaced three times, the reaction was stirred at 20 °C for 16 hours. Filtered, the filtrate was concentrated under reduced pressure, purified by high performance liquid chromatography [CH3CN-H2O (0.1% TFA), CH3CN (30%-70%)], freeze-dried to obtain the target product 4 (180.79 mg, white solid, 86.1 %). MS (ESI) m / z: 288.2 [M+H] + .

[0171] 1H NMR (400 MHz, CDC13) δ 10.10 (d, J = 7.6 Hz, 1H), 8.65 (d, J = 4.3 Hz, 1H), 8.11 (t, J = 7.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.58 (dd, J = 7.2, 5.0 Hz, 1H), 7.46 (s, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 5.16 (t, J = 8.4 Hz, 1H), 4.04 (d, J = 6.4 Hz, 1H), 2.37 - 2.30 (m, 1H), 1.48 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H).

[0172] Preparation of compound 5 of Preparation Example 5

[0173]

[0174] First step

[0175] To a solution of compound 5-1 (15 g, 0.21 mol) in dichloromethane (250 mL) was added 5-2 (27.5 g, 0.23 mol) and anhydrous copper sulfate (8.6 g, 0.05 mol), and the reaction was stirred at 25 °C for 24 hours. The reaction was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 10:1) to obtain the target product 5-3 (7 g, white oil, 42%). MS (ESI) m / z: 176.0 [M+H] + .

[0176] Second step

[0177] Compound 1,3-oxazole (1 g, 0.01 mol) and borane tetrahydrofuran solution (22 mL) were dissolved in tetrahydrofuran (30 mL), and then the reaction was cooled to -78 °C, and then n-butyllithium (2.4 M, 10 mL, 24 mmol) was added. After the reaction was stirred for 30 minutes, 5-3 (2.5 g, 0.01 mol) was slowly added, and the reaction was stirred at -78 °C (under nitrogen protection) for 3 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated sodium bicarbonate solution (10 mL x 2), saturated ammonium chloride solution (10 mL x 2), and saturated sodium chloride solution (10 mL x 2) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and methanol (V / V = 10:1) to obtain the target product 5-4 (1 g, white solid, 90.1%). MS (ESI) m / z: 245.2 [M+H] + .

[0178] Third step

[0179] To compound 5-4 (1 g, 4.10 mmol) was added hydrochloric acid 1,4 dioxane (10 mL) solution at 0 °C, the reaction was stirred at 0 °C for 1 hour. The reaction was rotary evaporated to dryness to give the target product 5-5 (400 mg, white solid, 36 %). MS (ESI) m / z: 141.2 [M+H] + .

[0180] Fourth step

[0181] Compound 5-5 (400 mg, 2.91 mmol), 5-6 (621 mg, 3.22 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (729 mg, 3.81 mmol), N, N- diisopropylethylamine (1890 mg, 14.62 mmol), 1-hydroxybenzotriazole (593 mg, 4.39 mmol) were dissolved in dichloromethane (30 mL) solution. The reaction was stirred at room temperature for 2 hours. The reaction was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium bicarbonate solution (10 mL x 2), saturated ammonium chloride solution (10 mL x 2), saturated sodium chloride solution (10 mL x 2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse column (CH3CN-H2O (0.1% TFA), CH3CN (30%-70%)), freeze-dried to give the target product 5 (340 mg, white solid, 80.7 %). MS (ESI) m / z: 316.1 [M+H] + .

[0182] 1 H NMR (400 MHz, DMSO-d6) δ 8.88-8.47 (m, 1H), 8.55-8.47 (m, 1H), 8.08-8.03 (m, 1H), 7.50-7.47 (m, 1H), 7.36-7.23 (m, 4H), 7.15-7.11 (m, 1H), 5.67-5.62 (m, 1H), 4.81-4.72 (m, 1H), 2.16-2.04 (m, 1H), 1.90-1.88 (m, 3H), 0.93-0.62 (m, 6H).

[0183] Preparation of compound 6 of Preparation Example 6

[0184]

[0185] First step

[0186] Compound 2-iodopyrimidine (2 g, 9.71 mmol) was dissolved in dichloromethane (30 mL), and then the reaction solution was cooled to -78 °C, and n-butyllithium (2.4 M, 4 mL, 9.6 mmol) was added. After stirring for 30 min, 5-3 (1.7 g, 9.71 mmol) was slowly added, and the reaction solution was stirred at -78 °C for 3 h under nitrogen protection. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and washed with saturated sodium bicarbonate solution (10 mL x 2), saturated ammonium chloride solution (10 mL x 2), and saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane and methanol (V / V = 10:1) as eluents to obtain the target product 6-1 (500 mg, yellow oil, 22.5%). MS (ESI) m / z: 256.1 [M+H] + .

[0187] Second step

[0188] Compound 6-1 (500 mg, 1.96 mmol) was added to a solution of hydrochloric acid in 1,4-dioxane (10 mL) at 0 °C, and the reaction was stirred at 0 °C for 1 h. Filtration gave the target product 6-2 (320 mg, yellow oil, 57.6%). MS (ESI) m / z: 152.2 [M+H] + .

[0189] Third step

[0190] Compound 6-2 (320 mg, 2.12 mmol), 5-6 (450 mg, 2.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (527 mg, 2.75 mmol), N,N-di-isopropylethylamine (1367 mg, 10.58 mmol), 1-hydroxybenzotriazole (429 mg, 3.17 mmol) were dissolved in dichloromethane (30 mL). The reaction was stirred at room temperature for 2 h. The reaction was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and washed with saturated sodium bicarbonate solution (10 mL x 2), saturated ammonium chloride solution (10 mL x 2), and saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column [CH3CN-H2O (0.1% TFA), CH3CN (30%-70%)], lyophilized to obtain the target product 6 (230 mg, white solid, 64.7%). MS (ESI) m / z: 327 [M+H] + .

[0191] 1H NMR (400 MHz, DMSO-d6) δ 8.81 - 8.47 (m, 1H), 7.43 - 7.20 (m, 6H), 5.75 - 5.67 (m, 1H), 4.82 - 4.72 (m, 1H), 2.21 - 2.08 (m, J = 27.5, 13.7, 6.8 Hz, 1H), 1.92 - 1.86 (m, 3H), 0.91 - 0.57 (m, 6H).

[0192] Preparation of compound 7 of Preparation Example 7

[0193]

[0194] To a solution of compound 5-6 (500 mg, 2.59 mmol) in dichloromethane (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (744 mg, 3.88 mmol), 1-hydroxybenzotriazole (524 mg, 3.88 mmol), N-methylmorpholine (785 mg, 7.76 mmol), 1-5 (540 mg, 3.88 mmol) sequentially at 0 °C. The reaction was stirred at 0 °C for 2 hours. The reaction was rotary evaporated to dryness, the residue was purified by silica gel column chromatography with elution of dichloromethane and methanol (V / V = 10:1), the crude product was further purified by preparative plate (eluent: dichloromethane:methanol = 10:1), lyophilized to give the target product 7 (425 mg, white solid, 52.3%). MS (ESI) m / z: 315.2 [M+H] + .

[0195] 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.42 (m, 1H), 7.37 - 7.22 (m, 4H), 6.96 - 6.88 (m, 2H), 5.44 - 5.42 (m, 1H), 4.79 - 4.66 (m, 1H), 2.21 - 2.14 (m, 1H), 1.99 (s, 3H), 0.98 (d, J = 6.7 Hz, 1.5H), 0.77 - 0.65 (m, 4.5H).

[0196] Preparation of compound 8 of Preparation Example 8

[0197]

[0198] In a 200 mL single necked flask, compound 5-5 (2.2 g, 15.69 mmol), compound 8-1 (3.3 g, 17.26 mmol) were taken, dichloromethane (100 mL) was added, cooled to -10 °C, N, N-diisopropyl ethylamine (10.14 g, 78.45 mmol) was added slowly, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g, 23.54 mmol) was added, 1-hydroxybenzotriazole (3.2 g, 23.54 mmol) was added, reaction was carried out for 2 h at -10 °C. The reaction was monitored by LCMS and TLC, after completion of reaction, quenched with water, extracted with dichloromethane (50 mL x 3), combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate: dichloromethane = 3: 1) to get compound 8 (1.4 g, 4.44 mmol, 28.29 % yield).

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

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 8.9 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 0.7 Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.29 - 7.23 (m, 1H), 7.19 (d, J = 0.6 Hz, 1H), 5.67 (d, J = 8.4 Hz, 1H), 4.74 (t, J = 8.2 Hz, 1H), 2.06 (dq, J = 13.7, 6.8 Hz, 1H), 1.88 (s, 3H), 0.69 (d, J = 6.7 Hz, 3H), 0.63 (d, J = 6.7 Hz, 3H).

[0201] Preparation of compound 9 of Preparation Example 9

[0202]

[0203] In a 200 mL single necked flask, compound 5-5 (2.1 g, 14.98 mmol), compound 9-1 (3.18 g, 16.48 mmol) were added, dichloromethane (100 mL) was added, cooled to -20 °C, N, N-diisopropyl ethylamine (9.6 g, 74.90 mmol) was added slowly, after stirring for 10 min at -20 °C, N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (6.8 g, 17.97 mmol) was added, the reaction was carried out for 2 h at -20 °C. After monitoring the reaction completion by LCMS and TLC, quenched with water, extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate: dichloromethane = 3: 1) to get compound 9 (605 mg, 1.92 mmol, 12.8 % yield).

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

[0205] 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.35 (d, J = 7.1 Hz, 2H), 7.25 (ddd, J = 10.7, 9.8, 5.3 Hz, 3H), 7.11 (s, 1H), 5.63 (d, J = 8.3 Hz, 1H), 4.79 (t, J = 8.2 Hz, 1H), 2.16 (dq, J = 13.8, 6.8 Hz, 1H), 1.90 (s, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H).

[0206] Preparation of compound 10 of Preparation Example 10

[0207]

[0208] First step

[0209] Compound 10-1 (1.00 g, 8.06 mmol) was dissolved in dichloromethane (15 mL), to the solution was added compound 5-2 (1.27 g, 10.48 mmol) and cesium carbonate (5.25 g, 16.12 mmol), the reaction was stirred at 25 °C for 12 hours. TLC and LCMS monitoring, after the reaction was completed, dichloromethane (50 mL) was added to the reaction solution, then washed with water once (50 mL), the aqueous phase was extracted with dichloromethane (50 mL) twice, the organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain the target product 10-2 (1.70 g, 7.48 mmol, yellow oil, 92 %). MS (ESI) m / z: 228.2 [M+H] + .

[0210] Second step

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

[0212] Third step

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

[0214] Fourth step

[0215] Compound 10-4 (0.58 g, 2.86 mmol) was dissolved in dichloromethane (10 mL), 2-6 (0.41 g, 3.15 mmol), HATU (1.30 g, 3.43 mmol) and DIPEA (1.11 g, 8.58 mmol) were added to the solution successively, the reaction was stirred at -20 °C for 3 hours, monitored by TLC and LCMS. After the reaction was completed, dichloromethane (50 mL) was added to the reaction solution, then washed with water once (50 mL), the aqueous phase was extracted with dichloromethane (50 mL) twice, the organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography, the obtained crude product was purified by silica gel column chromatography to obtain the product (0.20 g, 0.71 mmol white solid, 20%). MS (ESI) m / z: 281.1 [M+H] + .

[0216] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.6, 1H), 7.28 (t, J = 7.3, 1H), 7.22-7.09 (m, 2H), 4.84 (m, 1H), 4.43-4.31 (m, 1H), 1.93 (m, 1H), 1.78 (s, 3H), 1.21 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.7 Hz, 3H).

[0217] Preparation of compound 11 of Preparation Example 11

[0218]

[0219] First step:

[0220] Compound 11-1 (1.40 g, 10.0 mmol) was dissolved in dichloromethane (20 mL), compound 5-2 (1.57 g, 13.00 mmol) and cesium carbonate (6.50 g, 20.00 mmol) were added to the reaction solution, stirred at room temperature overnight, monitored by TLC, after the reaction was completed, filtered, the filter cake was washed with 20 mL of dichloromethane, and then stirred with silica gel, separated by column chromatography to obtain compound 11-2 (2.14 g, 8.80 mmol, yield: 88%). MS-ESI: M / Z = 244.2 [M+H] + .

[0221] Second step:

[0222] Compound 11-2 (2.14 g, 8.80 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction system was replaced with nitrogen three times, then the temperature was reduced to below -60°C, isopropyl magnesium bromide tetrahydrofuran solution (4.7 mL 2.8 mol / L) was slowly added dropwise, after dropwise addition, incubation was carried out for 1 h, slow warming to room temperature and continued stirring for 12 hours, the reaction was monitored by TLC. After the reaction was completed, saturated ammonium chloride solution (20 mL) was slowly added dropwise to the reaction liquid for quenching, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, mixed with silica gel, separated by column chromatography to obtain compound 11-3 (1.50 g, 5.22 mmol, yield: 59%). MS-ESI: M / Z = 288.2 [M+H] + .

[0223] Third step:

[0224] Compound 11-3 (1.50 g, 5.22 mmol) was added to tetrahydrofuran (15 mL), 4.0 mol / L hydrogen chloride dioxane solution (10 mL, 40 mmol) was slowly added dropwise at room temperature, after dropwise addition, stirring was continued at room temperature, and TLC was used for monitoring. After the reaction was completed, the solvent was recovered to dryness to obtain compound 11-4 hydrochloride crude product (1.03 g, 4.70 mmol, yield: 85%). MS-ESI: M / Z = 183.1 [M+H] + .

[0225] Fourth step 4:

[0226] Compound 11-4 (224 mg, 1.02 mmol), N-acetyl-D-alanine (160 mg, 1.22 mmol) were added to a reaction bottle with dichloromethane (15 mL), cooled to -20°C, slowly added HATU (463 mg, 1.22 mmol), N, N-diisopropyl ethylamine (263 mg, 2.04 mmol), maintained the temperature, continued stirring, and TLC and LCMS were used for monitoring the reaction. After the reaction was completed, water (20 mL) was added, the layers were separated, the aqueous phase was extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, and passed through a silica gel column to obtain compound 11 (245 mg, 0.83 mmol, yield: 82%). MS-ESI: M / Z = 297.2 [M+H] + .

[0227] 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.45 - 7.16 (m, 4H), 4.54 (t, J = 8.5 Hz, 1H), 4.36 (p, J = 7.1 Hz, 1H), 2.04 - 1.87 (m, 1H), 1.81 (d, J = 12.7 Hz, 3H), 1.19 (t, J = 8.9 Hz, 3H), 0.86 (t, J = 8.0 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H).

[0228] Preparation of compound 12 of Preparation Example 12

[0229]

[0230] First step:

[0231] Compound 12-1 (1.36 g, 10.00 mmol) was dissolved in dichloromethane (20 mL), 5-2 (1.57 g, 13.00 mmol) and cesium carbonate (6.50 g, 20.00 mmol) were added to the reaction solution, stirred at room temperature overnight, monitored by TLC, after the reaction was completed, filtered, the filter cake was washed with 20 mL of dichloromethane, and then stirred with silica gel, and separated by column chromatography to obtain compound 12-2 (2.25 g, 9.41 mmol, yield: 94%). MS-ESI: M / Z = 240.2 [M+H] + .

[0232] Second step:

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

[0234] Third step:

[0235] Compound 12-3 (0.45 g, 1.59 mmol) was added into tetrahydrofuran (15 mL), 4.0 mol / L hydrogen chloride solution in dioxane (10 mL, 40 mmol) was slowly added dropwise at room temperature, after the dropwise addition was completed, the stirring was continued at room temperature, and TLC was used for monitoring. After the reaction was completed, the solvent was recovered to dryness to obtain compound 12-4 (0.33 g, 1.53 mmol, yield: 96%). MS-ESI: M / Z = 180.1 [M+H] + .

[0236] Fourth step

[0237] Compound 12-4 (215 mg, 1.00 mmol), compound 2-6 (179 mg, 1.37 mmol) were added into a reaction flask with dichloromethane (15 mL), and the temperature was lowered to -20 °C, HATU (456 mg, 1.20 mmol), N,N-diisopropyl ethylamine (387 mg, 3.00 mmol) were slowly added, the temperature was maintained, the stirring was continued, and TLC and LCMS were used for monitoring the reaction. After the reaction was completed, water (20 mL) was added, the layers were separated, the aqueous phase was extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, and was passed through a silica gel column to obtain compound 12 (270 mg, 0.92 mmol, yield: 92%). MS-ESI: M / Z = 293.2 [M+H] + .

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.27-7.15 (m, 1H), 6.89-6.72 (m, 3H), 4.51 (t, J = 8.5 Hz, 1H), 4.38 (m, 1H), 3.73 (d, J = 4.2 Hz, 3H), 2.01-1.86 (m, 1H), 1.79 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H).

[0239] Preparation of compound 13 of Preparation Example 13

[0240]

[0241] First step

[0242] In a 250 mL single necked flask, compound 13-1 (2.00 g, 21.03 mmol) was dissolved in dichloromethane (40 mL), to the solution was added compound 5-2 (2.55 g, 21.03 mmol) and cesium carbonate (13.70 g, 42.06 mmol), the reaction was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS and TLC showed the reaction was complete, the reaction was filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by flash chromatography to give compound compound 13-2 (2.00 g, 10.09 mmol, 47.98 % yield). ESI-LCMS: m / z 199.1 [M+H] + .

[0243] Second step

[0244] In a 250 mL three-necked flask, compound 13-2 (1.7 g, 8.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), the reaction system was replaced with nitrogen three times, then the temperature was reduced to -60 °C, and a tetrahydrofuran solution of isopropyl magnesium bromide (20 mL, 40 mmol, 2.0 M) was slowly added to the reaction solution at this temperature, the reaction was slowly warmed to 25 °C and stirred for 12 hours. The reaction was monitored by LCMS and TLC showed the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography to give compound 13-3 (1.60 g, 6.60 mmol, 77.01 % yield). ESI-LCMS: m / z 243.2 [M+H] + .

[0245] Third step

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

[0247] Fourth step

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

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 9.4 Hz, 1H), 6.59 (q, J = 2.3 Hz, 1H), 5.93 - 5.81 (m, 2H), 4.66 (dd, J = 9.4, 7.1 Hz, 1H), 4.32 (p, J = 7.1 Hz, 1H), 1.92 (h, J = 6.9 Hz, 1H), 1.83 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.77 (dd, J = 22.2, 6.7 Hz, 6H).

[0250] Preparation of compound 14 of Preparation Example 14

[0251]

[0252] First step

[0253] In a 250 mL single necked flask, compound 14-1 (2.00 g, 20.81 mmol) was dissolved in dichloromethane (40 mL), to the solution was added compound 5-2 (2.52 g, 20.81 mmol) and cesium carbonate (13.56 g, 41.62 mmol), the reaction was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS and TLC showed the reaction was complete, the reaction was filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by flash chromatography to give compound 14-2 (3.00 g, 15.05 mmol, 72.32% yield). ESI-LCMS: m / z 200.1 [M+H] + .

[0254] Second step

[0255] In a 250 mL three-necked flask, compound 14-2 (2.00 g, 10.04 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), the reaction system was replaced with nitrogen three times, then the temperature was reduced to -60 °C, and a tetrahydrofuran solution of isopropyl magnesium bromide (25 mL, 50 mmol, 2M) was slowly added dropwise to the reaction solution, which was slowly warmed to 25 °C and stirred for 12 hours. After monitoring showed that the reaction was complete by LCMS and TLC, the reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 14-3 (2.20 g, 9.04 mmol, yield 90.04%). ESI-LCMS: m / z 244.2 [M+H] + .

[0256] Third step

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

[0258] Fourth step

[0259] In a 100 mL single-necked flask, compound 14-4 (600 mg, 3.42 mmol) was dissolved in DMF (10 mL), compound 5-6 (661 mg, 3.42 mmol), N, N-diisopropyl ethylamine (884 mg, 6.84 mmol) were added, T3P (3.26 g, 5.13 mmol, 50% DMF solution) was added, and the reaction was stirred at room temperature for 2 hours. After monitoring showed that the reaction was complete by LCMS and TLC, the reaction was diluted with ethyl acetate, the reaction was washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified again by reverse MPLC to obtain the product compound 14 (140 mg, 0.45 mmol, yield 13.16%). ESI-LCMS: m / z 315.2 [M+H] + .

[0260] 1H NMR (400 MHz, DMSO-d6) δ 12.53 (d, J = 31.7 Hz, 1H), 8.72 - 8.37 (m, 2H), 7.67 - 7.19 (m, 6H), 6.08 (d, J = 81.5 Hz, 1H), 5.62 (d, J = 8.3 Hz, 1H), 4.73 (s, 1H), 2.09 - 1.94 (m, 1H), 1.89 (d, J = 13.2 Hz, 3H), 0.82 (dd, J = 29.1, 6.7 Hz, 3H), 0.62 (dd, J = 14.2, 6.7 Hz, 3H).

[0261] Preparation of compound 1SA and compound 15B

[0262]

[0263] First step:

[0264] Compound 5-5 (4 g, 22.6 mmol), compound 15-1 (6 g, 23.8 mmol), compound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.6 g, 29.4 mmol), N, N-diisopropyl ethylamine (14.6 g, 112.8 mmol), 1-hydroxybenzotriazole (4.6 g, 33.8 mmol) were dissolved in dichloromethane (50 mL). The reaction was carried out at room temperature for 2 hours. Extraction was carried out with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated sodium bicarbonate solution (50 mL x 2), saturated ammonium chloride solution (50 mL x 2), saturated sodium chloride solution (50 mL x 2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 1:1) to obtain a mixture of product compound 15-2 (4 g, white solid, 38%). MS (ESI) m / z: 373 [M+H] + .

[0265] Second step:

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

[0267] Third step:

[0268] A mixture of compound 15-3 (4 g, 14.6 mmol) and N, N-diisopropylethylamine (11.3 g, 87.6 mmol) was dissolved in dichloromethane (40 mL) at 0 °C, then compound 9 (1.4 g, 17.5 mmol) was added slowly dropwise. The reaction was stirred at 0 °C for 1 hour. Purification was performed with a reverse column (acetonitrile-water (0.1% trifluoroacetic acid), acetonitrile (30%-70%)), the resulting residue was lyophilized, basified to give compound 15A and 15B.

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

[0270] 1 HNMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.35 - 7.22 (m, 5H), 7.11 (s, 1H), 5.63 (d, J = 8.3 Hz, 1H), 4.79 (t, J = 8.2 Hz, 1H), 2.14 (dt, J = 13.9, 6.9 Hz, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H).

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

[0272] 1 HNMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.35 - 7.22 (m, 5H), 7.11 (s, 1H), 5.63 (d, J = 8.3 Hz, 1H), 4.79 (t, J = 8.2 Hz, 1H), 2.14 (dt, J = 13.9, 6.9 Hz, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H).

[0273] Preparation of compound 16

[0274]

[0275] First step:

[0276] Compound 16-1 (2.5 g, 10.2 mmol), 1-hydroxybenzotriazole (2.07 g, 15.3 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g, 15.3 mmol) were added into dichloromethane (20 mL), the reaction was reduced to -15 °C, compound 5-5 (1.8 g, 10.2 mmol) and N-methylmorpholine (4.13 g, 40.8 mmol) were slowly added into the reaction, after stirring at -15 °C for 2 hours, the reaction was extracted with dichloromethane (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 3:1) to obtain the title product compound 16-2 (1.95 g, white solid, 52.1%). MS (ESI) m / z: 390 [M+Na] + .

[0277] Second step:

[0278] Compound 16-2 (1.95 g, 5.3 mmol) was added into dichloromethane (10 mL), the reaction temperature was reduced to 0 °C, trifluoroacetic acid (5 mL) was slowly added into the reaction, after stirring at 20 °C for 1 hour, saturated sodium bicarbonate solution was added into the reaction, the pH value was adjusted to 8, extracted with dichloromethane (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product compound 16-3 (1.38 g, colorless oil, 97.2%). MS (ESI) m / z: 268 [M+H] + .

[0279] Third step:

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

[0281] 1 HNMR (400 MHz, CDC13) δ 7.60 (s, IH), 7.07 (s, IH), 6.90 (d, J = 8.6 Hz, IH), 5.96 (d, J = 8.0 Hz, IH), 5.04 (dd, J = 8.8, 6.2 Hz, IH), 4.51 (td, J = 7.9, 5.2 Hz, IH), 2.23 (dq, J = 13.4, 6.7 Hz, IH), 1.93 (dd, J = 14.4, 5.1 Hz, IH), 1.45 (dd, J = 14.4, 7.7 Hz, IH), 0.93 (d, J = 4.1 Hz, 12H), 0.87 (d, J = 6.8 Hz, 3H).

[0282] Preparation of compound 17 of Preparation Example 17

[0283]

[0284] First Step:

[0285] To a solution of compound 17-1 (1.8 g, 7.3 mmol) in dichloromethane (18 mL) was added compound 5-5 (1.68 g, 9.49 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2.1 g, 10.95 mmol), 1-hydroxybenzotriazole (1.48 g, 10.95 mmol) and N, N-diisopropylethylamine (2.83 g, 21.9 mmol), and the reaction was stirred at room temperature for 18 hours. It was diluted with water 50 mL and extracted with dichloromethane (20 mL x 3), the organic phases were combined and washed with sodium bicarbonate solution (50 mL x 2) and saturated sodium chloride solution (50 mL x 2) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution of dichloromethane and ethyl acetate (V / V = 1:1) to give the title product compound 17-2 (2.6 g, light yellow solid, 87%). MS (ESI) m / z: 368.2 [M+H] + .

[0286] Second Step:

[0287] Compound 17-2 (2.6 g, 7.1 mmol) was dissolved in dichloromethane (21 mL), and trifluoroacetic acid (7 mL) was added, and the reaction was stirred at room temperature for 2 hours. It was concentrated under reduced pressure to give the title product compound 17-3 (2.7 g, yellow oil, crude), MS (ESI) m / z: 268.2 [M+H] + .

[0288] Third Step:

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

[0290] 1 H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.91 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 8.9, 6.0 Hz, 1H), 4.57 (td, J = 8.3, 4.3 Hz, 1H), 2.23 (dd, J = 13.1, 6.6 Hz, 1H), 1.98 (dd, J = 14.5, 4.3 Hz, 1H), 1.45 (dd, J = 14.5, 8.1 Hz, 1H), 0.97 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H).

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

[0292]

[0293] First step:

[0294] In a dry single neck flask, (tert-butoxycarbonyl)-L-alanine (4.5 g, 23.78 mmol) was dissolved in dichloromethane (50 mL) and stirred in an ice bath for 10 min. Then, L-valine methyl ester (3.12 g, 23.78 mmol), N,N-diisopropylethylamine (6.15 g, 47.56 mmol), 1-hydroxybenzotriazole (3.53 g, 26.16 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.01 g, 26.16 mmol) were added to the flask in sequence and stirred at room temperature for 2 h. After the reaction was completed as shown by TLC, water (50 mL) was added to quench and adjusted to be acidic with 2M hydrochloric acid, extracted with dichloromethane (50 mL x 2), the organic phase was adjusted to be basic with saturated sodium bicarbonate solution, 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 intermediate (tert-butoxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol, yield 90.39%). LCMS (M+H + + = 303.1.

[0295] Second step:

[0296] In a dry single neck flask, (tert-butoxycarbonyl)-L-alanyl-L-valine methyl ester (6.5 g, 21.50 mmol) was dissolved in dichloromethane (30 mL), then hydrochloric acid-1.4-dioxane (10 mL, 4M) was added to the flask and stirred at room temperature for 2 h. After the reaction was completed as shown by TLC, the organic phase was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10: 1) to obtain intermediate L-alanyl-L-valine methyl ester (3.7 g, 18.32 mmol, yield 87.22%). LCMS (M+H + 1 = 203.3.

[0297] 1 HNMR (400 MHz, CDCl3) 68.13 (s, 3H), 4.56 (s, 1H), 4.31 (s, 1H), 3.65 (s, 3H), 2.15 (d, J = 5.3 Hz, 1H), 1.57 (s, 3H), 0.92 (t, J = 6.8 Hz, 6H).

[0298] Third step:

[0299] Compound L-alanyl-L-valine methyl ester (3.7 g, 18.32 mmol) and N, N- diisopropylethylamine (4.72 g, 36.64 mmol) were dissolved in tetrahydrofuran (50 mL) and stirred at 0 °C after purging with nitrogen. After 10 min, acetic anhydride (2.8 g, 27.48 mmol) was added dropwise slowly and stirred at the same temperature for 10 min and then at room temperature for 2 h. After completion of the reaction as indicated by TLC, it was quenched with water (50 mL) and acidified with 2 M hydrochloric acid and extracted with dichloromethane (50 mL x 4). The organic layers were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and purified by column chromatography on silica gel (PE:EA = 5:1) to obtain compound ZZL-7 (acetyl-L-alanyl-L-valine methyl ester, 2.6 g, 10.67 mmol, 58.23 % yield). LCMS (M+H + + = 245.3. 1 HNMR (400 MHz, CDC13) δ 6.68 (d, J = 8.5 Hz, 1H), 6.21 (d, J = 7.1 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.44 (dd, J = 8.7, 4.9 Hz, 1H), 3.68 (s, 3H), 2.18 - 2.04 (m, 1H), 1.94 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H), 0.85 (dd, J = 10.1, 6.9 Hz, 6H).

[0300] Preparation of compound 19 of Preparation Example 19

[0301]

[0302] First step

[0303] Intermediate starting material 4-2 (0.46 g, 1.48 mmol) and hydrochloric acid dioxane solution (4.0 M, 5 mL) were added to a dry 50 mL three-necked flask and stirred at room temperature for 2 h. After completion of the reaction as monitored by TLC and LCMS, the reaction was concentrated to obtain compound 19-1 (0.30 g, 1.43 mmol, light yellow solid), yield: 96 %.

[0304] Second step

[0305] ​Compound 19-1 (0.10 g, 0.48 mmol) was dissolved in dry dichloromethane (10 mL), after stirring well, the temperature was lowered to about 0 degrees, then slowly drop cyclopropylcarbonyl chloride (25 mg, 0.24 mmol) and N, N-diisopropyl ethylamine (93 mg, 0.72 mmol). After the drop was completed, the temperature was kept for 1 hour. After monitoring the reaction by TLC and LCMS, the reaction was washed with water, the aqueous phase was extracted with dichloromethane (50 mL x 3), the organic phase was combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, purified by MPLC to obtain compound 19 (21 mg, 0.08 mmol, white solid), yield: 15%. MS m / z (ESI): 279.2 [M+H] + .

[0306] 1 H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 4.73 (dd, J = 9.1, 7.2 Hz, 1H), 4.44-4.35 (m, 1H), 2.67 (s, 0.5H), 2.33 (s, 0.5H), 2.18-1.13 (m, 6H), 0.95-0.49 (m, 8H).

[0307] Preparation of compound 20 of Preparation Example 20

[0308]

[0309] First step

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

[0311] Second step

[0312] In a 100 mL flask, 20-1 (295 mg, 1.45 mmol), 1-5 (202 mg, 1.45 mmol), N, N- diisopropylethylamine (561 mg, 4.35 mmol), anhydrous dichloromethane (7 mL) were added successively. After the reaction solution was stirred in an ice bath for 10 min, 1- hydroxybenzotriazole (294 mg, 2.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (418 mg, 2.18 mmol) were added and allowed to react slowly at room temperature for 3 h. After the reaction was completed as indicated by LCMS and TLC monitoring, saturated brine (50 mL) was added to quench, extracted with dichloromethane (50 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by normal phase column chromatography to give 20-2 (110 mg, 0.34 mmol, 23.4% yield). ESI-LCMS: m / z 325.2 [M+H] + .

[0313] Third step

[0314] In a 100 mL flask, 20-2 (110 mg, 0.34 mmol), anhydrous dichloromethane (2 mL), hydrochloric acid in 1,4-dioxane (4.0 M, 2 mL) were added. The reaction solution was stirred at room temperature for 1 h. After the reaction was completed as indicated by LCMS and TLC monitoring, the reaction solution was concentrated, diluted with dichloromethane (50 mL), then concentrated again to remove the residual hydrochloric acid dioxane solution. The residue was purified by reverse phase silica gel column chromatography to give 20-3 (69 mg, 0.31 mmol, 91.2% yield) after lyophilization. ESI-LCMS: m / z 225.2 [M+H] + .

[0315] Fourth step

[0316] In a 100 mL flask, 20-3 (69 mg, 0.31 mmol), anhydrous dichloromethane (6 mL), triethylamine (173 mg, 1.71 mmol) were added. After stirring in an ice bath for 10 min, a solution of acetyl chloride (73 mg, 0.93 mmol) in anhydrous dichloromethane (1 mL) was added dropwise slowly. After the reaction was completed as indicated by LCMS and TLC monitoring, dichloromethane (50 mL) was added to dilute, an equal volume of saturated aqueous sodium bicarbonate solution was added to quench, the aqueous phase was extracted with dichloromethane (50 mL x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by normal phase column chromatography to give compound 20 (12 mg, 0.05 mmol, 16.1% yield). MS (ESI) m / z: 267.2 [M+H] + .

[0317] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.12 (dd, J = 128.7, 9.0 Hz, 1H), 6.93 (d, J = 2.8 Hz, 2H), 5.08 - 4.47 (m, 2H), 2.74 (d, J = 81.2 Hz, 3H), 2.17 - 2.04 (m, 1H), 1.99 (d, J = 8.0 Hz, 3H), 1.27 (dd, J = 26.5, 7.1 Hz, 3H), 0.85 (dd, J = 10.4, 6.7 Hz, 3H), 0.72 (dd, J = 8.4, 6.7 Hz, 3H).

[0318] Preparation of compound 21 of Preparation Example 21

[0319]

[0320] First step:

[0321] Intermediate starting material 1-5 (0.40 g, 2.90 mmol) and 2-((tert- butylamido)-2-cyclopropylacetic acid (0.60 g, 2.80 mmol) were dissolved in DMF (10 mL), and the reaction solution was cooled to about -10°C. HOBt (0.40 g, 3.00 mmol) and EDCI (0.58 g, 3.00 mmol) were added to the reaction solution. Then, the reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed as monitored by TLC, the reaction solution was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by MPLC gave 21-1 (0.78 g, 2.32 mmol, yield: 80%). MS (ESI) m / z: 337.3 [M+H] + .

[0322] Second step:

[0323] 21-1 (0.78 g, 2.32 mmol) was added to a mixed solution of ethyl acetate (20 mL) and methanol (5 mL), and 4.0 M hydrogen chloride in dioxane (5 mL, 20.0 mmol) was slowly added dropwise at room temperature. After the addition was completed, stirring was continued at room temperature until the reaction was completed as monitored by TLC. Concentration under reduced pressure gave 21-2 hydrochloride (0.62 g, 2.27 mmol, yield: 98%) as a crude product, which was used directly in the next reaction. MS-ESI: M / Z = 237.2 [M+H] + .

[0324] Third step:

[0325] To a solution of 21-2 hydrochloride (0.62 g, 2.27 mmol) in acetic anhydride (10 mL) was added triethylamine (0.69 g, 6.81 mmol) and the reaction mixture was heated to 60 °C for 3 h. The reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to give compound 21 (0.18 g, 0.64 mmol, yield: 28%). MS (ESI) m / z: 279.2 [M+H] + .

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.28-8.10 (m, 1H), 7.98 (d, J = 9.1 Hz, 1H), 6.92 (s, 2H), 4.78-4.66 (m, 1H), 3.82-3.74 (m, 1H), 2.22-1.94 (m, 1H), 1.83 (d, J = 5.2 Hz, 3H), 1.06-0.94 (m, 1H), 0.85 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H), 0.49-0.14 (m, 4H).

[0327] Activity Experiment 1: Plasma stability determination

[0328] The mouse plasma was thawed in a water bath at 37 °C, and the supernatant was removed by centrifugation. The pH was recorded as 7-8. A certain volume of acetonitrile stock solution (concentration of 10 mM) of the test compound was diluted with acetonitrile to 1 mM as an intermediate solution. Propantheline was used as a positive control. A certain volume of the compound intermediate solution was added to the corresponding volume of plasma and mixed uniformly, so that the concentration of the test compound in the incubation system was 5 μM, and the content of the organic solvent acetonitrile was 0.5%. 50 μL of the mixed plasma was taken into a 96-well plate (N = 2), and after incubation at 37 °C for a certain time, 300 μL of methanol solution containing an internal standard was added to terminate the reaction. The supernatant was vortexed and centrifuged for LC-MS / MS analysis. The percentage of compound remaining and incubation time were plotted to obtain the k value, and the half-life of each compound was calculated. The formula is as follows:

[0329]

[0330] Table 1 shows the plasma stability data of some compounds, and the results show that the compounds of the present application exhibit excellent plasma stability, which is significantly better than that of ZZL-7.

[0331] Table 1 Plasma stability data for some compounds

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

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

[0334] Pharmacokinetic test of active experiment 2

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

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

[0337] Statistical calculation was performed on the above parameter data.

[0338] Table 2 shows the area under the curve (AUC) and bioavailability (F) data of the compounds of the present application after oral administration, and the results show that the compounds of the present application have good pharmacokinetic properties, which are significantly better than those of compound ZZL-7.

[0339] Table 2 Pharmacokinetic data for some compounds

[0340]

[0341]

[0342] Active experiment 3

[0343] In vivo efficacy test 1

[0344] 6-8 weeks old C57 / B6 mice were selected to make 28d animal chronic unpredictable mild stress model (CUMS, Chronic Unpredictable Mild Stress), and the success of the model was evaluated by open field test (Open Field Test, OFT). The experiment was divided into control group (Control), model group (Model), solvent control group (Vehicle), fluoxetine control group and compound group. The test compound was administered at a dose of 100 mg / kg by single intravenous injection (i.v), and 2h later, tail suspension test (Tail suspension test, TST) and forced swimming test (Forced swimming test, FST) were performed to evaluate the depression of mice. The prolonged immobility time of mice in TST and FST indicates that the mice are in despair. After data collection and statistics, SPSS data statistical software was used for analysis, and Graph Pad software was used to draw images according to the SPSS analysis results.

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

[0346] In vivo pharmacodynamic test 2

[0347] 6-8 weeks old C57 / B6 mice were selected to make 28d animal chronic unpredictable mild stress model (CUMS, Chronic Unpredictable Mild Stress), and the success of the model was evaluated by open field test (Open Field Test, OFT). The experiment was divided into control group (Control), model group (Model), solvent control group (Vehicle), fluoxetine control group, ZZL-7 control group and compound group. The test compound was administered at a dose of 25 mg / kg by single oral administration, and 2h later, tail suspension test (Tail suspension test, TST) was performed to evaluate the depression of mice. The prolonged immobility time of mice in TST indicates that the mice are in despair. After data collection and statistics, SPSS data statistical software was used for analysis, and Graph Pad software was used to draw images according to the SPSS analysis results.

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

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein, R1is R8-(CO)-; R2is hydrogen; R3is C1-C6 linear alkyl or C6 aryl; R4is hydrogen; X is -CO-; R5is hydrogen; R6is isopropyl; R7is a 5-6 membered monocyclic heteroaryl comprising 1 or 2 heteroatoms selected from N, O, S, said 5-6 membered monocyclic heteroaryl is optionally substituted with a substituent selected from C1-C3 linear alkyl and halogen; R8is C1-C6 linear alkyl, said C1-C6 linear alkyl is optionally substituted with 3 deuterium; 2. A compound of Formula (II) or a pharmaceutically acceptable salt thereof: wherein, The general formula (I) does not include R1is a 5-6 membered monocyclic heteroaryl; optionally, said 5-6 membered monocyclic heteroaryl is substituted with a substituent selected from halogen or C1-C3 alkyl; said 5-6 membered monocyclic heteroaryl comprises 1-2 heteroatoms selected from N, O and S; R2is C1-C6 alkyl or C6 aryl; R3is C1-C6 alkyl or C1-C6 deuterated alkyl; 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R3is methyl or deuterated methyl.

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1is a 5-6 membered monocyclic heteroaryl; optionally, said 5-6 membered monocyclic heteroaryl is substituted with a substituent selected from halogen or methyl; said 5-6 membered monocyclic heteroaryl comprises 1 or 2 heteroatoms selected from N or O. wherein C * the carbon atom is in the R or S configuration, C ** the carbon atom is in the R or S configuration; The formula (II) does not comprise 8. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C4 alkyl or C6 aryl.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein C * the carbon atom is in the S configuration.

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein C ** the carbon atom is in the R configuration.

10. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein, 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1is R1is a 5-6 membered monocyclic heteroaryl; optionally, said 5-6 membered monocyclic heteroaryl is substituted with a substituent selected from halogen or methyl; said 5-6 membered monocyclic heteroaryl comprises 1 or 2 heteroatoms selected from N or O; 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R2is methyl, R2is C1-C4 alkyl or C6 aryl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein, 12. A compound, or a pharmaceutically acceptable salt thereof, selected from:

13. A pharmaceutical composition comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. R1is R2is methyl, 14. A pharmaceutical preparation comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

15. Use of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 13, or a pharmaceutical preparation of claim 14, for the manufacture of a medicament for the treatment and / or prevention of depression.

16. Use of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 13, or a pharmaceutical preparation of claim 14, for the manufacture of a fast-acting medicament for the treatment and / or prevention of depression. ​ ​ 17. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 13, or a pharmaceutical preparation according to claim 14, for the manufacture of a medicament for the treatment and / or prevention of restlessness, 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, bipolar disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, and vasomotor symptoms or hot flushes.

Images