Indole-containing polycyclic compound, composition containing same and use thereof

Abstract

Disclosed in the present invention are an indole-containing polycyclic compound, a composition containing same and the use thereof. Provided in the present invention is a compound of formula (I), a deuterated compound thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof. The indole-containing polycyclic compound of the present invention has a new structure, and has a good agonistic activity on a Gq signaling pathway downstream of a 5-HT2A receptor.

Description

Indole-containing polycyclic compounds, compositions containing the same, and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024107375666, filed on June 7, 2024, Chinese Patent Application No. 2024109218513, filed on July 10, 2024, Chinese Patent Application No. 202411380129X, filed on September 30, 2024, Chinese Patent Application No. 2024118273670, filed on December 12, 2024, Chinese Patent Application No. 2025100759918, filed on January 17, 2025, and Chinese Patent Application No. 2025102308123, filed on February 28, 2025. This application incorporates the entirety of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to the field of medicine, in particular to indole-containing polycyclic compounds, compositions containing the same, and uses thereof. BACKGROUND

[0003] Depression is a common mental disorder that involves long-term low mood, diminished interest or anhedonia, and causes great burden to patients' physical and mental health. Depression is an important risk factor for suicide, and tens of thousands of people lose their lives every year. According to statistics, there are more than 300 million people worldwide with depression. In China, the lifetime prevalence of depression is 6.8%, nearly 95 million Chinese people have suffered from depression in their lifetime, and the disease burden is serious.

[0004] Drugs are the main means to treat depression. Currently, clinically recommended antidepressants include selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and specific serotonin reuptake inhibitors (NaSSAs), norepinephrine and dopamine reuptake inhibitors (NDRIs), etc. These drugs mainly inhibit the reuptake of monoamine neurotransmitters such as 5-hydroxytryptamine, norepinephrine and dopamine in the central nervous system, and increase the concentration of neurotransmitters between synapses to exert antidepressant effects. Although these drugs have improved tolerability and safety compared to traditional tricyclic antidepressants, they still have the following shortcomings: (1) drug side effects are common, and common adverse reactions include nausea, vomiting and sexual dysfunction, etc.; (2) the onset time of the drug is long, usually requiring continuous administration for 2-4 weeks; (3) the response rate of the drug is insufficient, about 1 / 3 of patients are insufficient for these drugs. Therefore, there is an urgent need for new mechanism-based antidepressants in clinical practice.

[0005] Psilocybin and other tryptamine psychedelics have been shown to rapidly and persistently alleviate depressive symptoms in multiple clinical studies. In 2019, Psilocybin was designated as a "breakthrough therapy" by FDA. Currently, Psilocybin is undergoing multi-center clinical trials to further verify its safety, effectiveness and therapeutic dose in treating depression. Patients will quickly experience hallucinations after taking Psilocybin and other tryptamine psychedelics, which will last for 4-6 hours, which limits the drug to be taken in hospitals and requires the supervision of psychologists. In addition, Psilocybin belongs to the first category of psychotropic drugs in China and is strictly controlled.

[0006] Several preclinical studies have shown that modifying the molecular structure of Psilocybin and other tryptamine psychedelics is expected to achieve the separation of rapid antidepressant effect and psychedelic effect, providing a new rapid antidepressant therapy. In the past three years, the molecules modified for tryptamine psychedelics mainly include TBG, AAZ-A-154, IHCH-7086, (R)-70 and 4-F,5-MeO-PyrT, which can exert rapid antidepressant effect in a depressive-like mouse model but avoid producing hallucinations, among which AAZ-A-154 has entered clinical phase I. On the mechanism of action, these compounds mainly act through 5-HT 2A receptor, but the relationship between the intensity of agonism and the hallucinogenic effect or antidepressant efficacy still needs to be explored. SUMMARY

[0007] The technical problem to be solved by the present application is to provide an indole-containing polycyclic compound, a composition containing the same and an application thereof. The indole-containing polycyclic compound of the present application has novel structure, has agonistic or partial agonistic activity on 5-HT 2A and is not hallucinogenic.

[0008] The present application solves the above technical problems by the following technical solutions.

[0009] The present application provides a compound of formula I-0, a deuterated compound thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof,

[0010] wherein: Cy is an 8-10 membered bicyclic heteroaryl, a 5-6 membered monocyclic heteroaryl, or a phenyl, the 8-10 membered bicyclic heteroaryl, the 5-6 membered monocyclic heteroaryl and the phenyl are optionally substituted with one or more R;

[0011] each R is independently selected from halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -SF5, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1-N(R 1.2 R 1.3 )-N(R 1.2 )C(O)R 1.1 -N(R 1.2 R 1.3 )-N(R 1.2 )C(O)OR 1.1 -OC(O)N(R 1.2 R 1.3 )-N(R 1.2 )C(O)N(R 1.2 R 1.3 )-S(O)2R 1.2 -S(O)2N(R 1.2 R 1.3 )alkylcycloalkyl, alkylheterocyclyl, cycloalkyl or heterocyclyl;

[0012] R 1.1 is selected from hydrogen, alkyl, haloalkyl, cycloalkyl or heterocyclyl;

[0013] R 1.2 and R 1.3 are each independently selected from hydrogen, alkyl, cycloalkyl or heterocyclyl;

[0014] R7, R8, R9, R 10 , R 12 and R 13 are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR 1.1 -SR 1.1 -C(O)R 1.1 -C(O)OR 1.1 -OC(O)R 1.1 -OC(O)OR 1.1 -N(R 1.2 R 1.3 )-N(R 1.2 )C(O)R 1.1 -C(O)N(R 1.2 R 1.3 )-N(R 1.2 )C(O)OR 1.1 -OC(O)N(R 1.2 R 1.3 )-N(R 1.2 )C(O)N(R 1.2 R 1.3 )-S(O)2R 1.2 -S(O)2N(R 1.2 R 1.3 alkylcycloalkyl, alkylheterocyclyl, cycloalkyl or heterocyclyl;

[0015] R 11 is selected from hydrogen, alkyl, cycloalkyl or heterocyclyl;

[0016] Ring B is selected from heterocyclyl or cycloalkyl, the heterocyclyl including mono-heterocyclyl, bridged-heterocyclyl or spiro-heterocyclyl, the cycloalkyl including mono-cycloalkyl, bridged-cycloalkyl or spiro-cycloalkyl;

[0017] R 14 each independently is selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl or heterocyclyl;

[0018] or, R1, R2and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, cycloalkenyl or heterocycloalkenyl group, or, R2, R3and the atoms to which they are attached together form a cycloalkenyl or heterocycloalkenyl group; or, R3, R4and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, cycloalkenyl or heterocycloalkenyl group; or, R4, R5and the atoms to which they are attached together form a cycloalkenyl or heterocycloalkenyl group; or, R5, R6and the atoms to which they are attached together form a heterocyclyl, cycloalkenyl or heterocycloalkenyl group; or, any two of R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 and the atoms to which they are attached together form a cycloalkyl, cycloalkenyl, heterocyclyl or heterocycloalkenyl group;

[0019] said cycloalkyl, heterocyclyl, cycloalkenyl and heterocycloalkenyl groups being optionally substituted by one or more R 1.4 ;

[0020] R 1.4 each independently selected from halogen, oxo, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR c1 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c2 R c3 ), -N(R c2 )C(O)R c1 , -C(O)N(R c2 R c3 ), -N(R c2 )C(O)OR c1 , -OC(O)N(R c2 R c3 ), -N(R c2 )C(O)N(R c2 R c3 ), -S(O)2R c2 , -S(O)2N(R c2 R c3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl;

[0021] R c1 is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocyclyl;

[0022] R c2 and R c3 are each independently selected from hydrogen, alkyl, cycloalkyl, or heterocyclyl;

[0023] x is 0, 1, 2, or 3;

[0024] y is 0 or 1;

[0025] n1and n2are each independently 0, 1, 2, or 3.

[0026] In one aspect of the application, Cy is selected from or phenyl.

[0027] In a preferred embodiment of the application, Cy is selected from

[0028] The present application provides a compound of Formula I, a deuterated form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[0029] wherein:

[0030] Ring A is heterocyclyl, heterocyclylalkenyl, or heteroaryl;

[0031] R1, R2, R3, R4, R5, and R6are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -SF5, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl;

[0032] R 1.1 is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocyclyl;

[0033] R 1.2 and R 1.3 are each independently selected from hydrogen, alkyl, cycloalkyl, or heterocyclyl;

[0034] R7, R8, R9, R 10 , R 12 , and R 13 are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl;

[0035] R 11 is selected from hydrogen, alkyl, cycloalkyl, or heterocyclyl;

[0036] Ring B is selected from heterocyclyl or cycloalkyl, with heterocyclyl including mono- heterocyclyl, bridged-heterocyclyl, or spiro-heterocyclyl, and cycloalkyl including mono- cycloalkyl, bridged-cycloalkyl, or spiro-cycloalkyl;

[0037] R 14 are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl;

[0038] or, R1, R2, and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl group, or, R2, R3, and the atoms to which they are attached together form a cycloalkenyl or heterocycloalkenyl group; or, R3, R4, and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl group; or, R4, R5, and the atoms to which they are attached together form a cycloalkenyl or heterocycloalkenyl group; or, R5, R6, and the atoms to which they are attached together form a heterocyclyl, cycloalkenyl, or heterocycloalkenyl group; or, R6, R7, R8, R9, R 10 , R 11 , R 12 , and R 13 any two of which, together with the atoms to which they are attached, form a cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl group;

[0039] said cycloalkyl, heterocyclyl, cycloalkenyl, and heterocycloalkenyl groups are optionally substituted with one or more R 1.4 ;

[0040] R 1.4 each independently is selected from the group consisting of halogen, oxo, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR c1 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c2 R c3 ), -N(R c2 )C(O)R c1 , -C(O)N(R c2 R c3 ), -N(R c2 )C(O)OR c1 , -OC(O)N(R c2 R c3 ), -N(R c2 )C(O)N(R c2 R c3 ), -S(O)2R c2 , -S(O)2N(R c2 R c3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl;

[0041] R c1 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocyclyl;

[0042] R c2 and R c3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, or heterocyclyl;

[0043] x is 0, 1, 2, or 3;

[0044] y is 0 or 1;

[0045] n1and n2are each independently 0, 1, 2, or 3.

[0046] In one embodiment, the present application is the compound of formula (I) as hereinbefore described is indolyl, indazolyl, or benzimidazolyl.

[0047] In one embodiment, the present application is the compound of formula (I) as hereinbefore described is

[0048] In one embodiment, the present application is the compound of formula (I) as hereinbefore described

[0049] In one embodiment, the present application is the compound of formula (I) as hereinbefore described R6and R7, R8, R9, R 10 , R 11 , R 12 , and R 13 , together with the atoms to which they are attached, form a C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocyclyl, or 3-6 membered heterocycloalkenyl; said C 3-6 cycloalkyl, C 3-6 heterocyclyl, 3-6 membered cycloalkenyl, and 3-6 membered heterocycloalkenyl is optionally substituted with one or more R 1.4 .

[0050] In one embodiment, the present application is the compound of formula (I) as hereinbefore described R1, R2, R3, R4, R5, and R6are each independently selected from hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 alkylamine, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -SF5, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3), -N(R 1.2 )C(O)OR 1.1 -OC(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 -S(O)2R 1.2 -S(O)2N(R) 1.2 R 1.3 C 1-6 Alkyl C 3-6 cycloalkyl, C 1-6 Alkyl 3-6 membered heterocyclic groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0051] Or, R7, R8, R9, R 10 R 12 and R 13 Each is independently selected from hydrogen, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkylamine, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups, -OR 1.1 -SR 1.1 -C(O)R 1.1 -C(O)OR 1.1 -OC(O)R 1.1 -OC(O)OR 1.1 -N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 -C(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 -OC(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 -S(O)2R 1.2 -S(O)2N(R) 1.2 R 1.3 C 1-6 Alkyl C 3-6 cycloalkyl, C 1-6 Alkyl 3-6 membered heterocyclic groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0052] Or, R11 selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0053] or, R 14 each independently selected from hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 alkylamine, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), C 1-6 alkyl C 3-6 cycloalkyl, C 1-6 alkyl 3-6 membered heterocyclyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0054] R 1.1 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0055] R 1.2 and R 1.3 each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0056] In one aspect, R1and R2together with the atom to which they are attached form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C3- 6 cycloalkenyl or 3-6 membered heterocycloalkenyl;

[0057] or, R2, R3 and the atoms to which they are attached together form a C 3-6 cycloalkenyl or 3-6 membered heterocycloalkenyl;

[0058] or, R3, R4 and the atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0059] or, R4, R5 and the atoms to which they are attached together form a C 4-6 cycloalkenyl or 4-6 membered heterocycloalkenyl;

[0060] or, R5, R6 and the atoms to which they are attached together form a C 3-6 cycloalkenyl or 3-6 membered heterocyclyl;

[0061] said cycloalkyl, heterocyclyl, cycloalkenyl and heterocycloalkenyl are optionally substituted with one or more R 1.4 substituents; R 1.4 each independently selected from the group consisting of halogen, oxo, cyano, nitro, C 1-6 alkyl, C 1-6 alkylamine, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl-OR c1 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c2 R c3 ), -N(R c2 )C(O)R c1 , -C(O)N(R c2 R c3 ), -N(R c2 )C(O)OR c1 , -OC(O)N(R c2 R c3 ), -N(R c2 )C(O)N(R c2 R c3 ), -S(O)2R c2 , -S(O)2N(R c2 R c3 ), C 1-6 alkyl C 3- 6 cycloalkyl, C 1-6 alkyl 3-6 membered heterocyclyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0062] R c1 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0063] R c2 and R c3 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0064] In one embodiment, R7, R8and the atom to which they are attached together form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3- 6cycloalkenyl or 3-6 membered heterocycloalkenyl;

[0065] or, R9, R 10 and the atom to which they are attached together form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 6cycloalkenyl or 3-6 membered heterocycloalkenyl;

[0066] or, R7, R 10 and the atom to which they are attached together form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 6cycloalkenyl or 3-6 membered heterocycloalkenyl;

[0067] or, R7, R 11 and the atom to which they are attached together form a 3-6 membered heterocyclyl or 3-6 membered heterocycloalkenyl;

[0068] or, R 10 , R 11 and the atom to which they are attached together form a 3-6 membered heterocyclyl or 3-6 membered heterocycloalkenyl;

[0069] or, R 11 , R 12 and the atom to which they are attached together form a 3-6 membered heterocyclyl or 3-6 membered heterocycloalkenyl;

[0070] or, R 12 , R 13 and the atom to which they are attached together form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 6cycloalkenyl or 3-6 membered heterocycloalkenyl;

[0071] said cycloalkyl, heterocyclyl, cycloalkenyl and heterocycloalkenyl groups are optionally substituted by one or more R 1.4 substituents; R 1.4each independently selected from the group consisting of halogen, oxo, cyano, nitro, C 1-6 alkyl, C 1-6 alkylamine, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl-OR c1 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c2 R c3 ), -N(R c2 )C(O)R c1 , -C(O)N(R c2 R c3 ), -N(R c2 )C(O)OR c1 , -OC(O)N(R c2 R c3 ), -N(R c2 )C(O)N(R c2 R c3 ), -S(O)2R c2 , -S(O)2N(R c2 R c3 ), C 1-6 alkyl C3-6cycloalkyl, C 1-6 alkyl 3-6 membered heterocyclyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0072] R c1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0073] R c2 and R c3 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0074] In one aspect, the C 3-6 membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0075] In one aspect, the 3-6 membered heterocyclyl group according to the present application described hereinbefore, the heteroatom is oxygen, nitrogen or sulfur, the number of heteroatoms is independently 1 or 2; preferably, the 3-6 membered heterocyclyl group is selected from the group consisting of oxiranyl, aziridinyl, oxetanyl, azetidinyl,

[0076] In one embodiment, the 3-6 membered heterocycloalkenyl group according to the application described hereinbefore is selected from 3-6 cycloalkenyl is selected from

[0077] In one embodiment, the 3-6 membered heterocycloalkenyl group according to the application described hereinbefore is selected from

[0078] In one embodiment, the 4-6 membered heterocycloalkenyl group according to the application described hereinbefore is selected from 4-6 cycloalkenyl is selected from

[0079] In one embodiment, the 4-6 membered heterocycloalkenyl group according to the application described hereinbefore is selected from

[0080] In one embodiment, the ring B according to the application described hereinbefore is

[0081] In one embodiment, the ring B according to the application described hereinbefore is

[0082] In one embodiment, the ring B according to the application described hereinbefore is

[0083] In one embodiment, the ring B according to the application described hereinbefore is

[0084] In one embodiment, the compound according to the application is represented by the general formula (II):

[0085] In one embodiment, R2according to the application described hereinbefore is selected from hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl;

[0086] R3is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl;

[0087] R4is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6Halogenated alkoxy groups, C 1-6 Halogenated alkyl groups;

[0088] R6 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups;

[0089] R7 is selected from hydrogen or C. 1-6 alkyl;

[0090] R9 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups;

[0091] R 11 Selected from hydrogen or C 1-6 alkyl;

[0092] R 14 Selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0093] x is 0 or 1.

[0094] In one aspect of the present invention, in general formula (II) of the present invention, R7, R 11 Together with the atoms attached thereto, they form a 5-6 membered heterocyclic group; preferably, R7, R 11 It forms together with the atoms it is attached to.

[0095] In one aspect of the present invention, in general formula (II), R6 and R9 together with their attached atoms form a 5-6 membered heterocyclic alkenyl group; preferably, R6 and R9 together with their attached atoms form

[0096] In one aspect of the present invention, in general formula (II), R9, R 11 Together with the atoms attached thereto, they form a 5-6 membered heterocyclic group; preferably, R9, R 11 It forms together with the atoms it is attached to.

[0097] In one embodiment, R1, R2, R3, R4, R5, and R6 described above are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, vinyl, propenyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -SF5, and -OR. 1.1 -SR1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, aziridinyl, or azetidinyl.

[0098] In one aspect, R7, R8, R9, R 10 , R 12 , and R 13 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, methylamine, ethylamine, vinyl, propenyl, acetylene, trifluoromethyl, difluoromethyl, trifluoroethyl, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3), cyclopropyl, cyclobutyl, cyclopentane, oxacyclopropyl, oxacyclobutyl, aziridine, aziridine or piperidinyl.

[0099] In one embodiment, the R described above in this invention... 11 It is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxecyclopropyl, oxecyclobutyl, azircyclopropyl, azircyclobutyl or piperidinyl.

[0100] In one embodiment, the R described above in this invention... 14 Each group is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, methylamine, ethylamine, vinyl, propenyl, ethynyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and -OR. 1.1 -SR 1.1 -C(O)R 1.1 -C(O)OR 1.1 -OC(O)R 1.1 -OC(O)OR 1.1 -N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 -C(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 -OC(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 -S(O)2R 1.2 -S(O)2N(R) 1.2 R 1.3 ), cyclopropyl, cyclobutyl, oxecyclopropyl, oxecyclobutyl, azircyclopropyl, azircyclobutyl or piperidinyl.

[0101] In one embodiment, the R described above in this invention... 1.1 It is selected from hydrogen, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, oxecyclopropyl, oxecyclobutyl, azircyclopropyl, azircyclobutyl or piperidinyl.

[0102] In one embodiment, the R described above in this invention... 1.2 and R 1.3 Each is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxecyclopropyl, oxecyclobutyl, azircyclopropyl, azircyclobutyl or piperidinyl.

[0103] In a certain embodiment, the R 1.4 each independently is selected from the group consisting of fluorine, chlorine, bromine, iodine, oxo, cyano, nitro, methyl, ethyl, propyl, methylamine, ethylamine, vinyl, propenyl, ethynyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -OR c1 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c2 R c3 ), -N(R c2 )C(O)R c1 , -C(O)N(R c2 R c3 ), -N(R c2 )C(O)OR c1 , -OC(O)N(R c2 R c3 ), -N(R c2 )C(O)N(R c2 R c3 ), -S(O)2R c2 , -S(O)2N(R c2 R c3 ), cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl or piperidinyl.

[0104] In a certain embodiment, the R c1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl or piperidinyl.

[0105] In a certain embodiment, the R c2 and R c3 each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl or piperidinyl.

[0106] In a certain preferred embodiment, the R2as described hereinbefore is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 1- 3haloalkoxy, C 1-3 haloalkyl;

[0107] said R3is selected from the group consisting of hydrogen, halogen, cyano, C 1-3 alkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Halogenated alkyl groups;

[0108] R4 is selected from hydrogen, halogen, cyano, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Halogenated alkyl groups;

[0109] R7 is selected from hydrogen or C. 1-3 alkyl;

[0110] R 11 Selected from hydrogen or C 1-3 alkyl;

[0111] R 14 Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0112] x is 0 or 1.

[0113] In a preferred embodiment, R2 mentioned above in this invention is selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

[0114] In a preferred embodiment, R3 mentioned above in this invention is selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

[0115] In a preferred embodiment, R7 as described above in this invention is hydrogen.

[0116] In a preferred embodiment, the R described above in this invention 11 It is hydrogen.

[0117] In a preferred embodiment, the R described above in this invention 14 It can be halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or trifluoromethoxy.

[0118] In a preferred embodiment, R6 mentioned above in this invention is hydrogen.

[0119] In a preferred embodiment, R9 as described above in this invention is hydrogen.

[0120] In a preferred embodiment, the R described above in this invention 11 Selected from hydrogen, methyl, or ethyl.

[0121] In a preferred embodiment, R7 and R8 described above are each hydrogen.

[0122] In a preferred embodiment, R9 and R described above in this invention 10 Each of them is hydrogen.

[0123] In a preferred embodiment, the R described above in this invention 12 and R 13 Each of them is hydrogen.

[0124] In a preferred embodiment, R6 as described above in this invention is hydrogen or C. 1-3 Alkyl; preferably hydrogen or methyl.

[0125] In a preferred embodiment, the R described above in this invention s For hydrogen, C 1-3 Alkyl or -OC 3-6 Cycloalkyl; preferably hydrogen, methyl or

[0126] In a preferred embodiment, R5 as described above in this invention is hydrogen.

[0127] In a preferred embodiment, R4 described above is hydrogen or halogen; preferably hydrogen, fluorine, chlorine, bromine or iodine; preferably hydrogen or iodine.

[0128] In a preferred embodiment, R4 as described above in this invention is hydrogen.

[0129] In a preferred embodiment, R3 mentioned above in this invention is hydrogen or halogen; preferably hydrogen, chlorine or bromine.

[0130] In a preferred embodiment, R3 mentioned above in this invention is hydrogen.

[0131] In a preferred embodiment, R1 described above is hydrogen, hydroxyl, or halogen; preferably hydrogen, fluorine, chlorine, or hydroxyl.

[0132] In a preferred embodiment, R1 mentioned above in this invention is hydrogen.

[0133] In a preferred embodiment, R1 as described above in this invention is hydrogen, hydroxyl, halogen, or C. 1-3 Alkyl or C 1-3 Alkoxy; preferably hydrogen, hydroxyl, fluorine, chlorine, methyl, ethyl, methoxy, or ethoxy.

[0134] In a preferred embodiment, R2 described above in this invention is a cyano group, a hydroxyl group, a halogen, or a C group. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy group; preferably cyano, hydroxyl, fluorine, chlorine, methyl, methoxy or -OCF3; more preferably cyano, methyl, fluorine, chlorine or methoxy group.

[0135] In a preferred embodiment, R2in the above-mentioned compounds of the present application is -SF5, -S(O)2CH3.

[0136] In a preferred embodiment, R3in the above-mentioned compounds of the present application is hydrogen or C 1-3 alkyl; preferably hydrogen or methyl; more preferably methyl.

[0137] In a preferred embodiment, R3in the above-mentioned compounds of the present application is hydrogen, C 1-3 alkyl or C 1-3 alkoxy; preferably hydrogen, methyl, ethyl, methoxy or ethoxy.

[0138] In a preferred embodiment, the compound of the present application is any one of the compounds in Table 1:

[0139] Table 1

[0140] The present application also provides a pharmaceutical composition containing a compound of Formula I, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0141] The present application provides a compound of Formula I, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use in the preparation of a 5-HT 2A receptor agonist.

[0142] The present application also provides a compound of Formula I, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use in the preparation of a medicament for treating or preventing a disease associated with 5-HT 2A receptors.

[0143] The present application also provides a compound of Formula I, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use in the preparation of a medicament for treating, preventing or alleviating a depressive disorder.

[0144] Terminology

[0145] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0146] The term "oxo" refers to =O, an oxygen atom replacing two hydrogens on the same carbon atom, i.e., a carbonyl group replacing a methylene group.

[0147] The term "alkyl" refers to saturated aliphatic hydrocarbon groups; for example, alkyl groups containing 1 to 8 carbon atoms; preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like, as well as various branched isomers thereof, and the like.

[0148] The term "alkenyl" refers to straight-chained or branched unsaturated aliphatic hydrocarbon groups consisting of carbon and hydrogen atoms having at least one double bond. Alkenes can contain 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms of alkenyl, more preferably 2 to 6 carbon atoms of alkenyl, most more preferably 2 to 3 carbon atoms of alkenyl. Non-limiting examples include: ethenyl 1-propenyl 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butenyl, and the like.

[0149] The term "alkynyl" refers to straight-chained or branched unsaturated aliphatic hydrocarbon groups consisting of carbon and hydrogen atoms having at least one triple bond. Alkynes can contain 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms. Non-limiting examples include: ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl, and the like.

[0150] The term "cycloalkyl" refers to saturated monocyclic or polycyclic cyclic hydrocarbon substituents; cycloalkyl rings contain 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, further preferably 3 to 6 carbon atoms, most preferably 3 to 4 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Polycyclic alkyl groups include spirocycloalkyl, bridged cycloalkyl, fused cycloalkyl.

[0151] The term "cycloalkenyl" refers to partially unsaturated cyclic hydrocarbon groups; for example, cycloalkenyl rings contain 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.

[0152] The term "heterocyclyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-8 membered, 5-6 membered, 7-12 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified species of heteroatoms (1, 2, or 3 of N, O, and S). For example, a heterocyclyl group contains 3 to 8 ring atoms; most preferably, 3 to 6 ring atoms. "Member" in the present invention refers to the number of ring atoms, e.g., 3-6 membered heterocyclyl means a ring containing 3-6 ring atoms. Heterocyclyl groups include monocyclic heterocyclyl groups, polycyclic heterocyclyl groups. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, preferably oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1- imino-1-oxothiopyran, azepanyl. Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl. A spiroheterocyclyl group refers to a polycyclic heterocyclic group in which a single ring shares one atom (referred to as a spiro atom) with each of the other rings in the system, non-limiting examples include

[0153] The term "heteroaryloxy" refers to a group -O-(heteroaryl), wherein heteroaryl is as defined above. Non-limiting examples of heteroaryloxy groups include: pyridyloxy, pyrimidinyloxy, thienyloxy, furanyloxy, imidazolyl-oxy, oxazolyl-oxy, thiazolyl-oxy, pyrazolyl-oxy, triazolyl-oxy, tetrazolyl-oxy, pyridazinyl-oxy, pyrazinyl-oxy, and pyrimidinyl-oxy.

[0154] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 to 8 membered, most preferably 5 or 6 membered, e.g., imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazolyl, pyridazinyl, or pyrazinyl, etc.; preferably triazolyl, thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, pyridazinyl, pyrazinyl, or pyrimidyl, etc.

[0155] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propyloxy, butyloxy, cyclopropyloxy. ​​​​

[0156] "Haloalkyl" means an alkyl group, as defined above, substituted with one or more halogens. Non-limiting examples include trifluoromethyl, difluoromethyl.

[0157] "Haloalkoxy" means an alkoxy group, as defined above, substituted with one or more halogens.

[0158] "Heteroalkyl" means an alkyl group, as defined above, in which one or more carbon atoms are replaced by heteroatoms. Non-limiting examples include -CH2-O-CH3, -CH2-CH2-O-CH3.

[0159] "X is A, B, or C," "X is A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like are used interchangeably and have the same meaning, i.e., X can be any one of A, B, or C, or any combination thereof.

[0160] The following abbreviations have the following meanings in the present invention: "substituted with" means the position at which the substituent is attached to the point of substitution.

[0161] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "an optionally alkyl substituted heterocycle" means that an alkyl group can or can not be present, and that the description includes instances where the heterocycle is substituted with an alkyl group and instances where the heterocycle is not substituted with an alkyl group.

[0162] "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more, preferably 1, 2, 3, or 4.

[0163] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are each, independently of one another, replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible (experimentally or theoretically) as determined by one of skill in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0164] The term "substituted with" or "substituted" means that any one or more hydrogen atoms on the specified atom are replaced with a substituent, provided that the valency of the specified atom is not exceeded, and that the substituted compound is stable.

[0165] When any variable (e.g., R 1.4) in the definition of a compound, the definition of the variable at each occurrence is independent of the definition at other occurrences, and the meanings are independent of and unaffected by the meanings of the other occurrences. Thus, if a group is substituted with 1, 2, or 3 R1-a groups, that is, the group can be substituted with up to 3 R1-a groups, the definition of R1-a at one occurrence is independent of and unaffected by the definition of R1-a at another occurrence. In other words, the R1-a group at one occurrence can have a definition that is different from the definition of the R1-a group at another occurrence. 1.4 ) in the definition of a compound, the definition of the variable at each occurrence is independent of the definition at other occurrences, and the meanings are independent of and unaffected by the meanings of the other occurrences. Thus, if a group is substituted with 1, 2, or 3 R1-a groups, that is, the group can be substituted with up to 3 R1-a groups, the definition of R1-a at one occurrence is independent of and unaffected by the definition of R1-a at another occurrence. In other words, the R1-a group at one occurrence can have a definition that is different from the definition of the R1-a group at another occurrence. 1.4 ) in the definition of a compound, the definition of the variable at each occurrence is independent of the definition at other occurrences, and the meanings are independent of and unaffected by the meanings of the other occurrences. Thus, if a group is substituted with 1, 2, or 3 R1-a groups, that is, the group can be substituted with up to 3 R1-a groups, the definition of R1-a at one occurrence is independent of and unaffected by the definition of R1-a at another occurrence. In other words, the R1-a group at one occurrence can have a definition that is different from the definition of the R1-a group at another occurrence. 1.4 ) in the definition of a compound, the definition of the variable at each occurrence is independent of the definition at other occurrences, and the meanings are independent of and unaffected by the meanings of the other occurrences. Thus, if a group is substituted with 1, 2, or 3 R1-a groups, that is, the group can be substituted with up to 3 R1-a groups, the definition of R1-a at one occurrence is independent of and unaffected by the definition of R1-a at another occurrence. In other words, the R1-a group at one occurrence can have a definition that is different from the definition of the R1-a group at another occurrence.

[0166] “Pharmaceutical composition” means a mixture of one or more compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The goal of a pharmaceutical composition is to facilitate administration to an organism and to facilitate absorption of the active ingredient(s) to elicit the biological activity.

[0167] “Pharmaceutically acceptable” or “pharmacologically acceptable” means relatively non-toxic, safe, and suitable for use with patients.

[0168] “Pharmaceutically acceptable salt” means a salt of a compound that is produced by reaction of the compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for specific examples.

[0169] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail.

[0170] For chiral carbons in the compounds of the present application, unless otherwise specified, the R configuration, the S configuration, or a racemic mixture is intended.

[0171] The above-mentioned preferred conditions can be combined arbitrarily without violating the common knowledge in the art, and each preferred example of the present application is obtained.

[0172] The reagents and materials used in the present application are commercially available or prepared according to the prior art.

[0173] The compounds of the present application for the preparation of compound in Water-Soluble Non-Classical Benzene Mimetics; Angew. Chem. Int. Ed. 2020, 59, 7161. (DOT: 10.1002 / anie.202000548). BRIEF DESCRIPTION OF DRAWINGS

[0174] Figure 1 is a graph of the antidepressant efficacy test results of compound 1 of the present application, with the detection index being the sugar water preference rate of mice.

[0175] Figure 2 is a graph of the antidepressant efficacy test results of compounds 4, 27, 28, 63, 67, 99, 101, and 109 of the present application, with the detection index being the sugar water preference rate of mice. DETAILED DESCRIPTION

[0176] The present application is further illustrated by the following examples without thereby limiting the present application to the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the commercial product.

[0177] Preparation of compound 1 of Example 1

[0178] Step one: under 0 degrees and nitrogen protection, lithium aluminum hydride solution 1.0 M (8 mL, 8 mmol, 2.0 eq.) was slowly added dropwise to a THF solution (5 mL) of 3-methylcyclobutene carboxylic acid ethyl ester (500 mg, 4.0 mmol, 1.0 eq.), and the reaction was carried out at 0 °C for 2 h. After the reaction was completed, sodium sulfate decahydrate (740 mg, 2 mmol, 0.5 eq.) was slowly added to the above system at 0 °C to quench the reaction, and then filtered. The filter residue was washed with THF, and the filtrate was combined. The filtrate was concentrated under reduced pressure at low temperature to obtain compound 1-2 (357 mg, 91%).

[0179] Step two: To a solution of compound 1-2 (357 mg, 3.64 mmol, 1.0 eq.) in water / methyl tert-butyl ether (1 mL / 2 mL) was added iodine (1.85 g, 7.28 mmol, 2.0 eq.) and sodium bicarbonate (612 mg, 7.28 mmol, 2.0 eq.) under nitrogen protection. The reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous sodium thiosulfate solution (10 mL). After dilution with water, the mixture was extracted with ethyl acetate twice. The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 1) to give compound 1-3 (652 mg, 80%). LCMS (ESI, m / z): 224.73 [M+H] + .

[0180] Step three: To a solution of 5-methoxytryptamine hydrochloride (367 mg, 1.9 mmol, 1.0 eq.) in DMF (5 mL) was added sodium bicarbonate (325 mg, 3.9 mmol, 2.0 eq.) and compound 1-3 (652 mg, 2.9 mmol, 1.5 eq.) successively at room temperature. After nitrogen replacement, the reaction was stirred at 60 °C for 4 h. After the reaction was completed and cooled to room temperature, the mixture was diluted with water. The mixture was extracted with ethyl acetate twice. The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 1 (375 mg, 69%). LCMS (ESI, m / z): 286.87 [M+H] + .

[0181] 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.59 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 2H), 3.41 (s, 2H), 3.34 (s, 2H), 3.24-3.15 (m, 2H), 1.94-1.83 (m, 2H), 1.49 (dd, J = 4.6, 1.8 Hz, 2H).

[0182] Preparation of Example 2 intermediate INT-AA

[0183] Step one: To a solution of INT-AA-1 (4.4 g, 29.7 mmol, 1.0 eq.) in acetic acid (100 mL) was added N-bromosuccinimide (5.8, 32.6 mmol, 1.1 eq.) under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound INT-AA-2 (5.7 g, 85%). LCMS (ESI, m / z): 229.0 [M+3] + .

[0184] Step two: To a solution of compound INT-AA-2 (5.7 g, 25.1 mmol, 1.0 eq.) and pyridine (6.0 g, 85.3 mmol, 3.0 eq.) in dichloromethane (80 mL) was added ethyl chloroformate (3.3 g, 20.1 mmol, 1.2 eq.) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane twice. The combined organic layers were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AA-3 (5.0 g, 67%).

[0185] Step three: To a solution of compound INT-AA-3 (1.8 g, 6.0 mmol, 1.0 eq.), bis(triphenylphosphine)palladium dichloride (423 mg, 0.6 mmol, 0.1 eq.), cuprous iodide (115 mg, 0.6 mmol, 0.1 eq.) and triethylamine (1.8 g, 18.1 mmol, 3.0 eq.) in tetrahydrofuran (15 mL) was added trimethylsilylethynyl (1.8 g, 6.0 mmol, 1.0 eq.) under nitrogen atmosphere. The reaction was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was filtered and diluted with water. The organic layer was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-AA-4 (1.7 g, 32%). LCMS (ESI, m / z): 317.1 [M+H] + .

[0186] Step four: To a solution of compound INT-AA-4 (860 mg, 2.7 mmol, 1.0 eq.) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (5.4 mL, 1 M in THF, 5.4 mmol, 2.0 eq.) under nitrogen protection, the reaction was warmed to 65 degree for 1 h. After completion of the reaction, diluted with water, extracted with ethyl acetate twice, combined the organic phase, dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AA-5 (440 mg, 94%). LCMS (ESI, m / z): 173.1 [M+H] + .

[0187] Step five: To a solution of compound INT-AA-5 (560 mg, 3.3 mmol, 1.0 eq.) and pyridine (566 mg, 3.6 mmol, 1.1 eq.) in chloroform (30 mL) was added N-bromosuccinimide (637.8 mg, 7.2 mmol, 2.2 eq.) under nitrogen protection, the reaction was warmed to 50 degree for 3 h. After completion of the reaction, diluted with water, extracted with dichloromethane twice, combined the organic phase, dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AA-6 (529 mg, 64%). LCMS (ESI, m / z): 251.0 [M+1] + .

[0188] Step six: To a solution of compound INT-AA-6 (629 mg, 2.5 mmol, 1.0 eq.) in N,N- dimethylformamide (10 mL) was added sodium hydride (200 mg, 5.0 mmol, 2.0 eq.) at 0 degree under nitrogen protection, the reaction was reacted for 0.5 h. Then 2- (trimethylsilyl)ethoxymethyl chloride (626 mg, 3.8 mmol, 1.5 eq.) was added to the reaction system, the reaction was reacted for 2 h at 0 degree. After completion of the reaction, quenched with ice water, extracted with ethyl acetate twice, the organic phase was washed with water three times, the organic phase was dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-AA-7 (900 mg, 94%). LCMS (ESI, m / z): 381.0 [M+I] + .

[0189] Step 7: Under nitrogen protection, cesium carbonate (2.5 g, 7.6 mmol, 3.0 eq.) was added to a toluene solution (2 mL) of compound INT-AA-7 (970 mg, 2.5 mmol, 1.0 eq.), potassium trifluoroborate (1.3 g, 5.1 mmol, 2.0 eq.), palladium acetate (57.6 mg, 0.25 mmol, 0.1 eq.), and 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (237.6 g, 0.51 mmol, 0.2 eq.) and water (2 mL). The reaction solution was heated to 95°C and reacted under nitrogen protection for 3 h. After the reaction was complete, the mixture was filtered, diluted with water, extracted twice with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-AA-8 (446 mg, 39%). LCMS (ESI, m / z): 446.1 [M+H] + .

[0190] Step 8: Under nitrogen protection, tetrabutylammonium fluoride (3.9 mL, 1 M in THF, 3.9 mmol, 5.0 eq.) was added to a tetrahydrofuran solution (20 mL) of compound INT-AA-8 (346 mg, 0.8 mmol, 1.0 eq.). The reaction solution was heated to 60°C and reacted for 24 h. After the reaction was complete, the solution was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-AA-9 (163 mg, 66%). LCMS (ESI, m / z): 316.1 [M+H] + .

[0191] Step 9: Under nitrogen protection, add 5 mL of ethyl acetate solution of hydrochloric acid (4 M) to 5 mL of an ethyl acetate solution of compound INT-AA-9 (190 mg, 0.6 mmol, 1.0 eq.). Incubate the reaction mixture at room temperature for 48 h. After the reaction is complete, filter to obtain the hydrochloride salt of compound INT-AA (123 mg, 81%). LCMS (ESI, m / z): 216.1 [M+H] + .

[0192] Example 3: Preparation of intermediate INT-AB

[0193] Step one: Dissolve 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (4 g, 17.09 mmol, 1.0 eq.) in methanol (30 mL), slowly add sodium methoxide solution (3.54 g, 19.66 mmol, 1.15 eq. 30% in MeOH) under ice bath, stir at 40 °C for 3 hours. After the reaction is completed, remove part of the methanol by concentration, dilute with water, extract with ethyl acetate twice, combine the organic phase, dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, the obtained residue is purified by normal silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound INT-AB-1 (4 g, 95%).

[0194] Step two: Add compound INT-AB-1 (4.9 g, 19.91 mmol, 1.0 eq.), zinc cyanide (2.46 g, 20.91 mmol, 1.05 eq.), DMF (20 mL) and tetrakis(triphenylphosphine)palladium (1.38 g, 1.195 mmol, 0.06 eq.) into a reaction bottle successively, replace with nitrogen for three times, stir at 85 °C for 16 hours. After the reaction is completed and cooled to room temperature, dilute with water, extract with ethyl acetate three times, combine the organic phase, dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, the obtained residue is purified by normal silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound INT-AB-2 (3.5 g, 91%). LCMS (ESI, m / z): 193.1 [M+H] + .

[0195] Step three: Dissolve compound INT-AB-2 (3.3 g, 17.17 mmol, 1.0 eq.) in DMF (50 mL), add N,N-dimethylformamide dimethyl acetal (10.23 g, 86 mmol, 5.0 eq.), replace with nitrogen for three times, stir at 113 °C for 4 hours. After the reaction is completed and cooled to room temperature, dilute with water, extract with ethyl acetate three times, combine the organic phase, dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, the obtained crude compound INT-AB-3 (4 g, 94%) is used directly in the next step without purification. LCMS (ESI, m / z): 248.2 [M+H] + .

[0196] Step four: Into a reaction flask was added compound INT-AB-3 (4 g, 16.18 mmol, 1.0 eq.), ethanol (50 mL), acetic acid (50 mL) and reduced iron powder (3.6 g, 64.7 mmol, 4.0 eq.) successively, replaced with nitrogen for three times, stirred at 80 °C for 3 hours. After the reaction was completed and cooled to room temperature, filtered, the filtrate was concentrated to remove ethanol, diluted with water, extracted with ethyl acetate for three times, combined the organic phase, dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography on normal silica gel (petroleum ether / ethyl acetate = 2 / 1) to give compound INT-AB-4 (1.2 g, 43%). LCMS (ESI, m / z): 173.3 [M+H] + .

[0197] Step five: Into anhydrous DMF (10 mL) was added phosphorus oxychloride (1.78 g, 11.62 mmol, 2.0 eq.) dropwisely under nitrogen protection with ice bath, stirred for 20 minutes, added compound INT-AB-4 (1.0 g, 5.81 mmol, 1.0 eq.) in DMF (8 mL) solution, continued to stir at room temperature for 2 hours. After the reaction was completed, quenched with saturated sodium bicarbonate solution, stirred overnight, settled, suction filtered, washed with water, oven dried to give compound INT-AB-5 (1 g, 86%). LCMS (ESI, m / z): 201.1 [M+H] + .

[0198] Step six: Into a reaction flask was added compound INT-AB-5 (1.0 g, 5 mmol, 1.0 eq.), ammonium acetate (1.16 g, 14.99 mmol, 3 eq.) and nitromethane (20 mL) successively, replaced with nitrogen for three times, stirred at 80 °C for 6 hours. After the reaction was completed and cooled to room temperature, concentrated to remove nitromethane, slurried with water and methanol (1 / 1), suction filtered, washed with water, oven dried to give compound INT-AB-6 (610 mg, 50%). LCMS (ESI, m / z): 244.3 [M+H] + .

[0199] Step seven: Compound INT-AB-6 (510 mg, 2.09 mmol, 1.0 eq.) was dissolved in methanol (6 mL) and DMF (6 mL), sodium borohydride (111 mg, 2.94 mmol, 1.4 eq.) was added in portions, stirred at room temperature for 2 hours. After the reaction was completed, 2M hydrochloric acid was added to adjust pH to 7, diluted with water, extracted with ethyl acetate three times, combined organic phase, dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, the obtained residue was purified by normal silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 5) to obtain compound INT-AB-7 (210 mg, 41%). LCMS (ESI, m / z): 246.2 [M+H] + .

[0200] Step eight: Compound INT-AB-7 (210 mg, 0.856 mmol, 1.0 eq) was dissolved in methanol (10 mL), Pd / C catalyst (21 mg, 10%) was added, replaced with hydrogen three times, stirred at room temperature for 16 hours. After the reaction was completed, filtration, the filtrate was concentrated under reduced pressure, the obtained crude compound INT-AB (180 mg, 98%) was directly used in the next step without purification. LCMS (ESI, m / z): 216.2 [M+H] + .

[0201] Preparation of Example 4 intermediate INT-AC

[0202] Step one: 5-bromo-6-fluoro-1H-indole (900 mg, 4.2 mmol, 1.0 eq.), zinc cyanide (987 mg, 8.41 mmol, 2.0 eq.), zinc powder (825 mg, 12.61 mmol, 3.0 eq), DMF (8 mL), Pd2(dba)3(770 mg, 0.841 mmol, 0.2 eq.) and Pd(dppf)Cl2(615 mg, 0.841 mmol, 0.2 eq.) were added into the reaction bottle in turn, replaced with nitrogen three times, stirred at 155°C for 3 hours. After the reaction was completed and cooled to room temperature, diluted with water, extracted with ethyl acetate three times, combined organic phase, dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, the obtained residue was purified by normal silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound INT-AC-1 (310 mg, 46%). LCMS (ESI, m / z): 161.4 [M+H] + .

[0203] Step two: To anhydrous DMF (5 mL) was added phosphorous oxychloride (613 mg, 4 mmol, 2.0 eq.) dropwise slowly under ice bath with nitrogen protection, stirred for 20 minutes, then added compound INT-AC-1 (320 mg, 1.99 mmol, 1.0 eq.) in DMF (3 mL) and continued to stir at room temperature for 2 hours. After the reaction was completed, quenched with saturated sodium bicarbonate solution, stirred overnight, settled, suction filtered, washed with water, oven dried to give compound INT-AC-2 (310 mg, 82%). LCMS (ESI, m / z): 189.2 [M+H] + .

[0204] Step three: To the reaction flask was added compound INT-AC-2 (310 mg, 1.65 mmol, 1.0 eq.), ammonium acetate (381 mg, 4.94 mmol, 3 eq.) and nitromethane (8 mL) in sequence, replaced with nitrogen for three times, stirred at 80 °C for 6 hours. After the reaction was completed and cooled to room temperature, concentrated to remove nitromethane, slurried with water and methanol (1 / 1), suction filtered, washed with water, oven dried to give compound INT-AC-3 (150 mg, 39%). LCMS (ESI, m / z): 232.0 [M+H] + .

[0205] Step four: Compound INT-AC-3 (150 mg, 0.65 mmol, 1.0 eq.) was dissolved in methanol (2 mL) and DMF (2 mL), added sodium borohydride (74 mg, 1.95 mmol, 3 eq.) in portions, stirred at room temperature for 2 hours. After the reaction was completed, adjusted pH to 7 with 2M hydrochloric acid, diluted with water, extracted with ethyl acetate for three times, combined the organic phase, dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by normal phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 5) to give compound INT-AC-4 (120 mg, 79%). LCMS (ESI, m / z): 234.2 [M+H] + .

[0206] Step five: Zinc powder (336 mg, 5.15 mmol, 10.0 eq.) was dissolved in 2M hydrochloric acid (6 mL), added compound INT-AC-4 (120 mg, 0.52 mmol, 1.0 eq.) in methanol (6 mL), stirred at 68 °C for 4 hours. After the reaction was completed, concentrated to remove methanol, adjusted pH to 12 with 2M sodium hydroxide, extracted with dichloromethane for three times, combined the organic phase, dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the obtained crude compound INT-AC (100 mg, 96%) was used directly in the next step without purification. LCMS (ESI, m / z): 204.1 [M+H] + .

[0207] Preparation of intermediate INT-AD in Example 5

[0208] Step one: 1-Dimethylamino-2-nitroethene (678 mg, 5.84 mmol, 1.1 eq.) was dissolved in dichloromethane (15 mL), replaced by nitrogen, and trifluoroacetic acid (5.2 g, 53.1 mmol, 10.0 eq.) was added under ice bath, stirred for 20 min, and a solution of 6-chloro-5-fluoro-1H-indole (900 mg, 5.31 mmol, 1.0 eq.) in dichloromethane (4 mL) was added, and the stirring was continued at room temperature for 2 h. After the reaction was completed, sodium bicarbonate was added for neutralization, and the mixture was extracted with dichloromethane for three times, and the combined organic phase was dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on normal silica gel (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-AD-1 (500 mg, 39%). LCMS (ESI, m / z): 241.1 [M+H] + .

[0209] Step two: Compound INT-AD-1 (430 mg, 1.79 mmol, 1.0 eq.) was dissolved in methanol (10 mL), and sodium borohydride (203 mg, 5.36 mmol, 3 eq.) was added in portions, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, 2M hydrochloric acid was added to adjust the pH to 7, and water was added for dilution, and the mixture was extracted with ethyl acetate for three times, and the combined organic phase was dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on normal silica gel (petroleum ether / ethyl acetate = 1 / 5) to obtain compound INT-AD-2 (200 mg, 46%). LCMS (ESI, m / z): 243.3 [M+H] + .

[0210] Step three: Zinc powder (539 mg, 8.24 mmol, 10.0 eq.) was dissolved in 2M hydrochloric acid (10 mL), and a solution of compound INT-AD-2 (200 mg, 0.824 mmol, 1.0 eq.) in methanol (10 mL) was added, and the mixture was stirred at 68°C for 4 h. After the reaction was completed, the methanol was removed by concentration, 2M sodium hydroxide was added to adjust the pH to 12, and the mixture was extracted with dichloromethane for three times, and the combined organic phase was dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained crude compound INT-AD (160 mg, 91%) was used directly in the next step without purification. LCMS (ESI, m / z): 213.2 [M+H] + .

[0211] Preparation of compound 103 in Example 6

[0212] Step one: To a solution of compound 96 (150 mg, 0.45 mmol, 1.0 eq.) in dimethyl sulfoxide (6 mL) was added sodium methanesulfinate (108 mg, 1.04 mmol, 2.3 eq.), cuprous iodide (15 mg, 0.067 mmol, 0.15 eq.), L-proline (15.55 mg, 0.14 mmol, 0.3 eq.) and sodium hydroxide (5.4 mg, 0.14 mmol, 0.3 eq.) under nitrogen protection. The reaction was heated to 150 °C for 18 h. After completion of the reaction, it was filtered, and the filtrate was purified by preparative high performance liquid chromatography (column specification: XBridge C18, 19 mm*250 mm; mobile phase A: water (0.1% formic acid / water), mobile phase B: acetonitrile; flow rate: 20 mL per minute; elution gradient: 5-15%; time: 16 minutes; detection wavelength: UV 254 nm / 214 nm; retention time (minutes): 8.1-8.6) to give compound 103 (50.54 mg, 33.63%). LCMS (ESI, m / z): 335.2 [M+H] + .

[0213] 1 H NMR (400 MHz, DMSO-d6) d 11.46 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.58 (dt, J = 17.3, 5.1 Hz, 2H), 7.41 (d, J = 1.9 Hz, 1H), 3.64 (s, 2H), 3.16 (s, 3H), 2.97 (d, J = 15.5 Hz, 6H), 2.86 (t, J = 3.0 Hz, 1H), 1.74 (s, 2H), 1.40-1.30 (m, 2H).

[0214] Preparation of Example 7 intermediate INT-AF

[0215] Step one: To a solution of INT-AF-1 (500 mg, 1.6 mmol, 1.0 eq.) in N,N- dimethylformamide (10 mL) was added cuprous iodide (609.4 mg, 3.2 mmol, 2.0 eq.) and the reaction was heated to 100 °C for 2 h. After completion of the reaction, it was filtered, diluted with water and extracted with ethyl acetate once. The organic phase was washed with water three times and dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound INT-AF-2 (140 mg, 36%). LCMS (ESI, m / z): 244.0 [M+H] + .

[0216] Step two: To a solution of compound INT-AF-2 (110 mg, 0.45 mmol, 1.0 eq.) in N,N- dimethylformamide (3 mL) was added phosphorus oxychloride (76.3 mg, 0.50 mmol, 1.1 eq.) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 18 h. The reaction was monitored by LCMS until the starting material was consumed. The reaction was diluted with water (3 mL) and stirred at 60 °C for 18 h. After completion of the reaction, the reaction was diluted with water and extracted with ethyl acetate (1X). The organic layer was washed with water (3X), dried over anhydrous sodium sulfate. The reaction was filtered and the filtrate was concentrated under reduced pressure to yield compound INT-AF-3 (70 mg, 57%). LCMS (ESI, m / z): 271.8 [M+H] + .

[0217] Step three: To a solution of compound INT-AF-3 (70 mg, 0.26 mmol, 1.0 eq.) in nitromethane (5 mL) was added ammonium acetate (423 mg, 0.6 mmol, 0.1 eq.) at 100 °C under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was diluted with water and extracted with ethyl acetate (2X). The organic layer was combined, dried over anhydrous sodium sulfate. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to yield compound INT-AF-4 (54 mg, 67%).

[0218] LCMS (ESI, m / z): 315.0 [M+H] + .

[0219] Step four: To a solution of compound INT-AF-4 (54 mg, 0.17 mmol, 1.0 eq.) in tetrahydrofuran (2 mL) was added lithium aluminum hydride (26.09 mg, 0.69 mmol, 2.0 eq.) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 18 h. After completion of the reaction, the reaction was cooled to 0 °C and quenched with sodium sulfate decahydrate. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to yield compound INT-AF (30 mg, 61%). LCMS (ESI, m / z): 287.0 [M+H] + .

[0220] Preparation of Example 8 intermediate INT-AG

[0221] Step one: To a solution of INT-AG-1 (500 mg, 2.45 mmol, 1.0 eq.) in tetrahydrofuran (24 mL) was added aluminum trichloride (1.63 g, 12.24 mmol, 5.0 eq.) and lithium aluminum hydride (465 mg, 12.24 mmol, 5.0 eq.) successively at 0 °C under nitrogen protection. The reaction was heated to 70 °C for 18 h under nitrogen protection. After the reaction was completed, the reaction was quenched by the addition of sodium sulfate decahydrate (1.0 g) at 0 °C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound INT-AG (210 mg, 45.30%) as a yellow solid. LCMS (ESI, m / z): 191.1 [M+H] + .

[0222] Preparation of intermediate INT-AH in Example 9

[0223] Step one: To a reaction flask was added 5-fluoroindole (1.5 g, 11.1 mmol, 1.0 eq.), methanol (30 mL), potassium hydroxide (0.69 g, 12.21 mmol, 1.1 eq.) and 1-Boc-3-azetidinone (2.09 g, 12.21 mmol, 1.1 eq.) successively. The mixture was stirred at 60 °C for 48 h under nitrogen protection. After the reaction was completed and cooled to room temperature, the mixture was diluted with water and extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 10) to give compound INT-AH-1 (1 g, 29%). LCMS (ESI, m / z): 307.2 [M+H] + .

[0224] Step two: Compound INT-AH-1 (680 mg, 2.22 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) under ice-bath cooling. Triethylsilane (2.58 g, 22.2 mmol, 10.0 eq.) was added and stirred for 15 min. Trifluoroacetic acid (653 mg, 6.66 mmol, 3.0 eq.) was added and stirred for another 15 min. After the reaction was completed, the mixture was quenched by the addition of sodium bicarbonate and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-AH-2 (350 mg, 54%). LCMS (ESI, m / z): 291.4 [M+H] + .

[0225] Step three: Into a reaction vial, was added compound INT-AH-2 (350 mg, 1.21 mmol, 1.0 eq.), dichloromethane (10 mL) and trifluoroacetic acid (1.42 g, 14.47 mmol, 12.0 eq.) successively, stirred at room temperature for 6 hours. After the reaction was completed, concentrated under reduced pressure, the residue was purified by normal silica gel column chromatography (dichloromethane / methanol = 4 / 1) to give trifluoroacetate salt of compound INT-AH (330 mg, 90%). LCMS (ESI, m / z): 191.2 [M+H] + .

[0226] Preparation of Example 10 intermediate INT-AI

[0227] Step one: Into a reaction vial, was added 2-amino-3-(5-fluoro-lH-indol-3-yl)propanoic acid (450 mg, 2.03 mmol, 1.0 eq.) in tetrahydrofuran (10 mL), nitrogen was replaced, lithium aluminum hydride (3.24 mL, 8.1 mmol, 4.0 eq. 2.5 M in THF) was added under ice bath, stirred at 68 °C for 18 hours. After the reaction was completed and cooled to room temperature, quenched by sodium sulfate decahydrate, diluted with ethyl acetate, stirred for 30 minutes, filtered by celite, the filtrate was concentrated under reduced pressure, the crude compound INT-AI-1 (450 mg, 107%) was used directly in the next step without purification. LCMS (ESI, m / z): 209.5 [M+H] + .

[0228] Step two: Into a reaction vial, was added compound INT-AI-1 (400 mg, 1.92 mmol, 1.0 eq.), tetrahydrofuran (15 mL), triethylamine (253 mg, 2.5 mmol, 1.3 eq.) and chloroacetyl chloride (260 mg, 2.31 mmol, 1.2 eq.) successively under ice bath, stirred at room temperature for 2 hours. After the reaction was completed, concentrated under reduced pressure, the residue was purified by normal silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-AI-2 (290 mg, 53%). LCMS (ESI, m / z): 285.3 [M+H] + .

[0229] Step three: Compound INT-AI-2 (290 mg, 1.02 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (7 mL), sodium hydride (81 mg, 2.04 mmol, 2.0 eq. 60% in mineral oil) was added under ice-bath, and the stirring was continued at room temperature for 2 hours. After the reaction was completed, water was added to quench, and ethyl acetate was extracted three times, and the organic phase was combined and dried over anhydrous sodium sulfate. Filtration, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on normal silica gel (dichloromethane / methanol = 15 / 1) to give compound INT-AI-3 (200 mg, 79%). LCMS (ESI, m / z): 249.1 [M+H] + .

[0230] Step four: Compound INT-AI-3 (170 mg, 0.69 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL), and replaced by nitrogen, and lithium aluminum hydride (0.55 mL, 1.37 mmol, 2.0 eq. 2.5 M in THF) was added under ice-bath, and the stirring was continued at room temperature for 16 hours. After the reaction was completed, sodium sulfate decahydrate was added to quench, and ethyl acetate was added to dilute, and stirred for 30 minutes, and filtered by diatomite, and the filtrate was concentrated under reduced pressure, and the obtained crude compound INT-AI (165 mg, 103%) was used directly in the next step without purification. LCMS (ESI, m / z): 235.2 [M+H] + .

[0231] Preparation of Example 11 intermediate INT-AJ

[0232] Step one: N-benzyloxycarbonyl proline (1.4 g, 5.62 mmol, 1.0 eq.) was dissolved in dichloromethane (14 mL), and oxalyl chloride (1.43 g, 11.23 mmol, 2.0 eq) and DMF (3 drops, cat.) were added under ice-bath in turn, and the stirring was continued at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure, and redissolved in dichloromethane and concentrated dry twice, and the obtained crude compound INT-AJ-1 (1.5 g, 100%) was used directly in the next step without purification.

[0233] Step two: Compound INT-AJ-2 (900 mg, 2.46 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL), lithium borohydride (214 mg, 9.83 mmol, 4.0 eq.) was added, and the mixture was stirred at 68 °C for 5 h. After the reaction was completed, sodium bicarbonate was added to quench, water was added to dilute, and ethyl acetate was added to extract three times. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on normal silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound INT-AJ-3 (680 mg, 79%). LCMS (ESI, m / z): 353.3 [M+H] + .

[0234] Step two: Compound INT-AJ-2 (900 mg, 2.46 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL), lithium borohydride (214 mg, 9.83 mmol, 4.0 eq.) was added, and the mixture was stirred at 68 °C for 5 h. After the reaction was completed, sodium bicarbonate was added to quench, water was added to dilute, and ethyl acetate was added to extract three times. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on normal silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound INT-AJ-3 (680 mg, 79%). LCMS (ESI, m / z): 353.3 [M+H] + .

[0235] Step two: Compound INT-AJ-2 (900 mg, 2.46 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL), lithium borohydride (214 mg, 9.83 mmol, 4.0 eq.) was added, and the mixture was stirred at 68 °C for 5 h. After the reaction was completed, sodium bicarbonate was added to quench, water was added to dilute, and ethyl acetate was added to extract three times. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on normal silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound INT-AJ-3 (680 mg, 79%). LCMS (ESI, m / z): 353.3 [M+H] + .

[0236] Example 12 Preparation of compound 99

[0237] To a solution of compound 1 (800 mg, 2.79 mmol, 1 eq), acetic acid (0.048 ml, 0.838 mmol, 0.3 eq), 40% aqueous solution of acetaldehyde (0.6 ml, 4.19 mmol, 1.5 eq) in methanol (10 ml) was added sodium cyanoborohydride (193 mg, 3.07 mmol, 1.1 eq) portion wise at 0 °C and stirred for 1.5 h. TLC (methanol / dichloromethane = 1 / 5) showed the completion of the reaction. The reaction mixture was basified to pH ~ 11 with 1 M aqueous NaOH solution at 0 °C and stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was purified by normal phase silica gel column chromatography (methanol / dichloromethane = 1 / 5) to get compound 99 (355 mg, 40.4%). LCMS: (ESI, m / z): 315.1 [M+H] + .

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 2H), 2.83 (s, 3H), 2.78 (s, 4H), 2.68 (q, J = 7.1 Hz, 2H), 1.75 (t, J = 4.5 Hz, 2H), 1.35 (dd, J = 4.4, 1.7 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H).

[0239] Preparation of compound 88 of example 13

[0240] Step one: To a solution of compound 88-1 (500 mg, 2.20 mmol, 1.0 eq.) in N,N- dimethylformamide (15 mL) was added 2-(5-methoxy-lH-indol-3-yl)ethan-l -amine (542 mg, 2.4 mmol, 1.1 eq.), 2-(7-azabenzotriazol-l -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.3 g, 3.30 mmol, 1.5 eq.) and N,N-diisopropyl ethylamine (1.7 g, 13.2 mmol, 6.0 eq.) at room temperature under nitrogen. After nitrogen replacement, the reaction was stirred at room temperature for 18 h. After the reaction was completed, the reaction was diluted with water and extracted with ethyl acetate for three times. The organic phase was washed with water for three times and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound 88-2 (700 mg, 79.74%). LCMS (ESI, m / z): 400.2 [M+H] + .

[0241] Step two: To a solution of 88-2 (200 mg, 0.5 mmol, 1.0 eq.) in tetrahydrofuran (10 mL) was added lithium aluminum hydride solution (1.8 mL, 2.5 M in THF, 4.5 mmol, 9.0 eq.) dropwise at 0 °C under nitrogen. The reaction was heated to 70 °C under nitrogen and stirred for 18 h. After the reaction was completed, the reaction was quenched by the slow addition of sodium sulfate decahydrate to the reaction mixture which was cooled to 0 °C. The reaction was filtered and the filtrate was washed with THF. The filtrate was concentrated under reduced pressure at low temperature. The residue was purified by preparative high performance liquid chromatography. The purification conditions were as follows: column specifications: XBridge C18, 19 mm * 250 mm; mobile phase A: water (0.05% trifluoroacetic acid / water), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 15-25%; time: 16 min; detection wavelength: UV 254 nm / 214 nm; retention time (min): 8.4-10.5. Compound 88 (5.82 mg, 3.89%) was obtained. LCMS (ESI, m / z): 300.1 [M+H] + .

[0242] 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.12 (s, 1H), 7.01 (s, 1H), 6.72 (d, J = 7.8 Hz, 1H), 3.76 (s, 3H), 3.24 (s, 2H), 3.06 (d, J = 20.6 Hz, 4H), 2.87 (s, 3H), 2.82 2.71 (m, 3H), 1.97 (s, 2H), 1.68 (s, 1H), 1.51 (s, 1H).

[0243] Preparation of compound 94 of example 14

[0244] Step one: To compound 88-2 (400 mg, 1.0 mmol, 1.0 eq.) in dichloromethane (10 mL) was added trifluoroacetic acid (3.4 g, 30 mmol, 30.0 eq.) at room temperature, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase high performance liquid chromatography (CH3CN in H2O (0.05% NH4HCO3) = 0-95%) to give compound 94-1 (100 mg, 33.44%). LCMS (ESI, m / z): 300.3 [M+H] + .

[0245] Step two: To a solution of compound 94-1 (100 mg, 0.33 mmol, 1.0 eq.) in tetrahydrofuran (5 mL) was added lithium aluminum hydride solution (0.66 mL, 2.5 M in THF, 1.65 mmol, 5.0 eq.) dropwise at 0 °C under nitrogen. The reaction was heated to 40 °C under nitrogen for 5 h. After the reaction was completed, the reaction mixture was cooled to 0 °C, and sodium sulfate decahydrate was added slowly to quench the reaction. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (column specification: XBridge C18, 19 mm*250 mm; mobile phase A: water (0.05% trifluoroacetic acid / water), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 12-17%; time: 16 min; detection wavelength: UV 254 nm / 214 nm; retention time (min): 7.5-8.8) to give compound 94 (9.08 mg, 9.65%). LCMS (ESI, m / z): 285.9 [M+H] + .

[0246] 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.21 (d, J = 104.5 Hz, 2H), 7.26 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.6 Hz, 1H), 3.77 (s, 3H), 3.53 (s, 3H), 3.24 (s, 3H), 3.04 (s, 2H), 2.86 (s, 1H), 2.17 (s, 2H), 1.60 (s, 2H).

[0247] Preparation of Example 15 intermediate INT-AK

[0248] Step one: To a solution of methyl 2-(bromomethyl)acrylate (5.0 g, 27.9 mmol, 1.0 eq.) and triethylamine (5.6 g, 55.9 mmol, 2.0 eq.) was added dropwise a solution of benzyl alcohol (30.2 g, 279.3 mmol, 10.0 eq.) in water (11.2 mL) under nitrogen protection at room temperature for 18 h. After completion of the reaction, it was diluted with water and extracted with ethyl acetate twice. The combined organic phase was dried over anhydrous sodium sulfate. Filtration was followed by concentration of the filtrate under reduced pressure. The residue was purified by column chromatography on normal silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-AK-1 (3.8 g, 66%). LCMS (ESI, m / z): 207.2 [M+H] + .

[0249] Step two: To a solution of compound INT-AK-1 (3.8 g, 18.4 mmol, 1.0 eq.) in tetrahydrofuran (24 mL) and water (3 mL) was added lithium hydroxide monohydrate (2.3 g, 55.3 mmol, 3.0 eq.) at 0 °C under nitrogen protection. The reaction was stirred at room temperature for 4 h. After completion of the reaction, it was cooled to 0 °C and adjusted to pH 2 with 1 N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate twice. The combined organic phase was dried over anhydrous sodium sulfate. Filtration was followed by concentration of the filtrate under reduced pressure to give compound INT-AK-2 (3.7 g, crude). It was used in the next step without further purification. LCMS (ESI, m / z): 191.0 [M-1] + .

[0250] Step three: To a solution of compound INT-AK-2 (3.7 g, 19.0 mmol, 1.0 eq.) in dichloromethane (30 mL) was added N, O-dimethylhydroxylamine hydrochloride (3.8 g, 38.5 mmol, 2.0 eq.), N, N-isopropylethylamine (7.5 g, 57.8 mmol, 3.0 eq.) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (5.5 g, 28.9 mmol, 1.5 eq.) successively under nitrogen protection at room temperature. The reaction was stirred for 18 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane twice. The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AK-3 (3.7 g, 83%). LCMS (ESI, m / z): 236.2 [M+H] + .

[0251] Step four: To a solution of compound INT-AK-3 (4.2 g, 17.9 mmol, 1.0 eq.) in tetrahydrofuran (50 mL) was added allylmagnesium chloride (17.9 mL, 2M in THF, 35.7 mmol, 2.0 eq.) at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 2 h and then at room temperature for 2 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution at 0 °C. The reaction mixture was extracted with ethyl acetate twice. The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AK-4 (440 mg, 94%). LCMS (ESI, m / z): 217.2 [M+H] + .

[0252] Step five: To a solution of compound INT-AK-4 (500 mg, 2.3 mmol, 1.0 eq.) in acetonitrile (15 mL) was added 4-isopropylthioxanthone (58.8 mg, 0.23 mmol, 1.1 eq.) under nitrogen protection at room temperature. The reaction was irradiated with UV light (365 nm) for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-AK-5 (230 mg, 46%). LCMS (ESI, m / z): 217.2 [M+H] + .

[0253] Step six: To a solution of compound INT-AK-5 (280 mg, 1.3 mmol, 1.0 eq.) in methanol (10 mL), palladium on carbon (90 mg, 10% Wt), palladium hydroxide on carbon (90 mg, 10% Wt) and one drop of acetic acid were added successively. After three times of hydrogen replacement, the reaction was stirred at room temperature for 18 h under hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound INT-AK-6 (160 mg, 98%). LCMS (ESI, m / z): 127.3 [M+H] + .

[0254] Step seven: To a solution of triphenylphosphine (365.9 mg, 1.4 mmol, 1.1 eq.) and imidazole (190 mg, 2.8 mmol, 2.2 eq.) in dichloromethane (5 mL), compound INT-AK-6 (160 mg, 1.7 mmol, 1.0 eq.) and iodine (354 mg, 1.74 mmol, 1.1 eq.) were added successively at 0 °C. The reaction was heated to 40 °C under nitrogen protection for 18 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane twice. The combined organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give intermediate INT-AK (200 mg, 67%). LCMS (ESI, m / z): 237.0 [M+H] + .

[0255] Preparation of Example 16 intermediate INT-AL

[0256] Step one: To a solution of compound INT-AK-5 (250 mg, 1.2 mmol, 1.0 eq.) in chloroform (5 mL), diethylaminosulfur trifluoride (3.05 mL, 23.1 mmol, 20 eq.) was added at 0 °C under nitrogen protection. The reaction was heated to 50 °C for 18 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane twice. The combined organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-AL-1 (230 mg, 84%).

[0257] Step two: To a solution of compound INT-AL-1 (150 mg, 0.63 mmol, 1.0 eq.) in methanol (5 mL), palladium on carbon (75 mg, 10% Wt), palladium hydroxide on carbon (75 mg, 10% Wt) and one drop of acetic acid were added, after three times of hydrogen gas purging, the reaction was heated to 50 degree under hydrogen gas for 3 h. After completion of the reaction, it was filtered, the filtrate was concentrated under reduced pressure to afford compound INT-AL-2 (50 mg, 54%).

[0258] Step three: To a solution of compound INT-AL-2 (20 mg, 0.14 mmol, 1.0 eq.) in dichloromethane (5 mL) at 0 degree under nitrogen atmosphere, p-toluenesulfonyl chloride (38.60 mg, 0.20 mmol, 1.5 eq.) and pyridine (32 mg, 0.41 mmol, 3.0 eq.) were added, the reaction was stirred at room temperature for 18 h. After completion of the reaction, it was diluted with water, extracted with dichloromethane twice, the combined organic phase was dried over anhydrous sodium sulfate. It was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to afford intermediate INT-AL (23 mg, 58%).

[0259] Preparation of intermediate INT-AM of example 17

[0260] Step one: 2-Chloro-4-aminobenzonitrile (10 g, 65.5 mmol, 1.0 eq.) was dissolved in acetic acid (60 mL), NIS (16.22 g, 72.1 mmol, 1.1 eq.) was added in portions, the reaction was stirred at room temperature for 16 h after three times of nitrogen purging. After completion of the reaction, it was diluted with water, extracted with ethyl acetate twice, washed with saturated sodium bicarbonate solution, the combined organic phase was dried over anhydrous sodium sulfate. It was filtered, the filtrate was concentrated under reduced pressure, slurry with n-heptane at 40 degree for 4 h. It was filtered, washed and dried to afford compound INT-AM-1 (13 g, 71%). LCMS (ESI, m / z): 278.8 [M+H] + .

[0261] Step two: Into a reaction vial, was added compound INT-AM-1 (7 g, 25.1 mmol, 1.0 eq.), acetonitrile (50 mL), cuprous iodide (239 mg, 1.257 mmol, 0.05 eq.), dichlorobis(triphenylphosphine)palladium (882 mg, 1.257 mmol, 0.05 eq.), triethylamine (5.09 g, 50.3 mmol, 2.0 eq.) and trimethylsilyl acetylene (4.94 g, 50.3 mmol, 2.0 eq.), and purged with nitrogen for three times, stirred at 72 °C for 3 h. After reaction was completed and cooled to room temperature, filtered with celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 9 / 1) to give compound INT-AM-2 (4.7 g, 75%). LCMS (ESI, m / z): 249.1 [M+H] + .

[0262] Step three: Into a reaction vial, was added compound INT-AM-2 (4.7 g, 18.89 mmol, 1.0 eq.) and methanol (30 mL), potassium carbonate (7.83 g, 56.7 mmol, 3.0 eq.), stirred at room temperature for 1 h. After reaction was completed, diluted with water, extracted with ethyl acetate twice, combined the organic phase and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4 / 1) to give compound INT-AM-3 (3.2 g, 96%). LCMS (ESI, m / z): 177.1 [M+H] + .

[0263] Step four: Into a reaction vial, was added compound INT-AM-3 (3.5 g, 19.82 mmol, 1.0 eq.) and pyridine (30 mL), RuCl(Cp)(PPh3)2 (1.44 g, 1.982 mmol, 0.1 eq.), purged with nitrogen for three times, stirred at 97 °C for 4 h. After reaction was completed and cooled to room temperature, diluted with water, extracted with ethyl acetate twice, washed with saturated ammonium chloride solution, combined the organic phase and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AM-4 (2.1 g, 60%). LCMS (ESI, m / z): 177.0 [M+H] + .

[0264] Step five: To anhydrous DMF (20 mL) was added phosphorous oxychloride (3.65 g, 23.78 mmol, 2.0 eq.) dropwise slowly under nitrogen protection in ice bath, stirred for 20 min, added compound INT-AM-4 (2.1 g, 11.89 mmol, 1.0 eq. in 10 mL DMF), and continued to stir at room temperature for 2 h. After the reaction was completed, quenched by saturated sodium bicarbonate solution, stirred for 6 h, stood for 6 h, suction filtered, washed with water, and oven dried to give compound INT-AM-5 (2 g, 82%). LCMS (ESI, m / z): 205.0 [M+H] + .

[0265] Step six: To a reaction flask was added compound INT-AM-5 (2 g, 9.77 mmol, 1.0 eq.), ammonium acetate (1.51 g, 19.55 mmol, 2 eq.), tetrahydrofuran (40 mL) and nitromethane (2.98 g, 48.9 mmol, 5.0 eq.) successively, replaced with nitrogen for three times, and stirred at 80 °C for 24 h. After the reaction was completed and cooled to room temperature, concentrated to remove nitromethane and tetrahydrofuran, slurried with water and methanol (4 / 1), suction filtered, washed with water, and oven dried to give compound INT-AM-6 (2.4 g, 99%). LCMS (ESI, m / z): 248.1 [M+H] + .

[0266] Step seven: Compound INT-AM-6 (2.2 g, 8.88 mmol, 1.0 eq.) was dissolved in methanol (15 mL) and DMF (15 mL), added sodium borohydride (1 g, 26.7 mmol, 3 eq.) in portions, and stirred at room temperature for 2 h. After the reaction was completed, adjusted pH to about 7 by adding 2 M hydrochloric acid, diluted with water, extracted with ethyl acetate for three times, combined the organic phase, and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by normal phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 and dichloromethane / methanol = 25 / 1) to give compound INT-AM-7 (1.3 g, 59%). LCMS (ESI, m / z): 250.1 [M+H] + .

[0267] Step eight: Zinc dust (6.91 g, 106 mmol, 24 eq.) was added to 2M hydrochloric acid solution (123 mL, 247 mmol, 56 eq.), compound INT-AM-7 (1.1 g, 4.41 mmol, 1.0 eq. in 123 mL MeOH.) was added, and the mixture was stirred at 68 °C for 3 h. After the reaction was completed and cooled to room temperature, 2M sodium hydroxide solution was added to adjust pH about 12, and the mixture was suction filtered through celite, washed with dichloromethane, the filtrate was extracted with dichloromethane for three times, the combined organic phase was dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The obtained crude compound INT-AM-8 (930 mg, 96%) was used directly in the next step without purification. LCMS (ESI, m / z): 220.1 [M+H] + .

[0268] Preparation of intermediate INT-AN in Example 18

[0269] Step one: 5-Fluoro-6-methoxy-lH-indole (180 mg, 1.09 mmol, 1.0 eq.) in N,N- dimethylformamide (12 mL) was slowly added to a solution of phosphorus oxychloride (0.12 mL, 1.20 mmol, 1.1 eq.) in N,N-dimethylformamide (2 mL) under nitrogen protection at 0 °C for 3 h. The reaction was monitored by LCMS and TLC until the starting material was consumed. Water (14 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred at 60 °C for 18 h. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate twice. The combined organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AN-1 (150 mg, 71%). LCMS (ESI, m / z): 194.1 [M+H] + .

[0270] Step two: To a solution of compound INT-AN-1 (150 mg, 0.78 mmol, 1.0 eq.) in tetrahydrofuran (8 mL) was added nitromethane (284.38 mg, 4.66 mmol, 6.0 eq.) and ammonium acetate (155.62 mg, 2.02 mmol, 2.6 eq.) under nitrogen protection, and the mixture was stirred at 80 °C for 18 h. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate twice. The combined organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-AN-2 (150 mg, 81.49%). LCMS (ESI, m / z): 237.1 [M+H] + .

[0271] Step 3: To a solution of INT-AN-2 (150 mg, 0.64 mmol, 1.0 eq.) in tetrahydrofuran (3 mL) was added lithium aluminum hydride (1.02 mL, 2.54 mmol, 2.5 M, 4.0 eq.) at -5 °C under nitrogen protection. After 30 min at -5 °C, the reaction was continued at room temperature for 18 h. After the reaction was completed, the reaction was quenched by slowly adding sodium sulfate decahydrate (0.5 g) at 0 °C. The mixture was filtered, and the filtrate was washed with tetrahydrofuran. The combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 4 / 1) to give compound INT-AN (80 mg, 60.1%). LCMS (ESI, m / z): 209.1 [M+H] + .

[0272] Preparation of compound 109 of Example 19

[0273] To a solution of compound 27 (120 mg, 0.394 mmol, 1.0 eq.) in methanol (3 mL) was added formaldehyde (48 mg, 0.591 mmol, 1.5 eq.), sodium cyanoborohydride (124 mg, 1.97 mmol, 5.0 eq.) and acetic acid (0.3 mL) at room temperature under nitrogen protection. The reaction was continued at room temperature for 18 h. After the reaction was completed, the mixture was filtered, and the crude product was purified by preparative high performance liquid chromatography (mobile phase A: 0.03% ammonia water / water, mobile phase B: acetonitrile) to give compound 109 (37.49 mg, 29.87%). LCMS: (ESI, m / z): 319.1 [M+H] +

[0274] 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.25 7.02 (m, 3H), 3.83 (s, 3H), 3.62 (s, 2H), 2.78 (dd, J = 18.4, 12.1 Hz, 3H), 2.67 (dd, J = 15.8, 8.2 Hz, 4H), 2.33 (s, 3H), 1.71 (s, 2H), 1.35 (d, J = 3.8 Hz, 2H).

[0275] The final product was synthesized according to the preparation method of Reference Example

[0276] Table 2

[0277] Biological test evaluation

[0278] Test Example 1: FLIPR-based test of the 5-HT 2A agonistic activity of the compounds of the present application

[0279] HEK293 cells stably overexpressing 5-HT2A(ATCC-CRL-1573) were cultured and resuspended for counting, then plated at 20000 cells / 20μL per well in a 384-well plate (Greiner-781090) and incubated overnight at 37°C in a 5% CO2incubator. Test compounds and reference compounds were diluted in 3-10 fold serial dilutions with DMSO, and 750nL was transferred to the compound plate using an Echo 555, and 30μL assay buffer (Invitrogen-F10471, Component C) was added. The cell plate was removed from the incubator and the old medium was removed, and 20μL assay buffer and 20μL Fluo-4 Direct TM Loading buffer (Invitrogen-F10471, Component A) was added and incubated for 50 minutes at 37°C in a 5% CO2incubator, followed by 10 minutes at room temperature. 10μL of compound was transferred to the cell plate and the fluorescence values were read using a FLIPR (Molecular Device). The highest concentration point for the reference compound 5-HT was 100nM, and the highest concentration point for the test compounds was 30μM. The DMSO content in the blank wells and the compound wells was 5‰. The data analysis for the 5-HT 2A agonistic activity of the compounds: Sample agonistic activity = 100% x (sample well signal value - average of blank well fluorescence signal) / (average of reference compound highest concentration point fluorescence signal - average of blank well fluorescence signal). The data was fitted using GraphPad Prism 5.0, and the "Dose-response-Stimulation-log(agonist) vs. response - Variable slope" model was selected for fitting analysis, and the EC 50 values and E max values for each test sample were obtained.

[0280] The results of the experiment are shown in Table 3 below:

[0281] Table 3

[0282] A: 1 nM < EC 50 < 10 nM; B: 10 nM < EC 50 < 100 nM; C: 100 nM < EC 50 < 1000 nM.

[0283] Other compounds of the present application were tested according to the present test method, and the EC 50 values of the compounds of the present application were within the range of 1-1000 nM, E max were within the range of 10-100%.

[0284] Experimental Conclusion:

[0285] The compounds of the present application have good agonistic activity on the Gq signal pathway downstream of 5-HT 2A receptors.

[0286] Test Example 2: Anti-depression efficacy test of the compound of the present application

[0287] Method: Depression-like mice were constructed based on the chronic unpredictable mild stimulation model. The mild stimulation included fasting and water deprivation, foot electrostimulation, wet bedding, cage tilting, behavioral restraint, shaking cage and olfaction, and the above seven experiments were randomly performed within one week to achieve unpredictability, and the mice were continuously stimulated for 4 weeks. The mouse strain was C57BL / 6J, 6-8 weeks old, male. The sugar water preference test was designed by using the preference of rodents for sweet taste as an index to detect whether the animal had anhedonia, a symptom of depression. After the animals were fasted for a period of time, pure water and low concentration sucrose water were given at the same time, and the degree of preference of animals for sucrose water (sugar water preference rate) was used as an index to detect whether the animal had anhedonia, a symptom of depression. After the continuous 28-day unpredictable mild stimulation, the depressed mice were randomly divided into a model group, a positive drug group and a compound 1 group. The control group (normal mice) and the model group (depressed mice) were given a vehicle (5% DMSO + 10% Solutol + 85% physiological saline, 1 day 1 time, continuously for 28 days), the positive drug group was given fluoxetine (30 mpk, gavage, 1 day 1 time, continuously for 28 days), and the test compound 1 group (vehicle gavage once a day for the first 27 days, and intraperitoneal injection of 20 mpk of compound 1 once on the 28th day). The sugar water preference rates of the control group, the model group, the fluoxetine group and the compound 1 group were detected 24 hours after the administration of compound 1 (24 hours after the administration ended on the 28th day, the four groups of mice were fasted at the same time for 24 hours).

[0288] Results: As shown in Figure 1, the sugar preference rate of the model group mice was significantly decreased compared with the control group. After 28 days of continuous administration of the positive drug fluoxetine (30 mpk) and once administration of compound 1 (20 mpk), the sugar preference rate of the depressed mice was significantly increased. Compound 1 showed a rapid-acting antidepressant effect.

[0289] As shown in Figure 2, after establishing a depressed mouse animal model by a similar method, the positive drug group was given psilocybin (3 mpk intraperitoneal injection once) or esketamine (10 mpk intraperitoneal injection once), and the rest of the compounds were 20 mpk, intraperitoneal injection once. The sugar preference rate was tested 24 hours after administration. The results showed that the compounds of the application had a rapid-acting antidepressant effect.

[0290] Test Example 3 C57 Male Mouse Head-Twitch Response

[0291] Method: Head-Twitch Response (HTR) refers to the rapid lateral and left-right rotation of the head movement of mice to characterize the hallucinogenic effect. Before the test, high-definition video equipment was installed on an aluminum profile combined rack, and a mouse cage (26.5 cm x 37 cm) was placed under each camera. C57BL / 6J mice were placed in the test environment for 60 min to ensure that the environmental temperature was (23±2)℃ and the humidity was 40%~60%. After environmental adaptation, the mice to be tested were intraperitoneally injected with the corresponding solvent (5% DMSO+10% solutol+85% physiological saline) or compound and immediately started recording. The mice to be tested were placed in the center of the mouse cage, and the mouse behavior within 30 min after administration was recorded using VideoCap V1.27.0.22 software. After each round, the feces and urine were removed and disinfected with 75% alcohol and dried. Three mice were tested for each compound, and each mouse was tested once. After the test, the number of head twitches (HTR) of the mice was counted by two people in a blind manner (non-behavioral test personnel were selected), and the total number of head twitches of each animal in 30 min and the number of head twitches every 10 min were counted. The average value was taken as the final result.

[0292] Results: Compound 1 did not cause the mice to produce head twitch behavior. Other compounds of the application were tested by the same method, and the results are shown in Table 4.

[0293] Table 4

[0294] Test Example 4 C57 Male Mouse PK Test

[0295] Table 5

[0296] Note: *, the animals in the oral administration group were fasted overnight (10-14 hours) before administration, and fed 4 hours after administration.

[0297] The solvent is 5% DMSO + 10% Solutol + 85% physiological saline, after administration, blood is taken from the cheek at each time point, about 0.05 mL of each sample is collected, anticoagulated with sodium heparin, and placed on wet ice after collection, and centrifuged to separate plasma within 30 minutes (centrifugation conditions: 6000g, 3 minutes, 2-8°C), and the plasma sample is stored in a -80°C refrigerator before analysis. The pharmacokinetic parameters are calculated by using Phoenix WinNonlin 8.2.0 from the blood concentration data at different time points.

[0298] Table 6

[0299] Conclusion: The compound of the present application has good oral bioavailability.

[0300] Test Example 5 Caco-2 Permeability Test

[0301] 1. Test procedure: The bidirectional permeability of the test solution containing the test product (transport buffer solution (HBSS, 10 mM HEPES, pH 7.4) from the apical side to the basolateral side and from the basolateral side to the apical side was detected. The test was incubated at 37°C for 120 minutes, and the control drugs digoxin (5 μM), minoxidil (5 μM) and atenolol (5 μM) were used to detect the transport activity of the system. The concentrations of the test product at the administration end and the receiving end at the beginning and at the end of incubation were quantitatively detected by HPLC-MS / MS, and the apparent permeability coefficient was calculated according to the concentration. The whole test was carried out in two parallel. The integrity of the cell monolayer membrane after 2 hours of incubation was evaluated by the leakage of fluorescein.

[0302] 1.1 Cell culture and seed plate

[0303] 1) Take out 100 mL (for later use) from DMEM culture medium (500 mL / bottle), add 100 mL fetal bovine serum FBS, 5 mL double antibody, 5 mL non-essential amino acid NEAA.

[0304] 2) After the Caco-2 cells are recovered, they are cultured in a culture dish, and the incubator is set to 37°C, 5% CO2, and the relative humidity is ensured to be 95%. After two passages, when the cell confluence reaches 70%-90%, they can be used for inoculation in the Transwell plate.

[0305] 3) Before cell inoculation, 25 mL of cell culture medium is added to the lower layer of the Transwell culture plate. The culture plate can be used for cell inoculation after being incubated in a 37°C, 5% CO2 incubator for 1 hour.

[0306] 4) After cell digestion, the cell suspension is transferred to a round-bottom centrifuge tube and centrifuged at 120g for five minutes.

[0307] 5) Resuspend the cells in medium to a final concentration of 3.43 x 10 5 cells / mL. Add 100 μL of the cell suspension to each well of the upper chamber of the 96-well Transwell plate for a final seeding density of 2.4 x 10 5 cells / cm 2 .

[0308] 6) Start medium exchange 48 h after seeding and continue for 14-18 days, changing medium every other day.

[0309] 7) Medium exchange is performed by separating the Transwell chamber from the receiver plate, discarding the 10 mL medium from the receiver plate, then discarding the medium from the Transwell chamber, and finally adding 100 μL fresh medium to each chamber and 10 mL fresh medium to the receiver plate.

[0310] 1.2 Evaluation of monolayer membrane integrity

[0311] 1) Caco-2 cells should be fully confluent and differentiated after 14 days of culture. At this time, they can be used for permeation experiments.

[0312] 2) Measure the electrical resistance of the monolayer membrane using an ohmmeter (Millipore, USA) and record the resistance for each well.

[0313] 3) After the measurement is complete, return the Transwell plate to the incubator.

[0314] 4) Calculation of resistance values: measured resistance x membrane area (cm 2 ) = TEE value (ohms.cm 2 ). If the TEE value is < 230 ohms.cm 2 , the well cannot be used for permeation experiments.

[0315] 1.3 Drug permeation experiments

[0316] 1) Remove the Transwell plate from the incubator and rinse the monolayer membrane twice with transport buffer (10 mM HEPES, pH 7.4), then add 100 μL HBSS and incubate for 30 minutes at 37°C.

[0317] 2) Measure the transport rate of the compound from the apical to the basolateral side. Add 100 μL of the donor solution to each well of the upper chamber (apical side) and 300 μL of the receiver solution to each well of the lower chamber (basolateral side).

[0318] 3) Determine the rate of transport of the compound from the basal end to the apical end. Add 100 μL of the receiving end solution to each well of the upper chamber (apical end) and 300 μL of the dosing end solution to each well of the lower chamber (basal end).

[0319] 4) Take 50 μL of the dosing solution and add to 200 μL of the stop solution containing internal standard as the 0 minute dosing sample for analysis.

[0320] 5) Combine the upper and lower transport devices and incubate at 37°C for 2 hours.

[0321] 6) After the incubation is complete, take 50 μL from each well of the upper and lower chambers of the Transwell plate and add to a new sample tube. Add 200 μL of the stop solution containing internal standard to the sample tube, vortex for 10 minutes, and centrifuge at 4000 rpm for 10 minutes. Take 100 μL of the supernatant and dilute with 100 μL of water before analysis by LC-MS / MS. All samples are prepared in duplicate.

[0322] 7) Evaluate the integrity of the cell monolayer membrane after 2 hours using a leak assay with fluorescein. Dilute the fluorescein stock solution with transport buffer to a final concentration of 100 μM. Add 100 μL of the fluorescein solution to each well of the upper Transwell insert plate and 300 μL of transport buffer to each well of the lower receiving plate. Incubate at 37°C for 30 minutes and then remove 80 μL from each well of the upper and lower chambers into a new 96-well plate. Measure the fluorescence using a microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0323] 2. Data Calculation

[0324] All calculations are performed using Microsoft Excel. Peak areas are determined from extracted ion chromatograms.

[0325] The apparent permeability coefficient (P app , units: x 10 -6 cm / s) is calculated using the following equation:

[0326] In the equation: V A is the volume of the receiving solution (Ap→B1 is 0.3 mL and B1→Ap is 0.1 mL), Area is the Transwell-96 well plate membrane area (0.143 cm 2 ), and time is the incubation time (units: s).

[0327] The efflux ratio is calculated using the following equation:

[0328] In the equation: P app(B-A) is the apparent permeability coefficient from the basal end to the apical end; P app (A-B) is the apparent permeability coefficient from the apical end to the basal end.

[0329] The recovery rate is calculated using the following formula:

[0330] In the formula, V A is the solution volume of the receiving end (unit: mL); V D is the solution volume of the giving end (unit: mL).

[0331] The fluorescence value of the Caco-2 cell monolayer membrane is calculated using the following formula:

[0332] Table 7

[0333] Conclusion: The other compounds of the application were tested by the same method, and it was shown that the compounds of the application have higher permeability.

[0334] Test Example 6 Plasma Protein Binding Rate

[0335] Take 747 μL of blank plasma, add 3 μL of test sample or warfarin working solution (500 μM), and mix well to obtain a plasma sample with a final concentration of 2 μM. Take 50 μL of each type of test sample and warfarin plasma sample into a sample plate, immediately add 50 μL of buffer; then add 500 μL of termination solution (50 ng / mL tolbutamide), to obtain a T0 sample, which is stored at 2-8°C, and is ready for subsequent processing with other dialysis samples. Add 150 μL of blank dialysate to the receiving side of the dialysis membrane, and 150 μL of plasma sample to the donor side, in duplicate, and seal the dialysis device after adding the sample in a 37°C incubator at a speed of 100 rpm for 5 h to achieve dialysis equilibrium. Place the remaining plasma sample in the incubator for 5 h for stability testing of the test sample in plasma, in duplicate. Take 50 μL of dialysate after dialysis equilibrium, add 500 μL of termination solution after adding blank plasma, to obtain a T5 receiving side sample; take 50 μL of plasma after dialysis equilibrium, add 500 μL of termination solution after adding 50 μL of buffer, to obtain a T5 donor side sample; take 50 μL of plasma sample after 5 h of incubation for stability testing, add 500 μL of termination solution after adding 50 μL of buffer, to obtain a T5 stability sample. After vortexing all samples (T0, T5 h, and stability samples) at 1000 rpm for 10 min, centrifuge at 4000 rpm for 15 min. Take 100 μL of supernatant into a new 96-well plate, add 100 μL of pure water and mix well, and analyze by HPLC-MS / MS.

[0336] All data calculation was performed by Microsoft Excel software, and the protein binding rate of the test sample in the plasma was calculated by the following formula:

[0337] Free rate (%) = (Area ratio receiving side / Area ratio donor side) x 100

[0338] Binding rate (%) = 100 - Free rate

[0339] Recovery rate (%) = (Area ratio receiving side + Area ratio donor side) / (Area ratio T0) x 100

[0340] Remaining rate (%) = Area ratio 5hr / Area ratio 0hr x 100

[0341] Wherein: Area ratio is the ratio of sample peak area to internal standard peak area.

[0342] Table 8

[0343] Results: The plasma protein binding rate of compound 1 is moderate. The same method is used to test other compounds of the application, which shows that the plasma binding rate of the compounds of the application is moderate.

[0344] Test Example 7 hERG inhibition

[0345] Experimental method

[0346] 1 Cell preparation

[0347] 1.1 CHO-hERG cells were cultured in 175cm 2 flasks, and when the cell density grew to 60-80%, the culture solution was removed, washed once with 7mL PBS (Phosphate Buffered Saline), and then 3mL Detachin was added for digestion.

[0348] 1.2 After complete digestion, 7mL culture solution was added for neutralization, then centrifuged, the supernatant was aspirated, 2mL external solution was added, and the cell density was counted to ensure that it was 5x10 5 / mL, and the corresponding amount of external solution was added.

[0349] 2 Solution preparation

[0350] Table 9 Composition of intracellular solution and external solution

[0351] 3 Electrophysiological recording process

[0352] The single cell high impedance seal and whole cell mode formation were all done automatically by the SyncroPatch 384 instrument. After obtaining the whole cell recording mode, the cell was clamped at -80 mV, before giving a 2 second +40 mV depolarization stimulus, a 50 ms -50 mV prepulse was given, then repolarized to -50 mV for 1 second, and back to -80 mV. This voltage stimulus was applied every 10 seconds, recording for 1 minute, then the extracellular solution was recorded for 3 minutes, then the drug administration process started, with the compound concentration starting from the lowest test concentration, each test concentration was given for 3 minutes, after all the concentrations were given continuously, the positive control compound 1 μM Cisapride was given. At least 2 cells were tested for each concentration (n≥2).

[0353] 4 Preparation of the test compound

[0354] 4.1 The test compound was prepared into a 12 mM stock solution with DMSO.

[0355] 4.2 On the day of detection, 30 μL of the compound stock solution was added to the 96-well plate; then the automated liquid workstation Bravo was used for dilution processing, first 10 μL of the compound stock solution was added to 20 μL of DMSO solution for 3-fold serial dilution, and 3-fold serial dilution was performed to 6 intermediate concentrations of DMSO; then 2 μL of the 6 intermediate concentrations of DMSO was added to 298 μL of extracellular solution, and 150-fold dilution was performed to the final test concentration; finally, 60 μL was transferred to the 384-well plate for machine detection.

[0356] 4.3 The highest test concentration of the test compound was 40.00 μM, and the concentrations were 40.00, 13.33, 4.44, 1.48, 0.49, and 0.16 μM, respectively.

[0357] 4.4 The DMSO content in the final test concentration was not more than 0.67%, and the DMSO at this concentration had no effect on the hERG potassium channel.

[0358] Experimental results: hERG IC of compound 1 50 was 48 uM, and there was no obvious inhibition. Other compounds of the application were tested by the same method, and it was shown that the compounds of the application had weak inhibition on hERG.

[0359] Test example 8: liver microsomal half-life

[0360] Experimental method: 1 μM compound was incubated with microsomal protein (0.5 mg / mL) containing 1 mM NAPDH at 37°C for 0, 5, 15, 30, 45, and 60 minutes, respectively, then the reaction system was quenched with ice acetonitrile containing an internal standard, the remaining compound proportion was tested by LC-MS / MS, and the compound half-life was calculated

[0361] Experimental results: The compounds of the present application are stable to liver microsomal metabolism.

[0362] Table 10

[0363] Test Example 9 Human microsomal CYP enzyme inhibition

[0364] Experimental method: Standard inhibitors (see table below) or test compounds (0.05, 0.15, 0.5, 1.5, 5, 15, 50 μM) were pre-incubated with human liver microsomes (1 mg / mL) containing a probe substrate (see table below) at 37 °C for 10 min, then NADPH (1 mM) was added to initiate the catalytic reaction and incubated for a specific time (see table below), and the reaction system was quenched with ice acetonitrile containing an internal standard. The residual amount of probe substrate was tested by LC-MS / MS, and the residual enzyme activity was calculated. The IC50values were fitted by SigmaPlot or XLfit. 50 .

[0365] Table 11

[0366] Experimental results: Compound 1 has no significant inhibitory effect on human CYP enzymes. Other compounds of the present application were tested by the same method, and it was shown that the compounds of the present application have weak inhibitory effects on the main subtypes of CYP.

[0367] Table 12

Claims

1. A compound of Formula I, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is heterocyclyl, heterocyclenyl or heteroaryl; R1, R2, R3, R4, R5, and R6are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -SF5, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl; R 1.1 selected from hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocyclyl; R 1.2 and R 1.3 each independently is selected from hydrogen, alkyl, cycloalkyl or heterocyclyl; R7, R8, R9, R 10 R 12 and R 13 Each group is independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, ynyl, haloalkyl, -OR 1.1 -SR 1.1 -C(O)R 1.1 -C(O)OR 1.1 -OC(O)R 1.1 -OC(O)OR 1.1 -N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 -C(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 -OC(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 -S(O)2R 1.2 -S(O)2N(R) 1.2 R 1.3 ), alkylcycloalkyl, alkylheterocyclic, cycloalkyl or heterocyclic; R 11 selected from hydrogen, alkyl, cycloalkyl or heterocyclyl; Ring B is selected from heterocyclyl or cycloalkyl, the heterocyclyl including mono-heterocyclyl, bridged-heterocyclyl or spiro-heterocyclyl, the cycloalkyl including mono-cycloalkyl, bridged-cycloalkyl or spiro-cycloalkyl; R 14 each independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR 1.1 , -SR 1.1 , -C(O)R 1.1 , -C(O)OR 1.1 , -OC(O)R 1.1 , -OC(O)OR 1.1 , -N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 , -C(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 , -OC(O)N(R 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 ), -S(O)2R 1.2 , -S(O)2N(R 1.2 R 1.3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl; or, R1, R2, and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl group, or, R2, R3, and the atoms to which they are attached together form a cycloalkenyl or heterocycloalkenyl group; or, R3, R4, and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl group; or, R4, R5, and the atoms to which they are attached together form a cycloalkenyl or heterocycloalkenyl group; or, R5, R6, and the atoms to which they are attached together form a heterocyclyl, cycloalkenyl, or heterocycloalkenyl group; or, R6, R7, R8, R9, R 10 , R 11 , R 12 , and R 13 any two of which, together with the atoms to which they are attached, form a cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl group; said cycloalkyl, heterocyclyl, cycloalkenyl and heterocycloalkenyl groups are optionally substituted by one or more R 1.4 substituents; R 1.4 each independently selected from halogen, oxo, cyano, nitro, alkyl, alkylamine, alkenyl, alkynyl, haloalkyl, -OR c1 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c2 R c3 ), -N(R c2 )C(O)R c1 , -C(O)N(R c2 R c3 ), -N(R c2 )C(O)OR c1 , -OC(O)N(R c2 R c3 ), -N(R c2 )C(O)N(R c2 R c3 ), -S(O)2R c2 , -S(O)2N(R c2 R c3 ), alkylcycloalkyl, alkylheterocyclyl, cycloalkyl, or heterocyclyl; R c1 selected from hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocyclyl; R c2 and R c3 each independently is selected from hydrogen, alkyl, cycloalkyl or heterocyclyl; x is 0, 1, 2 or 3; y is 0 or 1; n1 and n2 are each independently 0, 1, 2 or 3.

2. The compound, deuterated form thereof, prodrug thereof, or pharmaceutically acceptable salt thereof of claim 1, wherein The compound of formula (I) is further represented by formula (I-A), formula (I-B), or formula (I-C):

3. The compound, deuterated form, prodrug, or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Alkylamine, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups, -SF5, -OR 1.1 -SR 1.1 -C(O)R 1.1 -C(O)OR 1.1 -OC(O)R 1.1 -OC(O)OR 1.1 -N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 -C(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 -OC(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 -S(O)2R 1.2 -S(O)2N(R) 1.2 R 1.3 C 1-6 Alkyl C 3-6 cycloalkyl, C 1-6 Alkyl 3-6 membered heterocyclic groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; Or, R7, R8, R9, R 10 R 12 and R 13 Each is independently selected from hydrogen, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkylamine, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups, -OR 1.1 -SR 1.1 -C(O)R 1.1 -C(O)OR 1.1 -OC(O)R 1.1 -OC(O)OR 1.1 -N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 -C(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 -OC(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 -S(O)2R 1.2 -S(O)2N(R) 1.2 R 1.3 C 1-6 Alkyl C 3-6 cycloalkyl, C 1-6 Alkyl 3-6 membered heterocyclic groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; or R 11 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; Or, R 14 Each group is independently selected from hydrogen, halogen, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Alkylamine, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups, -OR 1.1 -SR 1.1 -C(O)R 1.1 -C(O)OR 1.1 -OC(O)R 1.1 -OC(O)OR 1.1 -N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)R 1.1 -C(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)OR 1.1 -OC(O)N(R) 1.2 R 1.3 ), -N(R 1.2 )C(O)N(R 1.2 R 1.3 -S(O)2R 1.2 -S(O)2N(R) 1.2 R 1.3 C 1-6 Alkyl C 3-6 cycloalkyl, C 1-6 Alkyl 3-6 membered heterocyclic groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; R 1.1 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; R 1.2 and R 1.3 each independently is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

4. The compound, deuterium isotope, prodrug, or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein R1, R2and the atoms to which they are attached together form C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkenyl or 3-6 membered heterocycloalkenyl; or R2, R3 together with the atoms to which they are attached form C 3-6 cycloalkenyl or 3-6 membered heterocycloalkenyl; or R3, R4 together with the atoms to which they are attached form C 3-6 cycloalkyl or 3-6 membered heterocyclyl; or R4, R5 together with the atoms to which they are attached form C 4-6 cycloalkenyl or 4-6 membered heterocycloalkenyl; or R5, R6and the atoms to which they are attached together form C 3-6 cycloalkenyl or 3-6 membered heterocyclyl; said cycloalkyl, heterocyclyl, cycloalkenyl and heterocycloalkenyl groups are optionally substituted with one or more R 1.4 substituents; R 1.4 each independently selected from the group consisting of halogen, oxo, cyano, nitro, C 1-6 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl-OR 1-6 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c1 )2, -N(R c2 )C(O)R c3 , -C(O)N(R c2 )2, -N(R c1 )C(O)OR c2 , -OC(O)N(R c3 )2, -N(R c2 )C(O)N(R c1 )2, -S(O)2R c2 , -S(O)2N(R c3 )2, C c2 1-6 alkyl, C c2 6 cycloalkyl, C c3 3-6 membered heterocyclyl, C c2 3-6 membered heterocyclyl; and c2 R c3 is selected from the group consisting of H, C 1-6 1-6 alkyl, C 3- 6 cycloalkyl, C 1-6 3-6 membered heterocyclyl, C 3-6 3-6 membered heterocyclyl; and R c1 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; R c2 and R c3 each independently is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

5. The compound, deuterated form, prodrug, or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein R7and R8together with the atom to which they are attached form C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkenyl or 3-6 membered heterocycloalkenyl; or, R9, R 10 with the atom to which it is attached to form C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkenyl or 3-6 membered heterocycloalkenyl; or, R7, R 10 with the atom to which it is attached to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkenyl or 3-6 membered heterocycloalkenyl; or, R7, R 11 with the atom to which it is attached forms a 3-6 membered heterocyclyl or 3-6 membered heterocycloalkenyl; or, R 10 , R 11 with the atom to which it is attached to form a 3-6 membered heterocyclyl or 3-6 membered heterocycloalkenyl; or, R 11 , R 12 with the atom to which it is attached to form a 3-6 membered heterocyclyl or 3-6 membered heterocycloalkenyl; or, R 12 or, R 13 with the atom to which it is attached to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkenyl or 3-6 membered heterocycloalkenyl; said cycloalkyl, heterocyclyl, cycloalkenyl and heterocycloalkenyl groups are optionally substituted with one or more R 1.4 ; R 1.4 each independently selected from the group consisting of halogen, oxo, cyano, nitro, C 1-6 1-6 aliphatic, C 1-6 1-6 aliphatic amine, C 2-6 1-6 alkenyl, C 2-6 1-6 alkynyl, C 1-6 haloalkyl-OR c1 , -SR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -OC(O)OR c1 , -N(R c2 R c3 ), -N(R c2 )C(O)R c1 , -C(O)N(R c2 R c3 ), -N(R c2 )C(O)OR c1 , -OC(O)N(R c2 R c3 ), -N(R c2 )C(O)N(R c2 R c3 ), -S(O)2R c2 , -S(O)2N(R c2 R c3 ), C 1-6 1-6 aliphatic C 3- 1-6 cycloalkyl, C 1-6 1-6 aliphatic 3-6 membered heterocyclyl, C 3-6 1-6 cycloalkyl or 3-6 membered heterocyclyl; R c1 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; R c2 and R c3 each independently is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

6. The compound, deuterated form, prodrug, or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein which satisfies one or more of the following conditions: (1) the C 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. (2) in the 3-6 membered heterocyclyl, the heteroatom is oxygen, nitrogen or sulfur, and the number of heteroatoms is independently 1 or 2; preferably, the 3-6 membered heterocyclyl is selected from the group consisting of oxiranyl, aziridinyl, oxetanyl, azetidinyl, (3) said C 3-6 cycloalkenyl is selected from (4) in the 3-6 membered heterocycloalkenyl group, the heteroatom is oxygen, nitrogen or sulfur, and the number of heteroatoms is independently 1 or 2; preferably, the 3-6 membered heterocycloalkenyl group is selected from (5) said C 4-6 cycloalkenyl is selected from (6) in the 4-6 membered heterocycloalkenyl group, the heteroatom is oxygen or nitrogen, and the number of heteroatoms is independently 1 or 2; preferably, the 4-6 membered heterocycloalkenyl group is selected from 7. The compound, its deuterated derivative, its prodrug, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein the compound of formula (I) has a structure as shown in formula II: wherein, R2, R3, R4, R6, R7, R9, R 11 , R 14 , x has the same defined range as in claim 1.

8. The compound of claim 7 of formula II, wherein R7, R 11 with the atom to which it is attached to form a 3-6 membered heterocyclyl.

9. The compound of claim 7 of formula II, wherein R9, R 11 with the atom to which it is attached to form a 3-6 membered heterocyclyl.

10. The compound of claim 7 of formula II, wherein R 14 is hydrogen, halogen.

11. A compound of formula II according to claim 7, wherein R2, R3, R4, are selected from hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl.

12. The compound of Formula II according to claim 7, wherein R6, R7, R9 are hydrogen.

13. A compound, deuterated form, prodrug, or pharmaceutically acceptable salt thereof, characterized in that, the compound is selected from the compounds of Table 1.

14. A pharmaceutical composition comprising a compound, deuterium isotope, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1-13; and a pharmaceutically acceptable excipient.

15. Use of a compound, deuterium isotope, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1-13, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for preventing, treating or ameliorating a depressive disorder.

Images