5-HT2A receptor agonist as well as preparation method and application thereof

Abstract

The invention provides a compound which is used as a 5-HT2A receptor agonist and has a brand new structure, a preparation method of the compound and application of the compound in the aspect of treating diseases related to a 5-HT2A receptor. Experiments prove that the compounds have strong affinity to 5-HT2A receptors, and can be used as promising compounds for treating diseases related to the 5-HT2A receptors.

Description

5-HT 2A Receptor agonist and its preparation method and application Technical Field

[0001] The present invention relates to a class of 5-hydroxytryptamine 2A (5-HT 2A ) receptor agonist compounds and preparation methods thereof, and their application in 5-HT 2A Research in the field of receptor-related diseases. Background Art

[0002] Depression is a psychiatric disorder characterized by a significant and persistent low mood, often caused by various factors. It is also the most common psychiatric illness associated with suicide. According to the World Health Organization, in 2015, over 320 million people worldwide suffered from depression. The point-in-time prevalence of depression in China is 3.02%, with over 40 million people currently suffering from depression.

[0003] Serotonin receptors, also known as serotonin receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels that appear in the central nervous system and peripheral nervous system. They regulate the transmission of excitatory and inhibitory neurotransmitters at the same time.

[0004] 5-HT 2A The receptor, which belongs to the 5-HT receptor family, is widely expressed throughout the central nervous system (CNS). It is expressed near most areas rich in serotonergic terminals, including the neocortex (primarily the prefrontal, parietal, and somatosensory cortices) and the olfactory tubercle.

[0005] 5-HT 2A The receptor is primarily coupled to the Gαq signaling pathway. Upon receptor stimulation with an agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways. Gαq stimulates phospholipase C (PLC) activity, subsequently promoting the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulates protein kinase C (PKC) activity and Ca 2+ release.

[0006] In addition to the classic G protein signaling pathway, another currently recognized signaling pathway for GPCRs is the β-arrestin-dependent signaling pathway. Following GPCR activation, a family of protein kinases known as G protein-coupled receptor kinases (GRKs) phosphorylate the intracellular domain of the released G protein. Phosphorylated GPCRs recruit β-arrestin, which mediates desensitization of GPCR signaling and endocytosis, thereby "turning off" signaling and resulting in negative feedback for G protein-dependent GPCR signaling.

[0007] Psilocybin, currently in Phase III clinical trials, has rapid, significant, and long-lasting antidepressant effects, but it also has strong hallucinogenic effects.

[0008] Therefore, the development of new 5-HT 2A Receptor agonists are urgently needed, especially small molecules such as 5-HT 2A Receptor partial agonist.

[0009] Summary of the Invention

[0010] The present invention provides a 5-HT 2A The invention relates to a compound with receptor agonist activity, and a pharmaceutical composition containing the compound for treating central nervous system diseases, and further provides a therapeutic use of the compound for central nervous system diseases.

[0011] The first aspect of the present invention provides a compound represented by the following formula (I), or its stereoisomers, pharmaceutically acceptable salts thereof, or mixtures thereof:

[0012] in,

[0013] Indicates a single bond or a double bond, with one and only one double bond;

[0014] X1 is selected from N, CR X1 ; X2 is selected from N, CR X2 ; X3 is selected from N, CR X3 ; X4 is selected from N, CR X4 ;

[0015] And X1, X2, X3, and X4 are not N at the same time;

[0016] Y1 is selected from O, S, NR Y11 , CR Y12

[0017] Y2 is selected from N, CR Y22 ;

[0018] Y3 is selected from N, C;

[0019] When Y3 is N, there is a single bond between Y3 and Y2; when Y3 is C, there is a double bond between Y3 and Y2;

[0020] R X1 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0021] R X2 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0022] R X3 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0023] R X4 is selected from hydrogen, deuterium, halogen, or optionally substituted C 1-4 Alkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0024] R Y11 is selected from hydrogen, deuterium, optionally substituted C 1-3 Alkyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0025] R Y12 is selected from hydrogen, deuterium, optionally substituted C 1-3 Alkyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0026] R Y22 is selected from hydrogen, deuterium, halogen, optionally substituted C 1-3 Alkyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0027] L is -Z-L'-, -L'-Z-, -L'-Z-L'-;

[0028] L' is selected from the group consisting of: -C 1-4Alkylene-, -C 1-4 Oxyalkylene-, -C 1-4 Thiaalkylene-, -C 1-4 Azaalkylene-, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 substituted by a haloalkoxy substituent;

[0029] Z is optionally replaced by a R A Substituted: 4-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl; wherein each R A independently selected from deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 substituted by a haloalkoxy substituent;

[0030] Ring B is C 6-14 Aryl, 5-16 membered heterocyclyl, 5-16 membered heteroaryl;

[0031] Each R B independently selected from deuterium, halogen, -OH, -CN, -NH2, oxo, optionally substituted with: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Oxaalkyl, C 1-4 Thiaalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 substituted by a haloalkyl substituent;

[0032] a is selected from 0, 1, 2, 3;

[0033] b is selected from 0, 1, 2, 3, 4;

[0034] Unless otherwise specified, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0035] The condition is that Z is not When Y1 is NH and X4 is N, L is not

[0036] In a preferred embodiment of the present invention, X1, X2, X3, and X4 are not N;

[0037] In a preferred embodiment of the present invention, X1 is N, X2 is CR X2 , X3 is CR X3 , X4 is CR X4 ;

[0038] In a preferred embodiment of the present invention, X2 is N, X1 is CR X1 , X3 is CR X3 , X4 is CR X4 ;

[0039] In a preferred embodiment of the present invention, X3 is N, X1 is CR X1 , X2 is CR X2 , X4 is CR X4 ;

[0040] In a preferred embodiment of the present invention, X4 is N, X1 is CR X1 , X2 is CR X2 , X3 is CR X3 ;

[0041] In a preferred embodiment of the present invention, X2 and X4 are N, and X1 is CR X1 , X3 is CR X3 ;

[0042] In a preferred embodiment of the present invention, X1 and X3 are N, X2 is CR X2 , X4 is CR X4 ;

[0043] In a preferred embodiment of the present invention, Y1 is CR Y12 , Y2 is CR Y22 , Y3 is N;

[0044] In a preferred embodiment of the present invention, Y1 is NR Y11 , Y2 is selected from N or CR Y22 , Y3 is C;

[0045] In a preferred embodiment of the present invention, Y1 is NR Y11 , Y2 is selected from CR Y22 , Y3 is C;

[0046] In a preferred embodiment of the present invention, Y1 is O, Y2 is N, and Y3 is C;

[0047] In a preferred embodiment of the present invention, R X1is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Oxaalkyl, C 1-4 Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0048] In a preferred embodiment of the present invention, R X1 is selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH2, or optionally substituted from the following groups: methoxy, ethoxy, methylthio; wherein optionally substituted means unsubstituted or substituted with one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0049] In a preferred embodiment of the present invention, R X1 Selected from hydrogen, -F, -OH, -OCH3.

[0050] In a preferred embodiment of the present invention, R X2 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Oxaalkyl, C 1-4 Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0051] In a preferred embodiment of the present invention, R X2 is selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH2, or optionally substituted from the following groups: methoxy, ethoxy, methylthio; wherein optionally substituted means unsubstituted or substituted with one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0052] In a preferred embodiment of the present invention, R X2 Selected from hydrogen, -F, -OCH3;

[0053] In a preferred embodiment of the present invention, R X2 Selected from hydrogen.

[0054] In a preferred embodiment of the present invention, R X3 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Oxaalkyl, C 1-4 Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0055] In a preferred embodiment of the present invention, R X3 is selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH2, or optionally substituted from the following groups: methoxy, ethoxy, methylthio; wherein optionally substituted means unsubstituted or substituted with one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0056] In a preferred embodiment of the present invention, R X3 Selected from hydrogen, -F, -OCH3;

[0057] In a preferred embodiment of the present invention, R X3 Selected from hydrogen.

[0058] In a preferred embodiment of the present invention, R X4 is selected from hydrogen, deuterium, halogen, or optionally substituted groups: methyl, ethyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0059] In a preferred embodiment of the present invention, R X4 Selected from hydrogen, deuterium, -F, -Cl, -Br;

[0060] In a preferred embodiment of the present invention, R X4 Selected from hydrogen.

[0061] In a preferred embodiment of the present invention, R Y11 is selected from the group consisting of hydrogen, deuterium, optionally substituted methyl, ethyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, -CN, -OH, -NH2;

[0062] In a preferred embodiment of the present invention, R Y11 is selected from hydrogen, methyl;

[0063] In a preferred embodiment of the present invention, R Y11 Selected from hydrogen.

[0064] In a preferred embodiment of the present invention, R Y22 is selected from the group consisting of hydrogen, deuterium, -F, -Cl, -Br, optionally substituted groups: methyl, ethyl, wherein optionally substituted means unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, halogen, oxo, -CN, -OH, -NH2;

[0065] In a preferred embodiment of the present invention, R Y22 is selected from hydrogen, -Br, methyl;

[0066] In a preferred embodiment of the present invention, R Y22 Selected from hydrogen.

[0067] In a preferred embodiment of the present invention, L' is an optionally substituted group: -C 1-4 Alkylene-, -C 1-4 Oxyalkylene-; wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 substituted by a haloalkyl substituent;

[0068] In a preferred embodiment of the present invention, L' is an optionally substituted group: -C 1-3 Alkylene-, -C 1-3 Oxyalkylene-; wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 substituted by a haloalkyl substituent;

[0069] In a preferred embodiment of the present invention, L' is an optionally substituted group: -C 1-3 Alkylene-, -C 1-3 Oxoalkylene-; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, methyl, methoxy, -CF3;

[0070] In a preferred embodiment of the present invention, L' is ** is the B-ring attachment site; * is the Z-ring attachment site;

[0071] In a preferred embodiment of the present invention, Z is optionally substituted by a R A Substituted: 4-10 membered heterocyclyl, 4-10 membered heterocycloalkenyl; wherein R A Selected from deuterium, halogen, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 alkoxy;

[0072] In a preferred embodiment of the present invention, Z is optionally substituted by a R A Substituted: 4-10 membered heterocyclyl, 4-10 membered heterocycloalkenyl; wherein R A Selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C1-3 Alkyl, halogenated C 1-3 alkoxy;

[0073] In a preferred embodiment of the present invention, Z is optionally substituted by a R A Substituted: 4-8 membered heterocyclic group, 4-8 membered heterocycloalkenyl group; wherein R A Selected from deuterium, F, Cl, methyl, ethyl, methoxy, -CH2F, -CHF2, -CF3;

[0074] In a preferred embodiment of the present invention, Z is

[0075] In a preferred embodiment of the present invention, Z is optionally substituted by a R A Replaces: * is connected to the L' end;

[0076] In a preferred embodiment of the present invention, L is

[0077] ** is the B-ring attachment site.

[0078] In a preferred embodiment of the present invention, ring B is phenyl, 5-12 membered heterocyclyl, 5-12 membered heteroaryl;

[0079] In a preferred embodiment of the present invention, ring B is phenyl, 5-6 membered monocyclic heteroaryl, 8-12 membered bicyclic heterocyclyl, 8-12 membered bicyclic heteroaryl;

[0080] In a preferred embodiment of the present invention, ring B is phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heterocyclyl, 8-10 membered bicyclic heteroaryl;

[0081] In a preferred embodiment of the present invention, ring B is phenyl, 5-membered monocyclic heteroaryl;

[0082] In a preferred embodiment of the present invention, Ring B is

[0083] In a preferred embodiment of the present invention, Ring B is In a preferred embodiment of the present invention, Ring B is

[0084] In a preferred embodiment of the present invention, each R B independently selected from deuterium, halogen, -OH, -CN, -NH2, oxo, optionally substituted with: C1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thiaalkyl, C 3-6 Cycloalkyl, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 substituted by a haloalkyl substituent;

[0085] In a preferred embodiment of the present invention, each R B independently selected from deuterium, halogen, -CN, -NH2, oxo, optionally substituted: C 1-3 Alkyl, C 1-3 Oxaalkyl, C 3-6 Cycloalkyl, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 substituted by a haloalkyl substituent;

[0086] In a preferred embodiment of the present invention, each R B independently selected from deuterium, F, Cl, Br, -CN, -NH2, oxo, optionally substituted with methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropane, cyclobutane, cyclopentane, cyclohexane, wherein optionally substituted means unsubstituted or substituted with one or more selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 substituted by a haloalkyl substituent;

[0087] In a preferred embodiment of the present invention, each R B Independently selected from F, CN, oxo, methyl, cyclopropane, cyclobutane, methoxy, trifluoromethyl,

[0088] In a preferred embodiment of the present invention, b is selected from 0, 1, 2, 3;

[0089] In a preferred embodiment of the present invention, b is selected from 0, 1, 2;

[0090] In a preferred embodiment of the present invention, a is selected from 0, 1, 2;

[0091] In a preferred embodiment of the present invention, a is selected from 0, 1;

[0092] In a preferred embodiment of the present invention, a is selected from 0;

[0093] In a preferred embodiment of the present invention, Selected from

[0094] The present invention also provides a compound represented by the following formula (II), or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof:

[0095] Among them, X1, X2, X3, X4, Y1, Y2, Y3, L', Ring B, R B 、R A , a, b are as described for the compound of formula (I);

[0096] W is -CH2-, -O-, -S-, or -N-;

[0097] Each R A independently selected from deuterium, halogen, -OH, oxo, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 substituted by an alkoxy substituent;

[0098] m is selected from 0, 1, 2, and 3.

[0099] In a preferred embodiment of the present invention, W is -CH2-, -O-, or -S-;

[0100] In a preferred embodiment of the present invention, W is -CH2-, -O-;

[0101] In a preferred embodiment of the present invention, W is -CH2-.

[0102] In a preferred embodiment of the present invention, each R A independently selected from deuterium, halogen, -OH, -CN, -NH2, Cl -3 Alkyl, C 1-3 Oxaalkyl;

[0103] In a preferred embodiment of the present invention, each R A independently selected from deuterium, halogen, C 1-3 alkyl;

[0104] In a preferred embodiment of the present invention, each R A Independently selected from F, methyl.

[0105] In a preferred embodiment of the present invention, Ring B is

[0106] In a preferred embodiment of the present invention, m is selected from 0;

[0107] In a preferred embodiment of the present invention, m is selected from 3;

[0108] In a preferred embodiment of the present invention, m is selected from 2;

[0109] In a preferred embodiment of the present invention, m is selected from 1.

[0110] In a preferred embodiment of the present invention, a is selected from 0, 1, 2;

[0111] In a preferred embodiment of the present invention, a is selected from 0;

[0112] In a preferred embodiment of the present invention, a is selected from 1.

[0113] The present invention also provides a compound represented by the following formula (III-1) to (III-8), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof:

[0114] Among them, L', ring B, R B ,b,W,R A , a, m are as described for the compounds of formula (I) and (II);

[0115] R is selected from deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0116] n is 0, 1, 2, or 3.

[0117] In a preferred embodiment of the present invention, W is -CH2-, and m is 1;

[0118] In a preferred embodiment of the present invention, R is selected from deuterium, -OH, F, Cl, Br, methyl, methoxy;

[0119] In a preferred embodiment of the present invention, R is selected from F;

[0120] In a preferred embodiment of the present invention, R is selected from -OH;

[0121] In a preferred embodiment of the present invention, n is 0, 1, or 2;

[0122] In a preferred embodiment of the present invention, n is 0;

[0123] In a preferred embodiment of the present invention, n is 1;

[0124] In a preferred embodiment of the present invention, in formula (III-2) for

[0125] The present invention also provides compounds represented by the following formulas (A1) to (A16), or stereoisomers thereof, pharmaceutically acceptable salts thereof, or mixtures thereof:

[0126] Among them, L', ring B, R B ,b,R A , a is as described for the compounds of formula (I), (II), (III-1) to (III-8);

[0127] In a preferred embodiment of the present invention, ring B is phenyl, 5-membered monocyclic heteroaryl;

[0128] In a preferred embodiment of the present invention, Ring B is

[0129] In a preferred embodiment of the present invention, L' is ** is the B-ring attachment site; * is the Z-ring attachment site.

[0130] The present invention also provides a compound represented by the following formula (a), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof:

[0131] Among them, R, L', ring B, R A 、R B , n, a, b are as described for the compounds of formula (I), (II), and (III-2);

[0132] In a preferred embodiment of the present invention, R is selected from -OH, methoxy;

[0133] In a preferred embodiment of the present invention, L' is selected from the group consisting of the optionally substituted: -C 3-4 Alkylene-, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3substituted by a haloalkoxy substituent;

[0134] In a preferred embodiment of the present invention, L' is selected from the group consisting of the optionally substituted following groups: -propylene-;

[0135] In a preferred embodiment of the present invention, ring B is C 6-10 Aryl, 5-10 membered heteroaryl;

[0136] In a preferred embodiment of the present invention, ring B is phenyl, or ring B is phenyl, For example

[0137] In a preferred embodiment of the present invention, each R A independently selected from deuterium, halogen, -OH, -CN, -NH2, Cl -3 Alkyl, C 1-3 alkoxy;

[0138] In a preferred embodiment of the present invention, each R A Independently selected from deuterium, F, Cl, -OH, CN, -NH2, methyl, ethyl, methoxy, ethoxy;

[0139] In a preferred embodiment of the present invention, each R B independently selected from deuterium, optionally substituted by: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thiaalkyl, C 3-6 Cycloalkyl, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, -OH, -NH2, C 1-4 substituted by an alkyl substituent;

[0140] In a preferred embodiment of the present invention, each R B independently selected from methyl, methoxy;

[0141] In a preferred embodiment of the present invention, n is 0;

[0142] In a preferred embodiment of the present invention, n is 1;

[0143] In a preferred embodiment of the present invention, a is selected from 0, 1;

[0144] In a preferred embodiment of the present invention, a is selected from 0;

[0145] In a preferred embodiment of the present invention, b is selected from 0, 1, 2;

[0146] In a preferred embodiment of the present invention, b is selected from 0;

[0147] In a preferred embodiment of the present invention, b is selected from 1.

[0148] The present invention also provides a compound represented by the following formula (b), or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof:

[0149] Among them, R, L', ring B, R A 、R B , a, and b are as described for the compound of formula (a).

[0150] The present invention also provides a compound represented by the following formula (c), or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof:

[0151] Among them, R, L', R A 、R B , m, n, a, b are as described for the compounds of formula (I), (II), and (III-2);

[0152] w1, w2, w3, w4 are independently selected from CH, N;

[0153] W is -CH, -CH2-, -O-, -S-;

[0154] represents a single bond or a double bond, but not both; when When it is a double bond, W is -CH-;

[0155] In a preferred embodiment of the present invention, R is selected from deuterium, F, Cl, -OH, -CN, -NH2, or the following optionally substituted groups: C 1-3 Alkyl, C 1-3 Oxaalkyl, C 1-3 Thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0156] In a preferred embodiment of the present invention, R is selected from F, -OH;

[0157] In a preferred embodiment of the present invention, L' is selected from the following optionally substituted groups: -propylene-, wherein optionally substituted means unsubstituted or substituted with one or more radicals selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 substituted by an alkoxy substituent;

[0158] In a preferred embodiment of the present invention, L' is selected from: -propylene-;

[0159] In a preferred embodiment of the present invention, each R B independently selected from deuterium, optionally substituted by: C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Oxaalkyl, C 1-3 Thiaalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 substituted by a haloalkyl substituent;

[0160] In a preferred embodiment of the present invention, each R B independently selected from methyl, isopropyl, cyclopropyl;

[0161] In a preferred embodiment of the present invention, w1, w2, w3, and w4 are selected from N;

[0162] In a preferred embodiment of the present invention, w1 and w4 are selected from N, w2 and w3 are selected from CH;

[0163] In a preferred embodiment of the present invention, w1 and w3 are selected from N, w2 and w4 are selected from CH;

[0164] In a preferred embodiment of the present invention, n is 0, 1, or 2;

[0165] In a preferred embodiment of the present invention, n is 0;

[0166] In a preferred embodiment of the present invention, n is 1;

[0167] In a preferred embodiment of the present invention, a is selected from 0, 1;

[0168] In a preferred embodiment of the present invention, a is selected from 1;

[0169] In a preferred embodiment of the present invention, b is selected from 0, 1;

[0170] In a preferred embodiment of the present invention, b is selected from 1;

[0171] In a preferred embodiment of the present invention, All are single bonds, W is -CH2-;

[0172] In a preferred embodiment of the present invention, m is 1;

[0173] In a preferred embodiment of the present invention, m is 2.

[0174] The present invention also provides a compound represented by the following formula (d), or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof:

[0175] Among them, R, L', ring B, R A 、R B , a, and b are as described for the compound of formula (c).

[0176] The present invention also provides a compound represented by the following formula (e), or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof:

[0177] Among them, R X1 、R X3 、R Y22 , L', Ring B, R A 、R B , a, b are as described for the compounds of formula (I), (II), and (III-2);

[0178] In a preferred embodiment of the present invention, R X1 Selected from hydrogen, -F, -OH, -OCH3;

[0179] In a preferred embodiment of the present invention, R X1 Selected from -OH;

[0180] In a preferred embodiment of the present invention, R X3 Selected from hydrogen, -F, -OCH3;

[0181] In a preferred embodiment of the present invention, R Y22 is selected from hydrogen, -Br, methyl;

[0182] In a preferred embodiment of the present invention, L' is

[0183] In a preferred embodiment of the present invention, ring B is C 6-10 Aryl, 5-membered nitrogen-containing heteroaryl or 9-membered heteroaryl;

[0184] In a preferred embodiment of the present invention, ring B is a phenyl group, a 5-membered nitrogen-containing heteroaryl group or a 9-membered heteroaryl group; the 5-membered nitrogen-containing heteroaryl group contains at least one N atom and, optionally, may further contain one O atom or an S atom; the 9-membered heteroaryl group contains one, two or three heteroatoms selected from N, O or S;

[0185] In a preferred embodiment of the present invention, ring B is a phenyl group, a 5-membered nitrogen-containing heteroaryl group or a 9-membered heteroaryl group; the 5-membered nitrogen-containing heteroaryl group contains 1, 2 or 3 N atoms, and optionally, may further contain 1 O atom or S atom; the 9-membered heteroaryl group contains 1, 2 or 3 heteroatoms, and the heteroatoms are selected from N, O or S;

[0186] In a preferred embodiment of the present invention, ring B is a phenyl group, a 5-membered nitrogen-containing heteroaryl group, or a 9-membered heteroaryl group; the 5-membered nitrogen-containing heteroaryl group contains 1, 2, or 3 N atoms, and optionally, may further contain 1 O atom or S atom; the 9-membered heteroaryl group contains 1, 2, or 3 heteroatoms, and the heteroatoms are selected from N, O, or S; and the connection site between ring B and L' is a C atom or a N atom;

[0187] In a preferred embodiment of the present invention, ring B is phenyl,

[0188] In a preferred embodiment of the present invention, each R B independently selected from methyl, methoxy, cyclopropyl;

[0189] In a preferred embodiment of the present invention, each R A independently selected from methyl;

[0190] In a preferred embodiment of the present invention, a is selected from 0, 1;

[0191] In a preferred embodiment of the present invention, a is selected from 0;

[0192] In a preferred embodiment of the present invention, b is selected from 0, 1;

[0193] In a preferred embodiment of the present invention, b is selected from 0;

[0194] In a preferred embodiment of the present invention, b is selected from 1.

[0195] The above preferred solutions can be combined arbitrarily.

[0196] The present invention also provides Compound 1-189, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof. Examples of the preparation of Compound 1-189 are provided below. The structural formula of Compound 1-189 is listed in the accompanying claims.

[0197] The present invention also aims to provide a method for preparing the above-mentioned compound, or its stereoisomer, its pharmaceutically acceptable salt, or its mixture.

[0198] These include but are not limited to the following methods:

[0199] General preparation method 1:

[0200] General preparation method 2:

[0201] General preparation method three:

[0202] General preparation method 4:

[0203] Wherein, in the above preparation method, R is a protecting group; X is H or halogen; R, R B , Ring B, L, n, and b are as defined above.

[0204] The present invention also provides a pharmaceutical composition comprising compounds represented by formula (I), (II), (III-1) to (III-8), (A1) to (A16), (a) to (e) of the present invention, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or mixtures thereof, optionally further comprising a pharmaceutically acceptable carrier. In the pharmaceutical composition of the present invention, the compound, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof may account for 0.1-99.9, 1-99, 10-90, 20-80, 30-70, 40-60, 45-55, 1-5, 5-8, 8-10, 10-20, or 20-30 weight %, based on the weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier may account for 99.9-0.1, 99-1, 90-10, 80-20, 70-30, 60-40, 55-45, 99-95, 95-92, 92-90, 90-80, or 80-70 weight %.

[0205] The present invention also aims to provide compounds of formula (I), (II), (III-1) to (III-8), (A1) to (A16), (a) to (e) of the present invention, or their stereoisomers, pharmaceutically acceptable salts, or mixtures thereof, or the pharmaceutical compositions thereof for use in the preparation of 5-HT. 2A Receptor agonists, especially 5-HT 2A The use of a partial agonist of a receptor in a drug, preferably, the drug is a drug for treating central nervous system diseases, preferably, the drug is a drug for treating depression.

[0206] The present invention also aims to provide the use of compounds represented by formula (I), (II), (III-1) to (III-8), (A1) to (A16), (a) to (e) of the present invention, or their stereoisomers, pharmaceutically acceptable salts, or mixtures thereof, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating central nervous system diseases, preferably depression.

[0207] The present invention also aims to provide compounds represented by formula (I), (II), (III-1) to (III-8), (A1) to (A16), (a) to (e) of the present invention, or their stereoisomers, pharmaceutically acceptable salts, or mixtures thereof, or pharmaceutical compositions thereof, for use in treating central nervous system diseases, preferably depression.

[0208] The present invention provides a method for treating central nervous system diseases, preferably depression, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I), (II), (III-1) to (III-8), (A1) to (A16), (a) to (e) of the present invention, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, or the above-mentioned pharmaceutical composition.

[0209] definition

[0210] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 alkyl), more preferably containing 1 to 4 carbon atoms (i.e., C 1-4 Alkyl), more preferably containing 1-3 carbon atoms (ie C 1-3 Alkyl), such as "C 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0211] "Alkyl" substituted by halogen refers to "haloalkyl", such as C 1-6 Alkyl substituted by halogen means C 1-6 Halogenated alkyl or halogenated C 1-6 alkyl.

[0212] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0213] Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 alkenyl), further preferably containing 2 to 8 carbon atoms (C 2-8 alkenyl), more preferably containing 2 to 6 carbon atoms (ie, C 2-6 alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl), 2-4 carbon atoms (ie C 2-4 alkenyl), 2-3 carbon atoms (ie C 2-3 alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example, "C 2-6 The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl.

[0214] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl), more preferably containing 2-6 carbon atoms (ie, C 2-6 Alkynyl), 2-5 carbon atoms (ie C 2-5 Alkynyl), 2-4 carbon atoms (ie C 2-4 Alkynyl), 2-3 carbon atoms (ie C 2-3 alkynyl), 2 carbon atoms (i.e., C2 alkynyl), for example, "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.

[0215] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0216] Unless otherwise specified, the term "oxaalkyl" refers to an alkyl residue in which one or more carbon atoms (and their associated hydrogen atoms) are replaced by oxygen, such as "alkoxy" and "alkoxyalkyl". Examples include methoxy, ethoxy, propoxy, methoxypropyl, and the like. The term oxaalkyl is understood in the art [see Nomenclature and Indexing of Chemical Substances for Chemical Extraction, published by the American Chemical Society, 196, but not limited to 127(a)], i.e., it refers to compounds in which an oxygen atom is bonded to its adjacent atom by a single bond (forming an ether bond); it does not refer to the double-bonded oxygen found in a carbonyl group.

[0217] Unless otherwise specified, the terms "thiaalkyl" and "azaalkyl" refer to groups in which the oxygen in the above "oxaalkyl" is replaced by sulfur or NH.

[0218] Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0219] Unless otherwise specified, the term "fused heterocyclic group" or "fused heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, wherein one ring does not have an aromatic system of completely conjugated π electrons. Preferably, the fused heterocyclic group is 6 to 14 members, preferably 7 to 12 members and more preferably 7 to 10 members. Depending on the number of member rings, the fused heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5 / 5 member, 5 / 6 member, 6 / 5 member, 4 / 6 member, 6 / 4 member or 6 / 6 member bicyclic fused heterocyclic group. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl or isoindolin-5-yl), octahydro-benzo[b][1,4]dioxin, dihydropyridoxazinyl (e.g., 2,3-dihydro-1H -pyrido[2,3-b][1,4]oxazinyl) or dihydrobenzoxazepinyl (e.g., 5-oxo-3,4-dihydrobenzo[f][1,4]oxazepinyl), benzoxazepinyl (e.g., 2,3,4,5-tetrahydro-1-oxo-2-benzoxazepin-6-yl), benzoxazepinyl (e.g., 5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl), dihydroisoquinolinyl (e.g., 1-oxo-2-methyl-3,4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (e.g., 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl), dihydrobenzoxazine (e.g., 3,4-dihydro-2H-1,4-benzoxazin-6-yl), benzopiperazinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 5,8-dihydro- 6H-pyrano[3,4-b]pyridinyl, 7,8-dihydro-5H-thiopyrano[4,3-b]pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydro-1,7-naphthyridinyl, 7,8-dihydro-5H-pyrano[4,3-d]pyridine, 3,4-dihydro-1H-pyrano[4,3-c]pyridine, 2H-1-benzopyranyl or 4H-1-benzopyranyl.

[0220] Unless otherwise specified, the term "heterocycloalkenyl" refers to a cycloalkenyl group containing 1 to 5 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heterocycloalkenyl group can be a monocyclic, bicyclic or polycyclic ring system (including cyclic, spirocyclic, bridged rings, etc.). Generally, the heterocycloalkenyl group usually includes 4-12 ring atoms (i.e., 4 to 12 membered heterocycloalkyls), preferably, includes 4-10 (e.g., 4, 5, 6, 7, 8) ring atoms (i.e., 4 to 7 membered heterocyclyls, or 4 to 6 membered heterocyclyls) and contains 1, 2, 3 or 4 (preferably 1 or 2) heteroatoms.

[0221] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0222] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic or polycyclic ring system containing a 5-16 membered structure, or a 5-14 membered structure, a 5-12 membered structure, a 5-10 membered structure, a 5-8 membered structure, or a 5-6 membered structure, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl groups can include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0223] Unless otherwise specified, the term "fused heteroaryl" refers to an unsaturated aromatic fused ring structure containing 5-14 ring atoms (including at least one heteroatom), which is formed by two or more cyclic structures sharing two adjacent atoms, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Preferably, it is a 5-12 membered fused heteroaryl, a 7-12 membered fused heteroaryl, a 9-12 membered fused heteroaryl, etc., more preferably a 5-membered / 5-membered fused heteroaryl, a 5-membered / 6-membered fused heteroaryl, a 6-membered / 5-membered fused heteroaryl, or a 6-membered / 6-membered bicyclic fused heteroaryl. Examples of fused heteroaryl groups can include, but are not limited to, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenolazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, and the like.

[0224] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0225] The compounds of the present invention also include their isotopic derivatives. Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically labeled or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0226] The compounds of the present invention also include solvates or solvates thereof. Unless otherwise specified, the terms "solvate" and "solvate" refer to the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0227] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0228] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0229] The compounds of the present invention also include co-crystals thereof. Unless otherwise specified, the term "co-crystal" is used to describe a situation in which the neutral molecular components are present in a crystalline compound in a well-defined stoichiometric ratio. The preparation of pharmaceutically acceptable co-crystals enables the crystalline form of the active pharmaceutical ingredient to be altered, which in turn can alter its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters and L. Quere, RSC Publishing, 2012).

[0230] The compounds of the present invention also include their polymorphs. Unless otherwise specified, the term "polymorph" refers to the different arrangements of chemical drug molecules, generally manifesting as the solid state forms of the drug substance. A drug can exist in multiple crystalline forms. Different crystalline forms of the same drug may dissolve and be absorbed differently in the body, thus affecting the dissolution and release of the formulation.

[0231] The compounds of the present invention also include their metabolites. Unless otherwise specified, the term "metabolite" refers to products resulting from the in vivo metabolism of a specific compound or its salt. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of the compounds, including metabolites produced by contacting the compounds of the present invention with a mammal for a sufficient period of time.

[0232] The compounds of the present invention also include prodrugs thereof. Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are often related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they may be bioavailable orally, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example, but not limited to, of a prodrug is any compound of the present invention administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug is a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0233] Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable site of the group is not replaced or is replaced by one or more substituents, the substituents being preferably selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 The aryl or 5-10 membered heteroaromatic ring group may be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by one or more substituents, and the oxo group means that two H groups at the same substitution position are replaced by the same O group to form a double bond. "Multiple" means 2, 3, 4, 5, 6, 7, 8, preferably 2, 3, 4.

[0234] Unless otherwise specified, the term "pharmaceutically acceptable carrier" refers to a medium generally recognized in the art for delivering biologically active agents to animals, specifically mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors that are well within the purview of those of ordinary skill in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers may include many different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for various reasons well known to those of ordinary skill in the art (e.g., stabilization of the active agent, binders, etc.). Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection are found in a variety of readily available resources.

[0235] The above technical features of the present invention can be combined arbitrarily, and the implementation schemes obtained by the combination also belong to the implementation schemes of the present invention.

[0236] Beneficial effects of the present invention

[0237] Through extensive research, the present invention has obtained a novel structure of 5-HT 2AReceptor agonists, particularly 5-HT 2A Receptor partial agonist. In vitro and in vivo tests have shown that the compound of the present application has excellent antidepressant effect. On this basis, it can achieve a non-hallucinogenic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0238] Figure 1 Evaluation of the efficacy of the compounds of the present invention in the mouse head-shake model

[0239] Figure 2 Evaluation of the efficacy of the compounds of the present invention in a mouse depression model DETAILED DESCRIPTION

[0240] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0241] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements were performed using a Bruker 400 MHz and / or a Varian 400 MHz instrument; LC-MS measurements were performed using an Agilent 1260 Infinity II-6120 / 6125MSD instrument; and HPLC measurements were performed using a Waters Acquity UPLC 2 and / or a Shimadzu LC2030 and / or an Agilent 1260 Infinity II instrument. Chiral compound separations were performed using an SFC-150 (Waters) instrument and a DAICEL column. Column volume: 20×250 mm (10 μm particle size packing).

[0242] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0243] The present invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0244] In the following examples, the abbreviations have the following meanings:

[0245] Example 1 (Compound 1)

[0246] Preparation of 3-(1-(2-(2-methoxyphenyl)ethyl)pyrrolidin-3-yl)-1H-indol-4-ol:

[0247] Step 1: Preparation of 3-(4-(Benzyloxy)-1H-indol-3-yl)pyrrolidine-2,5-dione: Pyrrolidine-2,5-dione (2 eq) and 4-benzyloxy-1H-indole (4.5 g, 1 eq) were added to acetic acid (100 mL) and stirred at 125°C for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (4.18 g).

[0248] LCMS (ESI) [M+H] + =321.4.

[0249] Step 2: Preparation of 4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole: 3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidine-2,5-dione (450 mg, 1 eq) was added portionwise to lithium aluminum tetrahydride (5 eq) in tetrahydrofuran (10 mL) at 0°C and stirred at 75°C for 5 hours. The mixture was cooled to room temperature, quenched with water (1 mL), diluted with ethyl acetate (10 mL), filtered through celite, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by reverse phase separation to obtain the title compound (190 mg).

[0250] LCMS (ESI) [M+H] + =293.2.

[0251] Step 3: Preparation of 4-(benzyloxy)-3-(1-(2-(2-methoxyphenyl)ethyl)pyrrolidin-3-yl)-1H-indole: 4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole (200 mg, 1 eq) and 1-(2-bromoethyl)-2-methoxybenzene (1 eq) were dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (1.5 eq) was added, and the reaction system was stirred at 80°C for 16 hours. Water (15 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated and purified by reverse phase separation to obtain the title compound (65 mg).

[0252] LCMS (ESI) [M+H] + =427.5.

[0253] Step 4: Preparation of 3-(1-(2-(2-methoxyphenyl)ethyl)pyrrolidin-3-yl)-1H-indole-4-ol: 4-(benzyloxy)-3-(1-(2-(2-methoxyphenyl)ethyl)pyrrolidin-3-yl)-1H-indole (230 mg, 1 eq) was dissolved in methanol (5 mL), and palladium on carbon (2 eq) was added. The reaction system was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative HPLC (0.1% trifluoroacetic acid in water:acetonitrile) to obtain the target compound. The target compound was lyophilized, and 0.5% aqueous hydrochloric acid solution was added and repeatedly lyophilized to obtain the target compound as a hydrochloride (14.29 mg).

[0254] LCMS (ESI) [M+H] + =337.1; 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),10.41(s,1H),9.57(d,J=29.4Hz,1H),7.30- 7.22(m,2H),7.13(s,1H),7.04-6.99(m,1H),6.95-6.90(m,1H),6.88-6.79(m,2H) ,6.38(d,J=7.2Hz,1H),4.12-3.86(m,2H),3.84-3.79(m,3H),3.76-3.66(m,1H),3 .63-3.55(m,1H),3.39(s,2H),3.25-3.13(m,1H),2.99(s,2H),2.40-2.09(m,2H).

[0255] Examples 2-3 (Compounds 2 and 3)

[0256] Compounds 2 and 3 were prepared using the preparation method of Reference Example 1:

[0257] Compound 2: LCMS (ESI) [M+H] + =351.2;

[0258] Compound 3: LCMS (ESI) [M+H] + =365.2;

[0259] Example 4 (Compound 4)

[0260] Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)piperidin-3-yl)-1H-indol-4-ol:

[0261] Step 1: Preparation of 4-(Benzyloxy)-3-(1-phenylmethylpiperidin-3-yl)-1H-indole: 1-Benzylpiperidin-3-one (2 g, 1 eq) and 4-(Benzyloxy)-1H-indole (1 eq) were dissolved in acetic acid (20 mL). 85% aqueous phosphoric acid (10 eq) was added, and the reaction system was stirred at 90°C for 2 hours. Ethyl acetate (30 mL) was added for dilution, and the organic phase was washed three times with water. The organic phase was concentrated to obtain a crude product, which was then purified by reverse phase chromatography (C18, 0.01% formic acid in water:acetonitrile) to obtain the title compound (300 mg).

[0262] LCMS (ESI) [M+H] + =397.2.

[0263] Step 2: Preparation of 3-(Piperidin-3-yl)-1H-indole-4-ol: Palladium on carbon (67 mg, 1 eq) was added to a solution of 4-(benzyloxy)-3-(1-phenylmethylpiperidin-3-yl)-1H-indole (250 mg, 1 eq) in methanol (5 mL) under a hydrogen atmosphere. The reaction system was stirred at room temperature for 1 hour. The reaction solution was filtered through celite and washed with methanol. The filtrate was concentrated to obtain the title compound (200 mg, crude product).

[0264] LCMS (ESI) [M+H] + =217.2.

[0265] Step 3: Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)piperidin-3-yl)-1H-indole-4-ol

[0266] 3-(Piperidin-3-yl)-1H-indol-4-ol (150 mg, crude) and 3-(2-methoxyphenyl)propanal (137 mg) were dissolved in tetrahydrofuran (5 mL). One drop of acetic acid was added, and the reaction system was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (294 mg) was then added, and the reaction solution was stirred at room temperature for 8 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by preparative HPLC (C18, 0.05% formic acid in water:acetonitrile) to obtain the title compound (21.97 mg).

[0267] LCMS (ESI) [M+H] + =365.3; 1H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.26(s,1H),7.15(dd,J=13.3,7.2Hz,2H),6.92 (d,J=8.2Hz,2H),6.85(t,J=7.3Hz,1H),6.76(dd,J=14.6,7.5Hz,2H),6.30(d,J=7.1Hz ,1H),3.75(s,3H),3.38-3.27(m,2H),2.95(d,J=9.2Hz,1H),2.58-2.53(m,2H),2.41(s ,2H),2.09-1.95(m,3H),1.76-1.69(m,3H),1.64(d,J=12.5Hz,1H),1.48-1.38(m,1H).

[0268] Example 5 (Compound 5)

[0269] Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole:

[0270] Step 1: Preparation of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione: Indole (15 g, 1 eq) was dissolved in acetic acid (150 mL), and 1H-pyrrole-2,5-dione (3 eq) was added. The reaction solution was reacted at 120°C overnight. The solvent was concentrated, ethyl acetate (100 mL) was added, and the pH was adjusted to 8 with saturated sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography to obtain the target compound (19 g).

[0271] LCMS (ESI) [M+H] + =215.3.

[0272] Step 2: Preparation of 3-(pyrrolidin-3-yl)-1H-indole: 3-(1H-indol-3-yl)pyrrolidine-2,5-dione (10 g, 1 eq) was dissolved in tetrahydrofuran (100 mL). Lithium aluminum tetrahydride (5 eq) was added at 0°C, and the reaction solution was heated and stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature, slowly quenched with water in an ice bath, and diluted with ethyl acetate (100 mL). The mixture was filtered through celite, the filtrate was concentrated, diluted with ethyl acetate (100 mL), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. The crude product was separated and purified by reverse phase flash chromatography (C18, 0.05% formic acid in water: acetonitrile) to obtain the title compound (5 g).

[0273] LCMS (ESI) [M+H] + =187.1.

[0274] Step 3: Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(2-methoxyphenyl)propanal (100 mg, 1 eq) was dissolved in dichloromethane (5 mL), 3-(pyrrolidin-3-yl)-1H-indole (1 eq) and acetic acid (0.2 mL) were added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (2 eq) was added, the atmosphere was replaced with nitrogen, and stirring was continued at room temperature for 1 hour. Ammonium chloride (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. The crude product was purified by preparative HPLC (C18, 0.05% formic acid in water: acetonitrile) to obtain the title compound (72.56 mg).

[0275] LCMS (ESI) [M+H] + =335.1;1H NMR(400MHz,MeOD-d4)δ8.49(s,1H),7.60(d,J=7.9Hz,1H),7.39(d,J=8.1Hz,1H),7.26-7 .21(m,2H),7.20-7.13(m,2H),7.06(t,J=7.5Hz,1H),6.97(d,J=8.2Hz,1H),6.91(t,J=7.4 Hz,1H),3.94-3.83(m,5H),3.60(s,2H),3.41(s,1H),3.28(dd,J=11.4,4.3Hz,2H),2.76( t,J=7.4Hz,2H),2.64-2.53(m,1H),2.36(ddd,J=13.1,8.7,4.7Hz,1H),2.11-2.02(m,2H).

[0276] Example 6 (Compound 6)

[0277] Preparation of 5-methoxy-1-(1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole:

[0278] Step 1: Preparation of 1-benzylpyrrolidin-3-yl methanesulfonate: Dissolve 1-benzylpyrrolidin-3-ol (4 g, 1 eq) in dichloromethane (40 mL). Add triethylamine (4 mL). Add methanesulfonyl chloride (1.5 eq) under ice-cooling. Warm the mixture to room temperature and react for 1.5 hours. Adjust the pH to >10 with saturated aqueous sodium bicarbonate. Extract the aqueous phase with dichloromethane (30 mL x 3). Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to yield the desired product (4 g).

[0279] LCMS (ESI) [M+H] + =256.4.

[0280] Step 2: Preparation of 1-(1-benzylpyrrolidin-3-yl)-5-methoxy-1H-indole: 5-methoxy-1H-indole (1 g, 1 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydroxide (3 eq) was added. After stirring at room temperature for half an hour, 1-benzylpyrrolidin-3-yl methanesulfonate (1.5 eq) was added, and the temperature was raised to 50° C. The reaction was continued for 16 hours. Water (20 mL) and ethyl acetate (30 mL × 2) were added, and the organic phase was washed with saturated brine (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and spin-dried to obtain the desired product (1.8 g).

[0281] LCMS (ESI) [M+H] + =307.5.

[0282] Step 3: Preparation of 5-methoxy-1-(pyrrolidin-3-yl)-1H-indole: 1-(1-benzylpyrrolidin-3-yl)-5-methoxy-1H-indole (1.7 g, 1 eq) was dissolved in methanol (30 mL), palladium on carbon (500 mg) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was dried to give a crude product, which was separated and purified by flash chromatography to give the title compound (730 mg).

[0283] LCMS (ESI) [M+H] + =217.3.

[0284] Step 4: Preparation of 5-methoxy-1-(1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole: 5-methoxy-1-(pyrrolidin-3-yl)-1H-indole (100 mg, 1 eq) and 3-(2-methoxyphenyl)propanal (1.3 eq) were dissolved in dichloromethane (5 mL), acetic acid (0.1 mL) was added, and sodium triacetoxyborohydride (3 eq) was slowly added, and stirred at room temperature. The mixture was quenched with water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate to give a crude product, which was separated and purified by preparative HPLC (C18, 0.05% formic acid in water:acetonitrile) to give the title compound (17.76 mg).

[0285] LCMS (ESI) [M+H] + =365.3; 1 H NMR (400MHz, CDCl3) δ7.34(d,J=8.8Hz,2H),7.19(d,J=1.4Hz,1H),7.13(dd,J=7.4,1.6Hz,1H),7.08(d,J=2.4Hz,1H),6.87(dt,J=10.9,7.3Hz,3H),6. 44(d,J=3.1Hz,1H),5.08(s,1H),3.84(s,3H),3.80(s,3H),3.12(s,3H),2. 71(pd,J=13.5,7.3Hz,4H),2.54(s,1H),2.23(s,1H),1.93(d,J=6.8Hz,3H).

[0286] Examples 7-9 (Compounds 7, 8 and 9)

[0287] Compound 7-9 was prepared by referring to the preparation method of Example 5:

[0288] Compound 7: LCMS (ESI) [M+H] + =353.2;

[0289] Compound 8: LCMS (ESI) [M+H] + =353.2; 1H NMR(400MHz, CDCl3)δ8.79(s,1H),8.49(s,1H),7.25-7.15(m,2H),7.15-7.0 3(m,3H),6.94-6.82(m,2H),6.76(dd,J=11.6,7.7Hz,1H),4.03-3.93(m,1H), 3.82(s,3H),3.66(s,1H),3.52-3.25(m,3H),3.11-3.04(m,2H),2.71(t,J=7. 4Hz,2H),2.47(dd,J=13.4,5.7Hz,1H),2.33-2.23(m,1H),2.17-2.05(m,2H);

[0290] Compound 9: LCMS (ESI) [M+H] + =365.2; 1 H NMR(400MHz, CDCl3)δ8.72(s,1H),8.27(s,1H),7.21-7.04(m,3H),6.99-6.80 (m,4H),6.48(d,J=7.8Hz,1H),4.00(s,1H),3.89(s,3H),3.80(s,3H),3.41(s ,1H),3.18(s,1H),2.94(s,1H),2.78(d,J=9.2Hz,3H),2.68(t,J=7.5Hz,2H), 2.37(td,J=13.4,8.0Hz,1H), 2.07(dd,J=19.7,7.6Hz,1H), 2.02-1.90(m,2H).

[0291] Example 10 (Compound 10)

[0292] Preparation of 3-(2-(4-(2-methoxyphenyl)piperidin-1-yl)ethyl)-1H-indol-4-ol:

[0293] Step 1: Preparation of tert-butyl 4-(2-methoxyphenyl)-3,6-dihydropyridine-1-carboxylate: 1-iodo-2-methoxybenzene (5 g, 1 eq) was dissolved in a mixed solution of N,N-dimethylformamide (40 mL) and water (3 mL), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1-carboxylate (1.2 eq), sodium acetate (1.5 eq) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride (0.05 eq) were added in sequence, and stirred overnight at 95 ° C under a nitrogen atmosphere. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was separated and purified by flash chromatography to obtain the target product (2.1 g).

[0294] LCMS (ESI) [M-100+H] + =190.2.

[0295] Step 2: Preparation of tert-butyl 4-(2-methoxyphenyl)piperidine-1-carboxylate: Dissolve tert-butyl 4-(2-methoxyphenyl)-3,6-dihydropyridine-1-carboxylate (1.9 g, 1 eq) in ethyl acetate (6 mL). Add palladium on carbon (0.5 eq). Replace the mixture with hydrogen three times and stir at room temperature under a hydrogen atmosphere for 3 hours. Filter the mixture through celite and wash with methanol. Concentrate the filtrate to obtain the title compound (1.2 g, crude product).

[0296] LCMS (ESI) [M-56+42] + =277.1.

[0297] Step 3: Preparation of 4-(2-methoxyphenyl)piperidine: Dissolve tert-butyl 4-(2-methoxyphenyl)piperidine-1-carboxylate (1 g, crude) in ethyl acetate (6 mL). Add ethyl acetate hydrochloride (6 mL, 3 M). The reaction mixture is allowed to react at room temperature for 2 hours, producing a white solid. LCMS analysis indicates the reaction is complete. Filter and dry the filter cake to obtain the desired product (600 mg).

[0298] LCMS (ESI) [M+H] + =192.1.

[0299] Step 4: Preparation of methyl 2-(4-(benzyloxy)-1H-indol-3-yl)-2-oxoacetate: 4-(benzyloxy)-1H-indole (5 g, 1 eq) was dissolved in ultra-dry tetrahydrofuran (50 mL). Oxalyl chloride (1.2 eq) was slowly added dropwise at 0°C. The reaction solution was stirred at 0°C for 4 hours. Methanol (6 mL) was slowly added dropwise at 0°C, followed by triethylamine (4 mL). The mixture was refluxed at 70°C for 2 hours. The solvent was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The mixture was washed with saturated brine (50 mL × 2). The organic phase was dried and concentrated to give a crude product, which was separated and purified by flash chromatography to give the title compound (3 g).

[0300] LCMS (ESI) [M+H] + =310.1.

[0301] Step 5: Preparation of 2-(4-(Benzyloxy)-1H-indol-3-yl)ethan-1-ol: Methyl 2-(4-(Benzyloxy)-1H-indol-3-yl)-2-oxoacetate (3 g, 1 eq) was dissolved in ultra-dry tetrahydrofuran (30 mL). A solution of lithium aluminum tetrahydride in tetrahydrofuran (19.4 mL, 1 M) was slowly added dropwise at 0°C. The reaction mixture was stirred for 1 hour and then heated and stirred at 70°C overnight. Water was slowly added dropwise at 0°C to quench the mixture, the mixture was filtered, and the mixture was washed several times with ethyl acetate. The filtrate was washed with saturated brine (20 mL x 2). The organic phase was concentrated to obtain the crude product, which was separated and purified by flash chromatography to obtain the title compound (2 g).

[0302] LCMS (ESI) [M+H] + =268.1.

[0303] Step 6: Preparation of 4-(benzyloxy)-3-(2-chloroethyl)-1H-indole: 2-(4-(benzyloxy)-1H-indol-3-yl)ethane-1-ol (2.0 g, 1 eq) was dissolved in dichloromethane (30 mL), triethylamine (3 eq) was added, and methylsulfonyl chloride (1.1 eq) was slowly added at 0°C. The reaction solution was stirred at 0°C for 4 hours. TLC confirmed the completion of the reaction. Water (10 mL) was added, the layers were separated, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (50 mL × 2). The organic phase was dried and concentrated to give a crude product, which was separated and purified by flash chromatography to give the desired product (300 mg, 14.0% yield).

[0304] Step 7: Preparation of 4-(benzyloxy)-3-(2-(4-(2-methoxyphenyl)piperidin-1-yl)ethyl)-1H-indole: 4-(benzyloxy)-3-(2-chloroethyl)-1H-indole (280 mg, 1 eq) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (271 mg, 2 eq) and 4-(2-methoxyphenyl)piperidine (187 mg, 1 eq) were added, and the reaction solution was stirred at 80°C overnight. The mixture was diluted with water (10 mL), extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL × 2), and the organic phase was dried and concentrated to give a crude product, which was separated and purified by flash chromatography to give the target product (210 mg).

[0305] LCMS (ESI) [M+H] + =441.2.

[0306] Step 8: Preparation of 3-(2-(4-(2-methoxyphenyl)piperidin-1-yl)ethyl)-1H-indole-4-ol: 4-(benzyloxy)-3-(2-(4-(2-methoxyphenyl)piperidin-1-yl)ethyl)-1H-indole (260 mg, 1 eq) was dissolved in methanol (5 mL), palladium on carbon (1 eq) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 minutes. The mixture was filtered and the filtrate was concentrated to give a crude product, which was isolated and purified by preparative HPLC (C18, 0.05% formic acid in water:acetonitrile) to give the title compound (75.33 mg).

[0307] LCMS (ESI) [M+H] + =351.1; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.16(s,1H),7.19(t,J=7.0Hz,2H),6.99-6.91(m,3H),6.84-6.74(m,2H),6.31(d,J =7.3Hz,1H),3.79(s,3H),3.19-3.14(m,2H),3.04-2.89(m,4H),2.83-2.75(m,2H),2.43-2.35(m,2H),1.81-1.70(m,4H).

[0308] Example 11 (Compound 11)

[0309] Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)azetidin-3-yl)-1H-indole:

[0310] Step 1: Preparation of tert-butyl 3-hydroxy-3-(1H-indol-3-yl)azetidine-1-carboxylate: Add indole (0.5 eq.) to N-tert-butyloxycarbonyl-3-azetidinone (1 g, 1.0 eq.) and potassium hydroxide (1.1 eq.) in methanol (20 mL), stir at 50°C for 12 hours, add water (30 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuo, and separate and purify by flash chromatography to give the title compound (550 mg).

[0311] LCMS (ESI) [M+H-18] + =271.1.

[0312] Step 2: Preparation of tert-butyl 3-(1H-indol-3-yl)azetidine-1-carboxylate: Triethylsilane (7.5 eq.) was added to tert-butyl 3-hydroxy-3-(1H-indol-3-yl)azetidine-1-carboxylate (6 g, 1.0 eq.) in dichloromethane (60 mL) at 0°C, and trifluoroacetic acid (3.3 eq) was added. The mixture was stirred at 0°C for 10 minutes, warmed to room temperature and stirred for 20 minutes. The reaction was quenched with saturated sodium bicarbonate, and dichloromethane (100 mL×3) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated and purified by flash chromatography to give the title compound (2.2 g).

[0313] LCMS (ESI) [M+H-56+CH3CN] + =258.2.

[0314] Step 3: Preparation of 3-(azetidine-3-yl)-1H-indole: Add trifluoroacetic acid (5 mL) to tert-butyl 3-(1H-indol-3-yl)azetidine-1-carboxylate (1 g, 1.0 eq.) in dichloromethane (20 mL), stir at room temperature for 0.5 hour, add dichloromethane (20 mL), concentrate in vacuo, and separate and purify by flash chromatography to give the title compound (900 mg, crude product).

[0315] LCMS (ESI) [M+H] + =173.3.

[0316] Step 4: Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)azetidin-3-yl)-1H-indole: 3-(2-methoxyphenyl)propanal (143 mg, 1.0 eq.) and 3-(azetidin-3-yl)-1H-indole (150 mg, crude) were added to tetrahydrofuran (10 mL), stirred at room temperature for 5 minutes, and sodium triacetoxyborohydride (2.0 eq.) was added to the system, and stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated and purified by preparative HPLC (C18, 0.1% formic acid in water:acetonitrile) to obtain the title compound (22.99 mg).

[0317] LCMS (ESI) [M+H] + =321.2; 1 H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 7.57 (d, J = 7.8Hz, 1H), 7.36 (dd, J = 5. 2,2.8Hz,2H),7.22-7.13(m,2H),7.11-7.06(m,1H),7.02-6.94(m,2H),6.88 (td,J=7.4,0.9Hz,1H),4.11-4.05(m,2H),4.04-3.95(m,1H),3.78(s,3H),3 .66(t,J=7.0Hz,2H),2.86(t,J=7.4Hz,2H),2.60(s,2H),1.72-1.62(m,2H).

[0318] Example 12-15 (Compound 12-15)

[0319] Compounds 12-15 were prepared by referring to the preparation methods of Examples 4 and 5:

[0320] Compound 12: LCMS (ESI) [M+H] + =337.2;

[0321] Compound 13: LCMS (ESI) [M+H] + =353.2;

[0322] Compound 14: LCMS (ESI) [M+H] + =353.2; 1H NMR (400MHz, CDCl3) δ8.77 (s, 1H), 8.61 (s, 1H), 7.29 (dd, J = 8.8, 4.4Hz, 1H), 7.24 -7.15(m,2H),7.11(d,J=5.5Hz,2H),6.98-6.82(m,3H),3.81(s,3H),3.76(d,J=8 .3Hz,1H),3.60(s,1H),3.35(d,J=27.4Hz,2H),3.14(s,1H),3.00(dd,J=10.5,5. 8Hz, 2H), 2.70 (t, J = 7.3Hz, 2H), 2.45 (dd, J = 12.2, 5.3Hz, 1H), 2.26-2.01 (m, 3H).

[0323] Compound 15: LCMS (ESI) [M+H] + =365.2; 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),7.47(d,J=8.6Hz,1H),7.21-7.12(m,2H),7.03(d,J=1.9Hz, 1H),6.94(d,J=8.1Hz,1H),6.90-6.82(m,2H),6.63(dd,J=8.6,2.2Hz,1H),3.77(s,3H),3.74(s,3H ),3.54(s,1H),3.24(d,J=8.8Hz,1H),3.00-2.94(m,1H),2.86(d,J=5.4Hz,1H),2.71(dt,J=15.7, 7.5Hz,3H),2.63-2.58(m,2H),2.31-2.22(m,1H),1.93(dd,J=12.4,7.6Hz,1H),1.82-1.73(m,2H).

[0324] Example 16 (Compound 16)

[0325] Preparation of 3-(7-(3-(2-methoxyphenyl)propyl)-7-azabicyclo[2.2.1]heptane-2-yl)-1H-indole:

[0326] Step 1: Preparation of 3-iodo-1-(4-toluenesulfonyl)-1H-indole: Dissolve indole (5 g, 1.0 eq.) in N,N-dimethylformamide (70 mL), add potassium hydroxide (2.5 eq.), and stir the mixture at room temperature for 30 minutes. Add a solution of iodine (1.05 eq.) in N,N-dimethylformamide (70 mL) dropwise, and continue stirring for 1 hour. Then, add potassium hydroxide (2.5 eq.) and 4-toluenesulfonyl chloride (2.1 eq.). Stir the reaction system at room temperature for 15 hours. Pour the reaction solution into water (500 mL). Filter off the precipitated solid, wash the filter cake with water, slurry it with a small amount of isopropyl alcohol, and then with petroleum ether. Filter and dry to obtain the title compound (10 g).

[0327] 1 H NMR (400MHz, CDCl3) δ7.97-7.93(m,1H),7.80-7.75(m,2H),7.69(s,1H),7.39 -7.34(m,2H),7.31(dd,J=7.0,1.4Hz,1H),7.24(d,J=8.1Hz,2H),2.35(s,3H).

[0328] Step 2: Preparation of tert-butyl 2-hydroxy-2-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-7-azabicyclo[2.2.1]heptane-7-carboxylate: 3-iodo-1-(4-toluenesulfonyl)-1H-indole (50 mg, 1.0 eq.) was dissolved in tetrahydrofuran (1 mL), and butyl lithium (1.6 M, 0.01 mL, 1.2 eq.) was added dropwise at -78°C. After the addition was complete, the temperature was maintained and stirred for 1 hour. A solution of tert-butyl 2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylate (1.1 eq.) in tetrahydrofuran (1 mL) was added dropwise, and the reaction system was stirred at -78°C for 1 hour. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by TLC to obtain the title compound (20 mg).

[0329] LCMS (ESI) [M+H-56-H2O] + =409.3.

[0330] Step 3: Preparation of 3-(7-azabicyclo[2.2.1]heptane-2-yl)-1-(4-methylphenylsulfonyl)-1H-indole: tert-Butyl 2-hydroxy-2-(1-(4-methylphenylsulfonyl)-1H-indol-3-yl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (300 mg, 1.0 eq.) was dissolved in ultra-dry dichloromethane (3 mL), and trifluoroacetic acid (5.5 eq.) and triethylsilane (2.5 eq.) were added sequentially. The reaction system was stirred at room temperature for 1 hour, and then trifluoroacetic acid (5.5 eq.) and triethylsilane (2.5 eq.) were added. Stirring was continued for 2 hours. The reaction solution was concentrated to remove trifluoroacetic acid to obtain a crude product, which was separated and purified by flash chromatography (C18, 0.1% FA / water, ACN) to obtain the title compound (150 mg).

[0331] LCMS (ESI) [M+H] + =367.3.

[0332] Step 4: Preparation of 3-(7-(3-(2-methoxyphenyl)propyl)-7-azabicyclo[2.2.1]hept-2-yl)-1-(4-methylbenzenesulfonyl)-1H-indole: 3-(2-methoxyphenyl)propanal (1.5 eq.) and 3-(7-azabicyclo[2.2.1]hept-2-yl)-1-(4-methylbenzenesulfonyl)-1H-indole (120 mg, 1.0 eq.) were dissolved in dichloromethane ( 5 mL), acetic acid (0.3 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.0 eq.) was then added, and the reaction system was stirred at room temperature for 2.5 hours. Water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by flash chromatography (C18, 0.1% formic acid in water:acetonitrile) to obtain the title compound (140 mg).

[0333] LCMS (ESI) [M+H] + =515.5.

[0334] Step 5: Preparation of 3-(7-(3-(2-methoxyphenyl)propyl)-7-azabicyclo[2.2.1]hept-2-yl)-1H-indole: 3-(7-(3-(2-methoxyphenyl)propyl)-7-azabicyclo[2.2.1]hept-2-yl)-1-(4-methylphenylsulfonyl)-1H-indole (120 mg, 1.0 eq.) was dissolved in methanol (5 mL), potassium hydroxide (10 eq.) was added, and the reaction was stirred at 70°C for 40 hours. Diluted with dichloromethane, water (15 mL) was added, and the mixture was extracted with dichloromethane and methanol (10:1, 15 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was separated and purified by preparative HPLC (C18, 0.1% trifluoroacetic acid in water:acetonitrile) to give the title compound (39 mg).

[0335] LCMS (ESI) [M+H] + =361.3; 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 8.66 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 8.1Hz, 1H) ,7.24-7.21(m,1H),7.19(d,J=7.4Hz,1H),7.11(t,J=7.0Hz,2H),6.95(d,J=2.4Hz ,1H),6.90(d,J=7.4Hz,1H),6.85(d,J=8.2Hz,1H),4.01(s,1H),3.81(s,3H),3.13 -3.08(m,1H),2.95-2.90(m,1H),2.70(dt,J=13.5,6.7Hz,3H),2.23-1.83(m,9H).

[0336] Example 17 (Compound 17)

[0337] Compound 17 was prepared by referring to the preparation method of Example 16:

[0338] LCMS (ESI) [M+H] + =375.2.

[0339] Example 18 (Compound 18)

[0340] Preparation of 3-(4-fluoro-1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole:

[0341] Step 1: Preparation of benzyl 3-hydroxy-4-(1H-indol-3-yl)pyrrolidine-1-carboxylate: Dissolve indole (1.8 g, 1.0 eq) in tetrahydrofuran (10 mL). Add 3M isopropylmagnesium chloride in tetrahydrofuran (1.0 eq) dropwise at 0°C. Stir at 0°C for 0.5 hours. Add 3-N-benzyloxycarbonyl-6-oxa-3-azabicyclo[3.1.0]hexane (1.0 eq) and stir at room temperature for 3.5 hours. Add saturated sodium bicarbonate solution (50 mL) dropwise and extract with ethyl acetate (50 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is separated and purified by flash chromatography to obtain the title compound (1.2 g).

[0342] LCMS (ESI) [M+Na] + =359.2.

[0343] Step 2: Preparation of benzyl 3-fluoro-4-(1H-indol-3-yl)pyrrolidine-1-carboxylate: Benzyl 3-hydroxy-4-(1H-indol-3-yl)pyrrolidine-1-carboxylate (1 g, 1.0 eq) was dissolved in dichloromethane (5 mL). Diethylaminosulfur trifluoride (DAST, 1.2 eq) was added at -78°C and stirred at room temperature for 2 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by flash chromatography to obtain the title compound (0.41 g).

[0344] LCMS (ESI) [M+Na] + =361.1.

[0345] Step 3: Preparation of 3-(4-fluoropyrrolidin-3-yl)-1H-indole:

[0346] Benzyl 3-fluoro-4-(1H-indol-3-yl)pyrrolidine-1-carboxylate (410 mg, 1.0 eq) was dissolved in methanol (5 mL). Palladium on carbon (0.1 eq) was added, and two drops of formic acid were added dropwise. The atmosphere was replaced with hydrogen and stirred at room temperature for 16 hours. LCMS indicated the reaction was complete. The reaction solution was filtered and concentrated to obtain the crude product, which was then separated and purified by reverse-phase flash chromatography (C18, 0.1% FA / H2O, ACN) to obtain the title compound (162 mg).

[0347] LCMS (ESI) [M+H] + =205.1.

[0348] Step 4: Preparation of 3-(4-fluoro-1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole:

[0349] 3-(4-Fluoropyrrolidin-3-yl)-1H-indole (100 mg, 1.0 eq) and 3-(2-methoxyphenyl)propanal (80 mg, 1.0 eq) were dissolved in tetrahydrofuran (5 mL). Glacial acetic acid (3 mg, 0.1 eq) was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (208 mg, 2.0 eq) was then added, and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (C18, 0.05% formic acid in water:acetonitrile) to obtain the title compound (49.70 mg).

[0350] LCMS (ESI) [M+H] + =353.2; 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.17(s,1H),7.56(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.24(d,J=2.2Hz,1H),7.21-7.13(m,2H),7. 12-7.06(m,1H),7.03-6.92(m,2H),6.86(td,J=7.4,1.0Hz,1H),5.15(d,J=55.8Hz,1H),3.78(s,3H),3.65 (s,1H),3.32(s,1H),3.07(d,J=12.7Hz,1H),2.75-2.56(m,4H),2.47-2.37(m,2H),1.73(p,J=7.3Hz,2H).

[0351] Example 19 (Compound 19)

[0352] Compound 19 was prepared by referring to the preparation method of Example 11:

[0353] LCMS (ESI) [M+H] + =355.2.

[0354] Example 20 (Compound 20)

[0355] Preparation of 3-(1-(3-(4,5-difluoro-2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole:

[0356] Step 1: Preparation of ethyl 3-(4,5-difluoro-2-methoxyphenyl)prop-2-enoate: Sodium hydroxide (1.3 eq.) was dissolved in tetrahydrofuran (30 mL), and a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.1 eq.) in tetrahydrofuran (70 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for half an hour, and then a solution of 4,5-difluoro-2-methoxybenzaldehyde (4.7 g, 1.0 eq.) in tetrahydrofuran (50 mL) was added dropwise. The mixture was reacted at 60°C for 12 hours, quenched with water, and dried by spin drying. The title compound (3.8 g) was obtained by flash chromatography (C18, 0.1% formic acid in water: acetonitrile).

[0357] LCMS (ESI) [M+H] + =243.1.

[0358] Step 2: Preparation of ethyl 3-(4,5-difluoro-2-methoxyphenyl)propanoate: Dissolve ethyl 3-(4,5-difluoro-2-methoxyphenyl)prop-2-enoate (3.5 g, 1.0 eq.) in methanol (35 mL), add 10% palladium carbon (1 g), react at room temperature under a hydrogen atmosphere for 1 hour, filter, and spin-dry the filtrate to obtain the target compound (3.2 g).

[0359] LCMS (ESI) [M+H] + =245.1.

[0360] Step 3: Preparation of 3-(4,5-difluoro-2-methoxyphenyl)propan-1-ol: Ethyl 3-(4,5-difluoro-2-methoxyphenyl)propionate (1.50 g, 1.0 eq.) was dissolved in tetrahydrofuran (15 mL), and lithium aluminum tetrahydride (2.0 eq.) was slowly added under ice bath. The mixture was warmed to room temperature and reacted for 1 hour. Water (1 mL) was added to quench the reaction, and the mixture was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was spin-dried. The title compound (800 mg) was obtained by separation and purification by flash chromatography (Silica gel, petroleum ether:ethyl acetate = 4:1).

[0361] LCMS(ESI)[M+H+ACN] + =244.2.

[0362] Step 4: Preparation of 3-(4,5-difluoro-2-methoxyphenyl)propanal: Dissolve 3-(4,5-difluoro-2-methoxyphenyl)propan-1-ol (400 mg, 1.0 eq.) in dichloromethane (10 mL). Slowly add Dess-Martin periodinane (2.0 eq.) in an ice bath. Warm to room temperature and react for 1 hour. TLC confirms the reaction is complete. Quench with saturated aqueous ammonium chloride, filter out the solid, and spin-dry the dichloromethane. Extract three times with water and ethyl acetate. The organic phase is collected, washed with saturated brine, and then spin-dried. Purify by flash chromatography to obtain the title compound (250 mg).

[0363] Step 5: Preparation of 3-(1-(3-(4,5-difluoro-2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(4,5-difluoro-2-methoxyphenyl)propanal (100 mg, 1.0 eq.) and 3-(pyrrolidin-3-yl)-1H-indole (1.0 eq.) were dissolved in tetrahydrofuran (5 mL), acetic acid (0.5 mL) and sodium triacetoxyborohydride (3.0 eq.) were added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) and ethyl acetate (5 mL×3) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The title compound (9.78 mg) was obtained by separation and purification by preparative HPLC (C18, 0.05% formic acid in water: acetonitrile).

[0364] LCMS (ESI) [M+H] + =371.2; 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),8.31(s,1H),7.57(d,J=7.9Hz,1H),7.40(d,J=8.1Hz,1H),7.20 (s,1H),7.14(dd,J=11.0,3.9Hz,2H),6.94(dd,J=10.5,9.0Hz,1H),6.66(dd,J=12.1,6.7Hz,1H),3 .97-3.87(m,1H),3.77(s,3H),3.72(s,1H),3.49(s,1H),3.31(s,1H),3.16(s,1H),3.04-2.96(m, 2H), 2.64 (t, J = 7.5Hz, 2H), 2.53 (d, J = 7.5Hz, 1H), 2.30 (dd, J = 13.0, 9.1Hz, 1H), 2.16-2.05 (m, 2H).

[0365] Example 21 (Compound 21)

[0366] Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-pyrrolo[3,2-b]pyridine:

[0367] Step 1: Preparation of 3-bromo-1H-pyrrolo[3,2-b]pyridine: N-bromosuccinimide (NBS, 1.51 g, 1.0 eq.) was added to 1H-pyrrolo[3,2-b]pyridine (1.0 eq) in N,N-dimethylformamide (20 mL) at 0°C and stirred for 0.5 h. Water (20 mL) was added to precipitate a large amount of solid. The solid was collected by filtration to give the title compound (989 mg).

[0368] LCMS (ESI) [M+H] + =199.1.

[0369] Step 2: Preparation of tert-butyl 3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate: At room temperature, (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.1 eq.) was added to 3-bromo-1H-pyrrolo[3,2-b]pyridine (600 mg, 1.0 eq) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.0 eq.) and potassium carbonate (3.0 eq.) in 1,4-dioxane (20 mL) and water (2 mL). The temperature was raised to 90°C under a nitrogen atmosphere and stirred for 6 hours. Water (30 mL) was added and extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine. The residue was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Silica gel, PE:EA=1:1) to give the title compound (400 mg).

[0370] LCMS (ESI) [M+H] + =286.2.

[0371] Step 3: Preparation of tert-butyl 3-(1H-pyrrolo[3,2-b]pyridin-3-yl)pyrrolidine-1-carboxylate: Palladium on carbon (100 mg) was added to tert-butyl 3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (400 mg, 1.0 eq.) in methanol (10 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The mixture was filtered, and the filtrate was added with water (30 mL). The mixture was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (Silica gel, PE:EA = 3:1) to obtain the title compound (145 mg).

[0372] LCMS (ESI) [M+H] + =288.2.

[0373] Step 4: Preparation of 3-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-b]pyridine: tert-Butyl 3-(1H-pyrrolo[3,2-b]pyridin-3-yl)pyrrolidine-1-carboxylate (140 mg, 1.0 eq.) was added to a solution of ethyl acetate hydrochloride (4 M, 2 mL) and ethyl acetate (5 mL) at room temperature and stirred for 2 hours. The solid was filtered and dried to afford the title compound (100 mg, crude product).

[0374] LCMS (ESI) [M+H] + =188.2.

[0375] Step 5: Preparation of 3-(1-(3-(2-methoxyphenyl)propyl)pyrrolidin-3-yl)-1H-pyrrolo[3,2-b]pyridine: 3-(2-methoxyphenyl)propanal (88 mg, 1.0 eq.) was added to a solution of 3-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-b]pyridine (1.0 eq.) in tetrahydrofuran (5 mL) at room temperature and stirred for five minutes. Acetic acid (0.1 mL) and sodium triacetoxyborohydride (2.0 eq) were added and stirred for 2 hours. Saturated sodium bicarbonate (15 mL) was added and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The title compound (23.66 mg) was obtained by separation and purification using preparative HPLC (C18, 0.1% formic acid in water: acetonitrile).

[0376] LCMS (ESI) [M+H] + =336.2; 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.29(dd,J=4.6,1.4Hz,1H),7.72(dd,J=8.2,1.4Hz,1H),7.50(d,J=2.4 Hz,1H),7.17(ddd,J=9.3,8.3,1.6Hz,2H),7.09(dd,J=8.2,4.6Hz,1H),6.95(d,J=7.7Hz,1H),6.87(td,J=7.4, 1.0Hz,1H),3.77(s,3H),3.70(d,J=8.0Hz,1H),3.37-3.32(m,1H),3.09-3.02(m,1H),2.97-2.87(m,2H),2.76( dd,J=13.9,7.0Hz,2H),2.65-2.59(m,2H),2.35-2.28(m,1H),2.07(dd,J=11.8,7.3Hz,1H),1.84-1.75(m,2H).

[0377] Examples 22-23

[0378] Compounds 22-23 were prepared using the preparation method of Reference Example 21:

[0379] Compound 22: LCMS (ESI) [M+H] + =336.2; 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.22(s,1H),8.18(dd,J=4.6,1.5Hz,1H),8.07-8.02(m,1H),7. 29(d,J=2.3Hz,1H),7.16(ddd,J=9.4,8.3,1.6Hz,2H),7.01(dd,J=7.9,4.7Hz,1H),6.94(d,J=7.6Hz,1 H),6.86(td,J=7.4,1.0Hz,1H),3.76(s,3H),3.58-3.52(m,1H),3.11(t,J=8.5Hz,1H),2.87-2.76(m, 2H),2.69-2.55(m,5H),2.34-2.22(m,1H),1.92(td,J=15.5,8.1Hz,1H),1.75(dq,J=15.1,7.5Hz,2H).

[0380] Compound 23: LCMS (ESI) [M+H] + =336.1; 1H NMR (400MHz, CDCl3) δ8.65(s,1H),7.67(d,J=8.2Hz,1H),7.47(d,J=8.4Hz,1H),7.41-7.34(m,1H), 7.23-7.07(m,3H),6.86(ddd,J=11.6,9.0,4.6Hz,2H),4.15-4.01(m,1H),4.00-3.84(m,1H),3.80( s,3H),3.62(t,J=11.6Hz,1H),3.34(dd,J=10.8,8.3Hz,1H),3.03(dd,J=8.7,2.8Hz,3H),2.69(t,J =7.4Hz, 2H), 2.60 (dd, J = 13.0, 8.1Hz, 1H), 2.28 (td, J = 6.3, 1.5Hz, 1H), 2.08 (dd, J = 9.1, 7.5Hz, 2H).

[0381] Examples 24-28

[0382] Compounds 24-28 were prepared by referring to the preparation methods of Examples 16, 18, and 21:

[0383] Compound 24: LCMS (ESI) [M+H] + =365.2;

[0384] Compound 25: LCMS (ESI) [M+H] + =379.2;

[0385] Compound 26: LCMS (ESI) [M+H] + =350.2;

[0386] Compound 27: LCMS (ESI) [M+H] + =347.2;

[0387] Compound 28: LCMS (ESI) [M+H] + =363.2;

[0388] Example 29 (Compound 29)

[0389] Preparation of 2-(1H-indol-3-yl)-4-(3-(2-methoxyphenyl)propyl)morpholine:

[0390] Step 1: Preparation of 2-(1H-indol-3-yl)-2-oxoacetyl chloride: Indole (15.0 g, 1.0 eq.) was dissolved in tetrahydrofuran (300 mL), replaced with nitrogen, and oxalyl chloride (1.0 eq.) was added dropwise at 0°C. The mixture was stirred at room temperature for 0.5 hours, resulting in the precipitation of a large amount of solid. Petroleum ether (300 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filter cake was concentrated to remove the solvent to obtain the target compound (21.7 mg).

[0391] Step 2: Preparation of 2-(1H-indol-3-yl)-2-oxoacetamide: 2-(1H-indol-3-yl)-2-oxoacetyl chloride (11 g, 1.0 eq.) was dissolved in ammonia methanol solution (19.82 eq.), stirred at room temperature for 8 hours, the reaction solution was concentrated, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the title compound (3.5 g).

[0392] LCMS (ESI) [M+H] + =189.2.

[0393] Step 3: Preparation of 1H-indole-3-carbonyl cyanide: 2-(1H-indol-3-yl)-2-oxyacetamide (5.6 g, 1.0 eq.) was dissolved in N,N-dimethylformamide (50 mL), thionyl chloride (15.83 eq.) was added at 0°C, and stirred at room temperature for 2 hours. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the target compound (4.5 g).

[0394] LCMS (ESI) [M+H] + =171.1.

[0395] Step 4: Preparation of 2-amino-1-(1H-indol-3-yl)ethyl-1-ol: 1H-indole-3-carbonyl cyanide (1.5 g, 1.0 eq.) was dissolved in tetrahydrofuran (20 mL), lithium aluminum tetrahydride (2.0 eq.) was added at -10°C, and stirred at -10°C for 4 hours. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The mother liquor was concentrated to obtain a crude product, which was separated and purified by flash chromatography to obtain the title compound (0.8 g).

[0396] LCMS (ESI) [M+H-H2O] + =159.2.

[0397] Step 5: Preparation of 2-chloro-N-(2-hydroxy-2-(1H-indol-3-yl)ethyl)acetamide: 2-amino-1-(1H-indol-3-yl)ethyl-1-ol (500 mg, 1.0 eq.) was dissolved in N,N-dimethylformamide (20 mL), diisopropylethylamine (2.0 eq.) was added, 2-chloroacetyl chloride (1.1 eq.) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (20 mL) was added at room temperature, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to give a crude product, which was separated and purified by flash chromatography to give the title compound (300 mg).

[0398] LCMS (ESI) [M+H-H2O] + =235.1.

[0399] Step 6: Preparation of 6-(1H-indol-3-yl)morpholin-3-one: 2-Chloro-N-(2-hydroxy-2-(1H-indol-3-yl)ethyl)acetamide (170 mg, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL), sodium hydride (2.0 eq.) was added at 0°C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was quenched with water (1 mL) and separated and purified by flash chromatography (C18, 0.05% FA / water, MeCN) to give the title compound (26 mg).

[0400] LCMS (ESI) [M+H] + =217.1.

[0401] Step 7: Preparation of 3-(morpholin-2-yl)-1H-indole: Dissolve the raw material 6-(1H-indol-3-yl)morpholin-3-one (500 mg, 1 eq.) in tetrahydrofuran (5 mL), add borane-tetrahydrofuran complex (1 M, 4.62 mL, 2 eq.), stir at room temperature for 3 hours, slowly add methanol dropwise until no bubbles are generated, stir thoroughly for 30 minutes, and concentrate the reaction solution to obtain the title compound (400 mg, crude product).

[0402] LCMS (ESI) [M+H] + =203.1.

[0403] Step 8: Preparation of 2-(1H-indol-3-yl)-4-(3-(2-methoxyphenyl)propyl)morpholine: The raw materials 3-(2-methoxyphenyl)propanal (389.7 mg) and 3-(morpholin-2-yl)-1H-indole (400 mg, crude product) were dissolved in dichloromethane (4 mL) and methanol (0.4 mL), and acetic acid (0.1 mL) was added dropwise, followed by sodium triacetoxyborohydride (838.33 mg). The mixture was stirred at room temperature for 0.5 hour, and water (20 mL) was added. The mixture was extracted with dichloromethane / methanol (10:1, 15 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was separated and purified by preparative HPLC (C18, 0.1% NH3 / water, ACN) to obtain the title compound (10.43 mg).

[0404] LCMS (ESI) [M+H] + =351.3; 1 H NMR (400MHz, CDCl3) δ8.08(s,1H),7.74(d,J=8.0Hz,1H),7.36(d,J=8.1Hz,1H),7.20 (dd,J=4.0,1.8Hz,2H),7.18-7.13(m,2H),7.13-7.10(m,1H),6.86(ddd,J=12.6,9.5, 4.6Hz,2H),4.98(s,1H),4.04(d,J=10.0Hz,1H),3.96(d,J=14.0Hz,1H),3.80(s,3H) ,3.10(s,1H),2.86(s,1H),2.71-2.64(m,2H),2.48(s,2H),1.85(s,2H),1.57(s,2H).

[0405] Examples 30-33

[0406] Compounds 30-33 were prepared by referring to the preparation methods of Examples 21 and 29:

[0407] Compound 30: LCMS (ESI) [M+H] + =337.4;

[0408] Compound 31: LCMS (ESI) [M+H] + =352.2;

[0409] Compound 32: LCMS (ESI) [M+H] + =367.2;

[0410] Compound 33: LCMS (ESI) [M+H] + =352.2.

[0411] Example 34 (Compound 34)

[0412] Preparation of 4-(3-(2-methoxyphenyl)propyl)-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine:

[0413] Step 1: Preparation of 2-bromo-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one: Dissolve 1H-pyrrolo[3,2-c]pyridine (2 g, 1 eq) in dichloromethane (20 mL). Slowly add aluminum chloride (3.5 eq). Stir at 40°C for 20 minutes. Add 2-bromoacetyl bromide (1 eq) dropwise. Maintain stirring at this temperature for 40 minutes. Cool to room temperature. Add the reaction mixture to ice water (200 mL). A white solid precipitates. Filter, wash the filter cake with water, collect the solid, and dry to obtain the title compound (1 g).

[0414] LCMS (ESI) [M+H] + =241.0.

[0415] Step 2: Preparation of 2-((2-hydroxyethyl)amino)-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethane-1-one: Dissolve 2-bromo-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethane-1-one (100 mg, 1 eq) in N,N-dimethylformamide (2 mL), cool the reaction solution to 0°C, add ethanolamine (1 eq), maintain the temperature and stir the reaction for 5 minutes, then warm to room temperature and stir the reaction for 1 hour. Solid precipitated and was filtered. The filter cake was washed twice with acetonitrile (2*2 mL), collected and spin-dried to obtain the title compound (80 mg).

[0416] LCMS (ESI) [M+H] + =220.1.

[0417] Step 3: Preparation of 2-((2-hydroxyethyl)amino)-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-ol: Dissolve 2-((2-hydroxyethyl)amino)-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one (80 mg, 1 eq) in methanol (5 mL), add sodium borohydride (8 eq), stir at room temperature for 16 hours, cool the reaction solution to room temperature, add 3N hydrochloric acid solution (3 mL) to quench the reaction solution, spin dry the reaction solvent to obtain the target compound (70 mg, crude product), which is directly used in the next reaction.

[0418] LCMS (ESI) [M+H] + =222.2.

[0419] Step 4: Preparation of 2-(1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine: Dissolve 2-((2-hydroxyethyl)amino)-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethane-1-ol (70 mg, crude product) in methanol (3 mL), add 3M methanolic hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, raise to 80°C and stir for 3 hours, filter out the salt, and concentrate to obtain the target compound (80 mg, crude product), which is used directly in the next reaction.

[0420] LCMS (ESI) [M+H] + =204.1.

[0421] Step 5: Preparation of 4-(3-(2-methoxyphenyl)propyl)-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine: 2-(1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine (80 mg, crude) was dissolved in tetrahydrofuran (6 mL), 3-(2-methoxyphenyl)propanal (64.63 mg) was added, and 2 drops of acetic acid were added dropwise. The mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (166.05 mg) was added and the reaction was continued with stirring for 1 hour. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (0.1% ammonia in water:acetonitrile) to give the title compound (31 mg, yield 22.6%).

[0422] LCMS (ESI) [M+H] + =352.2; 1 HNMR(400MHz,MeOD-d4)δ8.91(s,1H),8.13(d,J=5.9Hz,1H),7.46-7.32(m,2H),7.14(dd,J=1 3.9,7.3Hz,2H),6.91-6.81(m,2H),4.92(dd,J=10.3,2.1Hz,1H),4.01(d,J=10.1Hz,1H),3.88 (td,J=11.4,2.1Hz,1H),3.79(s,3H),3.06(d,J=11.5Hz,1H),2.88(d,J=11.7Hz,1H),2.66(t ,J=7.6Hz,2H),2.44(dt,J=22.0,9.4Hz,3H),2.31(td,J=11.5,3.4Hz,1H),1.90-1.76(m,2H).

[0423] Examples 35-36

[0424] Compounds 35-36 were prepared by referring to the preparation methods of Examples 16 and 34:

[0425] Compound 35: LCMS (ESI) [M+H] + =379.2;

[0426] Compound 36: LCMS (ESI) [M+H] + =393.2.

[0427] Example 37 (Compound 37)

[0428] Preparation of 3-(4-(3-(2-methoxyphenyl)propyl)morpholin-2-yl)-1H-indazole:

[0429] Step 1: Preparation of 2-bromo-1-(1H-indazol-3-yl)ethane-1-one: Copper bromide (13.39 g, 2 eq) was added to ethyl acetate (540 mL), heated to 82 ° C, and 1-(1H-indazol-3-yl)ethane-1-one (4.8 g, 1 eq) was added. The reaction system was stirred at 82 ° C for 4 hours. The reaction solution was washed with 20% sodium thiosulfate solution (450 mL × 2) and then with saturated brine (100 mL × 2). The organic phase was dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by slurrying with ethyl acetate and petroleum ether (1:1) to obtain the target compound (5 g).

[0430] LCMS (ESI) [M+H] + =239.0.

[0431] Step 2: Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1H-indazol-3-yl)ethan-1-one: 2-(benzylamino)ethan-1-ol (10 eq) was dissolved in acetonitrile (20 mL), and 2-bromo-1-(1H-indazol-3-yl)ethan-1-one (2 g, 1 eq) was added in batches under ice bath. The reaction system was stirred in an ice bath for 20 minutes, water (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by flash chromatography to obtain the target compound (1.8 g).

[0432] LCMS (ESI) [M+H] + =310.0.

[0433] Step 3: Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1H-indazol-3-yl)ethan-1-ol: 2-(benzyl(2-hydroxyethyl)amino)-1-(1H-indazol-3-yl)ethan-1-one (1.8 g, 1 eq) was dissolved in methanol (20 mL), and sodium borohydride (2 eq) was slowly added under ice bath. After the addition was completed, the mixture was stirred at room temperature for 30 minutes. Water was added under ice bath until no more bubbles were generated, and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound (1.7 g, crude product), which was used directly in the next step.

[0434] LCMS (ESI) [M+H] + =312.2.

[0435] Step 4: Preparation of 3-(4-benzylmorpholin-2-yl)-1H-indazole: 2-(benzyl(2-hydroxyethyl)amino)-1-(1H-indazol-3-yl)ethane-1-ol (1.5 g, crude product) was dissolved in 48% aqueous hydrobromic acid solution (15 mL), and the reaction system was stirred at 100°C for 3 hours. Dichloromethane (15 mL) and water (15 mL) were added, and the pH was adjusted to 10 with saturated potassium carbonate. The mixture was extracted with dichloromethane (30 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography to obtain the title compound (800 mg).

[0436] LCMS (ESI) [M+H] + =294.1.

[0437] Step 5: Preparation of 3-(morpholin-2-yl)-1H-indazole: 3-(4-benzylmorpholin-2-yl)-1H-indazole (750 mg, 1 eq) was dissolved in methanol (8 mL). 10% palladium on carbon (0.28 eq) and 8 drops of acetic acid were added under a hydrogen atmosphere. The reaction system was stirred at room temperature for 24 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound (500 mg, crude product), which was used directly in the next step.

[0438] LCMS (ESI) [M+H] + =204.1.

[0439] Step 6: Preparation of 3-(4-(3-(2-methoxyphenyl)propyl)morpholin-2-yl)-1H-indazole: 3-(2-methoxyphenyl)propanal (121.19 mg) and 3-(morpholin-2-yl)-1H-indazole (150 mg, crude product) were dissolved in dichloromethane (2 mL), acetic acid (0.1 mL) was added, and the mixture was stirred for 10 minutes. Sodium triacetoxyborohydride (311.35 mg) was then added, and the reaction system was stirred for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by preparative HPLC (C18, 0.05% formic acid in water:acetonitrile) to obtain the title compound (111.79 mg).

[0440] LCMS (ESI) [M+H] + =352.2; 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),8.15(s,1H),7.85(d,J=8.1Hz,1H),7.49(d,J=8.4Hz,1H),7.35-7 .30(m,1H),7.19-7.12(m,2H),7.08(t,J=7.5Hz,1H),6.92(d,J=8.0Hz,1H),6.85(t,J=7.4Hz,1H),4.91( dd,J=10.3,2.3Hz,1H),3.95(d,J=9.9Hz,1H),3.80-3.73(m,4H),3.02(d,J=11.3Hz,1H),2.81(d,J=11.2 Hz, 1H), 2.59 (td, J = 7.2, 3.4Hz, 2H), 2.47-2.34 (m, 3H), 2.20 (td, J = 11.3, 3.1Hz, 1H), 1.77-1.67 (m, 2H).

[0441] Examples 38-42

[0442] Compounds 38-42 were prepared by referring to the preparation methods of Examples 29 and 37:

[0443] Compound 38: LCMS (ESI) [M+H] + =385.2;

[0444] Compound 39: LCMS (ESI) [M+H] + =403.2;

[0445] Compound 40: LCMS (ESI) [M+H] + =373.2;

[0446] Compound 41: LCMS (ESI) [M+H] + =362.2;

[0447] Compound 42: LCMS (ESI) [M+H] + =351.2.

[0448] Examples 43-44

[0449] Compounds 43-44 were prepared using the preparation method of Reference Example 5:

[0450] Compound 43: LCMS (ESI) [M+H] + =341.1; 1 H NMR (400MHz, CDCl3) δ7.98 (s, 1H), 7.67 (d, J = 7.9Hz, 1H), 7.35 (d, J = 8.1Hz, 1H), 7.18 (dd, J = 8.1, 1. 1Hz,1H),7.10(ddd,J=8.0,7.1,1.0Hz,1H),7.02(d,J=2.0Hz,1H),6.67(d,J=5.8Hz,1H),6.55(d,J= 5.8Hz,1H),3.87(s,3H),3.66(dd,J=16.9,8.2Hz,1H),3.18(t,J=8.4Hz,1H),2.93(dd,J=14.7,8.2H z,1H),2.66-2.49(m,6H),2.42-2.33(m,1H),2.01(ddd,J=12.6,7.3,2.7Hz,1H),1.85-1.79(m,2H).

[0451] Compound 44: LCMS (ESI) [M+H] + =324.2; 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.18(s,1H),7.61(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.24(d,J=2.2 Hz,1H),7.11-7.05(m,1H),7.01-6.95(m,1H),3.69-3.64(m,1H),3.45(d,J=8.4Hz,1H),3.21-3.11(m,2H),2.97 (t,J=9.4Hz,1H),2.92-2.82(m,2H),2.41-2.33(m,3H),2.30(s,3H),2.16(s,3H),2.09-2.01(m,1H),1.80-1.71(m,2H).

[0452] Example 45 (Compound 45)

[0453] Preparation of 3-(1-(3-(2-methyl-1,3-oxazol-4-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0454] Step 1: Preparation of ethyl 3-(2-methyl-1,3-oxazol-4-yl)prop-2-enoate: Sodium hydroxide (1.3 eq) was dissolved in tetrahydrofuran (20 mL), and a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.2 eq) in tetrahydrofuran (30 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for half an hour, and then a solution of 2-methyloxazole-4-carboxaldehyde (950 mg, 1 eq) in tetrahydrofuran (10 mL) was added dropwise. The mixture was reacted at room temperature for 2 hours, quenched with water, and extracted three times with ethyl acetate. The organic phase was collected and washed with saturated brine. The organic phase was spin-dried to give a crude product, which was separated and purified by flash chromatography to obtain the target compound (980 mg).

[0455] LCMS (ESI) [M+H] + =182.1.

[0456] Step 2: Preparation of ethyl 3-(2-methyl-1,3-oxazol-4-yl)propanoate: Dissolve ethyl 3-(2-methyl-1,3-oxazol-4-yl)prop-2-enoate (800 mg, 1 eq) in methanol (12 mL), add palladium carbon (60 mg, 10%), and stir at room temperature under a hydrogen atmosphere for 3 hours. Monitor the reaction until completion, filter through celite to obtain a filtrate, and dry the filtrate to obtain the target compound (600 mg).

[0457] 1 H NMR (400MHz, CDCl3) δ7.29 (s, 1H), 4.13 (t, J = 7.1Hz, 2H), 2.81 (t, J = 7.4Hz, 2H), 2.63 (t, J = 7.3Hz, 2H), 2.41 (s, 3H), 1.24 (t, J = 7.1Hz, 3H).

[0458] Step 3: Preparation of 3-(2-methyl-1,3-oxazol-4-yl)propanal: Ethyl 3-(2-methyl-1,3-oxazol-4-yl)propionate (700 mg, 1 eq) was dissolved in dichloromethane (15 mL), the temperature was lowered to -78°C, and diisobutylaluminum hydride toluene solution (1.5 M, 3.8 mL, 1.5 eq) was slowly added dropwise while maintaining the temperature. The reaction was continued at -78°C for 1 hour, monitored by TLC plate, and the reaction was complete when developed with 2,4-dinitrophenylhydrazine. Water (2 mL) was added to quench the reaction, and anhydrous sodium sulfate was added. A tetrahydrofuran solution was added and stirred for 5 minutes. The filtrate was filtered and separated and purified by flash chromatography to obtain the target compound (300 mg).

[0459] LCMS (ESI) [M+H] + =140.2.

[0460] Step 4: Preparation of 3-(1-(3-(2-methyl-1,3-oxazol-4-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(2-methyl-1,3-oxazol-4-yl)propanal (1.2 eq.) and 3-(pyrrolidin-3-yl)-1H-indole (200 mg, 1.0 eq.) were dissolved in tetrahydrofuran (5 mL), and acetic acid (0.5 mL) and sodium triacetoxyborohydride (3.0 eq.) were added. The mixture was stirred at room temperature for 1 hour, and water (10 mL) and ethyl acetate (5 mL×3) were added for extraction. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate to give the crude product, which was separated and purified by preparative HPLC (C18, 0.05% formic acid in water: acetonitrile) to give the title compound (105.94 mg).

[0461] LCMS (ESI) [M+H] + =310.2; 1 H NMR (400MHz, CDCl3) δ8.54 (s, 1H), 8.52 (s, 1H), 7.56 (d, J = 7.9Hz, 1H), 7.45-7.33 (m, 2H) ,7.24-7.18(m,1H),7.13(dd,J=11.5,4.4Hz,2H),3.90(t,J=8.5Hz,1H),3.82-3.67(m,1 H),3.50(d,J=7.9Hz,1H),3.36(s,1H),3.20(s,1H),3.14-3.06(m,2H),2.59(t,J=7.1Hz ,2H),2.55-2.46(m,1H),2.42(s,3H),2.29(d,J=9.2Hz,1H),2.16(dd,J=9.8,6.4Hz,2H).

[0462] Examples 46-48

[0463] Compounds 46-48 were prepared by referring to the preparation methods of Examples 18 and 45:

[0464] Compound 46: LCMS (ESI) [M+H] + =342.2;

[0465] Compound 47: LCMS (ESI) [M+H] + =325.2;

[0466] Compound 48: LCMS (ESI) [M+H] + =340.2

[0467] Example 49 (Compound 49)

[0468] Preparation of 3-(1-[3-(1,2,4-oxadiazol-3-yl)propyl]pyrrolidin-3-yl)-1H-indole:

[0469] Step 1: Preparation of 4-[3-(1H-indol-3-yl)pyrrolidin-1-yl]butyronitrile:

[0470] 3-(Pyrrolidin-3-yl)-1H-indole (4 g, 1.0 eq.) and sodium carbonate (3.0 eq.) were dissolved in acetonitrile (40 mL) at room temperature, followed by the addition of 4-bromobutyronitrile (1.1 eq.). The reaction mixture was incubated at 80°C for 16 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then isolated and purified by flash chromatography (Silica gel, PE:EA = 3:1-2:1) to obtain the title compound (3 g).

[0471] LCMS (ESI) [M+H] + =254.1.

[0472] Step 2: Preparation of (Z)-N'-hydroxy-4-[3-(1H-indol-3-yl)pyrrolidin-1-yl]butyramidine: 4-[3-(1H-indol-3-yl)pyrrolidin-1-yl]butyronitrile (2.2 g, 1.0 eq.) and hydroxylamine hydrochloride (3.5 eq.) were dissolved in a mixed solvent of ethanol (28 mL) and water (14 mL) at room temperature. Potassium carbonate (3.0 eq.) was added and the mixture was reacted at 80°C for 12 hours. The reaction solution was concentrated and extracted with dichloromethane / methanol (10:1, 15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the crude product, which was isolated and purified by flash chromatography (C18, 0.1% ammonia in water:acetonitrile) to obtain the title compound (2 g).

[0473] LCMS (ESI) [M+H] + =287.2.

[0474] Step 3: Preparation of 3-(1-[3-(1,2,4-oxadiazol-3-yl)propyl]pyrrolidin-3-yl)-1H-indole: (Z)-N'-hydroxy-4-[3-(1H-indol-3-yl)pyrrolidin-1-yl]butyramidine (120 mg, 1.0 eq.) was dissolved in triethyl orthoformate (2.25 mL) at room temperature, and a catalytic amount of trifluoroacetic acid (0.3 mL) was added. The mixture was stirred at room temperature for 10 minutes, then heated to 60°C and reacted for 30 minutes. The reaction solution was concentrated, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was filtered and concentrated. The crude product was separated and purified by preparative HPLC (C18, 0.1% formic acid in water: acetonitrile) to obtain the title compound (14.94 mg).

[0475] LCMS (ESI) [M+H] + =297.1; 1 H NMR(400MHz,MeOD-d4)δ9.19(s,1H),8.39(s,1H),7.59(d,J=7.9Hz,1H),7.37 (d,J=8.1Hz,1H),7.21(s,1H),7.12(dd,J=8.1,1.0Hz,1H),7.06(dd,J=7.9,0 .9Hz,1H),3.91(d,J=4.9Hz,2H),3.63(s,2H),3.50-3.35(m,3H),2.95(t,J=7 .3Hz,2H),2.59(td,J=13.1,6.3Hz,1H),2.46-2.31(m,1H),2.31-2.13(m,2H).

[0476] Example 50 (Compound 50)

[0477] Preparation of 3-(1-(3-(1,3,4-thiadiazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0478] Step 1: Preparation of methyl 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butanoate: 3-(Pyrrolidin-3-yl)-1H-indole (4.00 g, 1.0 eq.) and methyl 4-bromobutyrate (1.1 eq.) were dissolved in acetonitrile (40 mL), sodium carbonate (3.0 eq.) was added, and the mixture was stirred at 80° C. for 16 hours. The mixture was filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was dried to give the crude product, which was separated and purified by flash chromatography (Silica gel, DCM:MeOH=20:1) to give the title compound (3.8 g).

[0479] LCMS (ESI) [M+H] + =287.2.

[0480] Step 2: Preparation of 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyric acid: 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyric acid methyl ester (2.6 g, 1 eq.) was dissolved in methanol (26 mL), sodium hydroxide (42.96 eq.) was added, and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to adjust the pH to 7-8, and the reaction solution was spin-dried and purified by flash chromatography (C18, 0.1% formic acid in water: acetonitrile) to give the title compound (1.5 g).

[0481] LCMS (ESI) [M+H] + =273.1.

[0482] Step 3: Preparation of N'-formyl-4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyric acid (1.5 g, 1.0 eq.) was dissolved in DMF (15 mL), and HATU (1.5 eq.), N,N-diisopropylethylamine (3.0 eq.) and formic acid hydrazide (1.5 eq.) were added. The mixture was stirred at room temperature for 20 minutes. The reaction solution was separated and purified by flash chromatography (C18, 0.1% formic acid in water: acetonitrile) to give the title compound (550 mg).

[0483] LCMS (ESI) [M+H] + =315.2.

[0484] Step 4: Preparation of 3-(1-(3-(1,3,4-thiadiazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole: N'-formyl-4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butanoylhydrazide (450 mg, 1.0 eq.) was dissolved in dioxane (10 mL), and Lawesson's reagent (1.2 eq.) was added, and the mixture was stirred at 100°C for 1 hour. The reaction solution was spin-dried and purified by flash chromatography to give 300 mg of crude product, which was separated and purified by preparative HPLC (C18, 0.05% ammonia solution: acetonitrile) to give the title compound (9.88 mg).

[0485] LCMS (ESI) [M+H] + =313.2; 1 H NMR (400MHz, CDCl3-d) δ9.04(s,1H),7.97(s,1H),7.67(d,J=7.9Hz,1H),7.37(d,J=7.9Hz,1H),7.20(t,J=7.5Hz,1 H),7.11(t,J=7.5Hz,1H),7.06(s,1H),3.72(s,1H),3.30(t,J=7.3Hz,3H),2.76(s,5H),2.41(s,1H),2.16(s,3H).

[0486] Example 51 (Compound 51)

[0487] Compound 51 was prepared by referring to the preparation method of Example 50:

[0488] LCMS (ESI) [M+H] + =313.1.

[0489] Example 52 (Compound 52)

[0490] Preparation of 3-(1-(3-(1,3,4-oxadiazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0491] 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butanoic acid hydrazide (300 mg, 1.0 eq.) was dissolved in acetic acid (4 mL) and triethyl orthoformate (8 mL) was added. The atmosphere was replaced with nitrogen and the reaction was stirred at 110° C. for 3 hours. The solvent was evaporated and the product was separated and purified by preparative HPLC (C18, 0.05% formic acid in water: acetonitrile) to give the title compound (46.41 mg).

[0492] LCMS (ESI) [M+H] + =297.2; 1H NMR (400MHz, CDCl3) δ8.54(s,1H),8.35(s,1H),8.24(s,1H),7.61(d,J=7.9Hz,1H),7 .38(d,J=8.1Hz,1H),7.22(t,J=7.5Hz,1H),7.13(t,J=7.5Hz,1H),7.09(d,J=2.2Hz, 1H),3.84(p,J=8.5Hz,1H),3.67-3.58(m,1H),3.37(dd,J=18.1,7.6Hz,1H),3.25-3. 14(m,1H),3.13-2.96(m,5H),2.49(ddd,J=15.8,10.4,6.6Hz,1H),2.37-2.12(m,3H).

[0493] Example 53 (Compound 53)

[0494] Compound 53 was prepared by referring to the preparation method of Example 52:

[0495] LCMS (ESI) [M+H] + =297.2.

[0496] Example 54 (Compound 54)

[0497] Preparation of 3-(1-(3-(4-methyl-1,2,5-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0498] Step 1: Preparation of 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-methyl-1,2,5-oxadiazole: 3,4-dimethyl-1,2,5-oxadiazole (2 g, 1 eq) was dissolved in tetrahydrofuran (20 mL). The reaction temperature was lowered to -70 ° C. n-Butyl lithium (12.7 mL, 1 eq, 1.6 M, in THF) was slowly added dropwise over 20 minutes. The temperature was maintained and the reaction was stirred for 40 minutes. (2-bromo To the reaction mixture was added (1 eq) of (tert-butyl)dimethylsilane (1 eq), and the reaction was continued with stirring at the same temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×80 mL). The organic phases were combined and washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography to obtain the target compound 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-methyl-1,2,5-oxadiazole (1.3 g).

[0499] LCMS (ESI) [M+H] + =257.1.

[0500] Step 2: Preparation of 3-(4-methyl-1,2,5-oxadiazol-3-yl)propan-1-ol: Dissolve 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-methyl-1,2,5-oxadiazole (200 mg, 1 eq) in dichloromethane (2 mL) and add trifluoroacetic acid (2 mL). Stir at room temperature for 1 hour. The solvent is then evaporated to obtain the title compound (100 mg, crude product). This product is used directly in the next reaction without further purification.

[0501] LCMS (ESI) [M+H] + =143.1.

[0502] Step 3: Preparation of 3-(4-methyl-1,2,5-oxadiazol-3-yl)propyl methanesulfonate: Dissolve 3-(4-methyl-1,2,5-oxadiazol-3-yl)propan-1-ol (100 mg, crude) in dichloromethane (5 mL). Add triethylamine (213.54 mg). Cool the reaction mixture to 0°C. Slowly add methylsulfonyl chloride (96.69 mg) dissolved in dichloromethane (1 mL) dropwise. Stir at room temperature for 1 hour. Add water (10 mL) and extract with dichloromethane (3 × 10 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Use directly in the next step without further purification.

[0503] LCMS (ESI) [M+H] + =221.1.

[0504] Step 4: Preparation of 3-(1-(3-(4-methyl-1,2,5-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: Dissolve 3-(4-methyl-1,2,5-oxadiazol-3-yl)propyl methanesulfonate (80 mg, crude product, obtained from the previous step) in N,N-dimethylformamide (5 mL). Add 3-(pyrrolidin-3-yl)-1H-indole (81.18 mg) and potassium carbonate (150.6 mg). Stir in an oil bath at 70°C for 16 hours. Add water (5 mL) and extract with ethyl acetate (3 × 20 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated and purified by preparative HPLC (C18, 0.1% formic acid in water:acetonitrile) to obtain the title compound (22 mg).

[0505] LCMS (ESI) [M+H] + =311.3; 1HNMR(400MHz,DMSO-d6)δ10.79(s,1H),8.19(s,1H),7.59(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7 .16(d,J=2.0Hz,1H),7.06(t,J=7.5Hz,1H),6.96(t,J=7.4Hz,1H),3.57-3.51(m,1H),3.13(t,J=8. 5Hz,1H),2.90-2.84(m,1H),2.81(dd,J=13.5,6.0Hz,2H),2.73(dd,J=14.2,8.7Hz,1H),2.68(dd,J =7.0,4.8Hz,1H),2.61(dd,J=17.2,8.2Hz,2H),2.35(s,3H),2.31-2.19(m,1H),1.98-1.84(m,3H).

[0506] Example 55 (Compound 55)

[0507] Preparation of 3-(1-(3-(1,2,4-thiadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0508] Step 1: Preparation of 4-chlorobutyramide: Dissolve the raw material 4-chlorobutyryl chloride (15 g, 1 eq) in tetrahydrofuran (150 mL), add aqueous ammonia (75 mL) dropwise under ice bath, stir at room temperature for 16 hours, extract with ethyl acetate (100 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain the target compound (5 g, crude product), which is used directly in the next step.

[0509] LCMS (ESI) [M+H] + =122.1.

[0510] Step 2: Preparation of 5-(3-chloropropyl)-1,3,4-oxathiazol-2-one: 4-chlorobutyramide (5 g, 1 eq) was dissolved in 1,4-dioxane (2 mL), and carbonochloridic hypochlorous thioanhydride (1.1 eq) was added under ice bath. The reaction system was sealed and reacted at 100°C for 1 hour. TLC showed that the reaction was complete. Water (50 mL) was added and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by flash chromatography to obtain the target compound (3 g).

[0511] Step 3: Preparation of ethyl 3-(3-chloropropyl)-1,2,4-thiadiazole-5-carboxylate: 5-(3-chloropropyl)-1,3,4-oxathiazol-2-one (3 g, 1 eq) was dissolved in o-dichlorobenzene (30 mL), ethyl cyanoformate (5 eq) was added, and the reaction system was stirred at 140°C for 12 hours. The reaction solution was directly separated and purified by flash chromatography to obtain the target compound (2.5 g).

[0512] LCMS (ESI) [M+H] + =235.1.

[0513] Step 4: Preparation of 3-(3-chloropropyl)-1,2,4-thiadiazole: Ethyl 3-(3-chloropropyl)-1,2,4-thiadiazole-5-carboxylate (1 g, 1 eq) was dissolved in water (10 mL) and ethanol (2 mL), sodium hydroxide (1.1 eq) was added, and the reaction system was stirred at 100 ° C for 2 hours. The reaction solution was placed in an ice bath, concentrated hydrochloric acid (1.1 eq) was added, and the reaction system was stirred at 100 ° C for 3 hours. Water (20 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by a reverse phase system (C18, 0.1% trifluoroacetic acid in water: acetonitrile) to obtain the title compound (100 mg).

[0514] LCMS (ESI) [M+H] + =163.1.

[0515] Step 5: Preparation of 3-(1-(3-(1,2,4-thiadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(pyrrolidin-3-yl)-1H-indole (91.61 mg, 1 eq) and 3-(3-chloropropyl)-1,2,4-thiadiazol (1 eq) were dissolved in N,N-dimethylformamide (2 mL), disodium carbonate (2 eq) was added, and the reaction system was stirred at 70°C for 12 hours. Water (10 mL) was added and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by preparative HPLC (C18, 0.05% formic acid in water: acetonitrile) to obtain the title compound (21.95 mg).

[0516] LCMS (ESI) [M+H] + =313.3; 1H NMR(400MHz,Chloroform-d)δ9.79(s,1H),8.56(s,1H),8.35(s,1H),7.58(d,J=7.8Hz,1H), 7.40(s,1H),7.22(t,J=7.5Hz,1H),7.17-7.10(m,2H),3.89(dd,J=17.0,8.5Hz,1H),3.82-3 .72(m,1H),3.58-3.47(m,1H),3.42-3.33(m,1H),3.22(d,J=9.9Hz,1H),3.17(t,J=7.0Hz,4 H), 2.52 (dd, J = 12.8, 4.9 Hz, 1H), 2.41 ( dd, J = 15.5, 7.5 Hz, 2H), 2.28 ( dq, J = 17.1, 8.5 Hz, 1H).

[0517] Example 56 (Compound 56)

[0518] Compound 56 was prepared according to the preparation method of Example 55: LCMS (ESI) [M+H] + =329.1.

[0519] Example 57 (Compound 57)

[0520] Preparation of 3-(1-(3-(1-methyl-1H-pyrazol-4-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0521] 3-(1-Methyl-1H-pyrazol-4-yl)propanal (80 mg, 1.0 eq.) and 3-(pyrrolidin-3-yl)-1H-indole (1.1 eq.) were dissolved in tetrahydrofuran (10 mL) and stirred. Two drops of acetic acid were then added dropwise to the reaction mixture, and the reaction was allowed to proceed at 30°C for 0.5 hours. Sodium triacetoxyborohydride (2 eq.) was added to the reaction mixture, and the reaction was continued for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC (C18, 0.1% formic acid in water:acetonitrile) to yield the title compound (58.15 mg).

[0522] LCMS (ESI) [M+H] + =309.2; 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),8.19(s,1H),7.60(d,J=7.5Hz,1H),7.45(s,1H),7.32(d,J =8.0Hz,1H),7.23(s,1H),7.14(d,J=2.3Hz,1H),7.05(t,J=7.0Hz,1H),6.95(t,J=7.0Hz,1H),3. 76(s,3H),3.55(d,J=8.3Hz,2H),3.08(s,1H),2.82(d,J=6.9Hz,1H),2.67(s,1H),2.57(d,J=7.9 Hz, 2H), 2.43 (d, J = 7.5Hz, 2H), 2.25 (s, 1H), 1.92 (d, J = 7.8Hz, 1H), 1.70 (dd, J = 14.9, 7.4Hz, 2H).

[0523] Examples 58-68 (Compounds 58-68)

[0524] Compounds 58-68 were prepared by referring to the preparation method of Example 69:

[0525] Compound 58: LCMS (ESI) [M+H] + =327.2;

[0526] Compound 59: LCMS (ESI) [M+H] + =310.2;

[0527] Compound 60: LCMS (ESI) [M+H] + =325.2;

[0528] Compound 61: LCMS (ESI) [M+H] + =327.2;

[0529] Compound 62: LCMS (ESI) [M+H] + =323.2;

[0530] Compound 63: LCMS (ESI) [M+H] + =324.2;

[0531] Compound 64: LCMS (ESI) [M+H] + =324.2;

[0532] Compound 65: LCMS (ESI) [M+H] + =310.2;

[0533] Compound 66: LCMS (ESI) [M+H] + =310.2;

[0534] Compound 67: LCMS (ESI) [M+H] + =311.2;

[0535] Compound 68: LCMS (ESI) [M+H] + =329.2.

[0536] Example 69 (Compound 69)

[0537] Preparation of 3-(1-(3-(1-methyl-1H-pyrazol-4-yl)propyl)pyrrolidin-3-yl)-1H-indazole:

[0538] Step 1: Preparation of ethyl (E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate: To a suspension of NaH (60% dispersed in mineral oil, 15.6 g) in THF (260 mL) was slowly added dropwise 2-(diethoxyphosphoryl)acetate (1.5 eq) at 0°C. The mixture was allowed to return to room temperature and stirred for 30 minutes. Subsequently, a solution of 1-methyl-1H-pyrazole-4-carboxaldehyde (13 g, 1 eq) in THF (20 mL) was added dropwise at 0°C. The mixture was then brought to room temperature and the reaction continued for 5 hours. Water (100 mL) was slowly added dropwise at 0°C, and the mixture was extracted with ethyl acetate (100 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by flash chromatography to obtain the title compound (14.3 g).

[0539] LCMS (ESI) [M+H] + =181.1.

[0540] Step 2: Preparation of ethyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate: To a solution of ethyl (E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate (14.3 g, 1 eq) in THF (200 mL) was added palladium on carbon (10%, 3.0 g, 0.2 eq) at room temperature. The atmosphere was replaced with hydrogen using a double-layer hydrogen balloon and the mixture was allowed to react for 20 hours. The reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was evaporated to dryness to obtain the title compound (14 g, crude product), which was used directly in the next reaction.

[0541] LCMS (ESI) [M+H] + =183.1.

[0542] Step 3: Preparation of 3-(1-methyl-1H-pyrazol-4-yl)propan-1-ol: Under nitrogen protection, in an ice bath, LiAlH4 (1.37eq) was slowly added to a solution of ethyl 3-(1-methyl-1H-pyrazol-4-yl)propionate (14g, 1eq) in THF (200mL), and the mixture was slowly warmed to room temperature and reacted overnight. Under an ice bath, ethanol (20mL) and water (20mL) were slowly added dropwise to the reaction solution to quench the reaction. Ethyl acetate (100mL) was then added to dilute the mixture, and anhydrous magnesium sulfate (10g) was subsequently added to dry the mixture. After stirring at room temperature for 5 minutes, the mixture was filtered, the filter cake was washed with ethyl acetate (100mL), and the filtrate was spin-dried to obtain the target compound (10.1g, crude product), which was directly used in the next step.

[0543] LCMS (ESI) [M+H] + =141.1.

[0544] Step 4: Preparation of 3-(1-methyl-1H-pyrazol-4-yl)propanal: To a solution of 3-(1-methyl-1H-pyrazol-4-yl)propan-1-ol (10.1 g, crude) in DCM (200 mL) was slowly added Dess-Martin periodinane (30.5 g, 1 eq) under ice-cooling. The mixture was slowly warmed to room temperature and allowed to react overnight. Petroleum ether (50 mL) was then added, and the mixture was stirred at -78°C for 30 minutes before filtration. The filtrate was then spin-dried and separated by silica gel chromatography to afford the title compound (7.5 g).

[0545] Step 5: Preparation of tert-butyl 3-(1H-indazol-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate: At room temperature, 3-iodoindazole (400 mg, 1.0 eq), tert-butyl 3-(3,3,4,4-tetramethylborane-1-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.2 eq), potassium carbonate (3.0 eq), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.1 eq) were added to a 1,4-dioxane / water (10:1, 11 mL) solution, and the mixture was reacted at 110°C under a nitrogen atmosphere for 3 hours. The mixture was filtered and the filtrate was concentrated, and then separated and purified by flash chromatography to obtain the title compound (450 mg).

[0546] LCMS (ESI) [M+H] + =284.2.

[0547] Step 6: Preparation of tert-butyl 3-(1H-indazol-3-yl)pyrrolidine-1-carboxylate: To a solution of tert-butyl 3-(1H-indazol-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (450 mg, 1 eq) and palladium on carbon (0.2 eq) in methanol (30 mL) was added three drops of acetic acid at room temperature. The mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and the solvent was evaporated to obtain the title compound (430 mg).

[0548] LCMS (ESI) [M+H] + =286.2.

[0549] Step 7: Preparation of 3-(pyrrolidin-3-yl)-1H-indazole: To a solution of tert-butyl 3-(1H-indazol-3-yl)pyrrolidine-1-carboxylate (430 mg, 1.0 eq) in DCM (6 mL) was added TFA (0.5 mL) dropwise at room temperature. The mixture was stirred for 1 hour and then spun down to dryness. The mixture was then diluted with DCM (30 mL). Saturated sodium bicarbonate solution (30 mL) was slowly added dropwise to the solution under an ice bath. After separation, the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was spun down to obtain the title compound (275 mg).

[0550] LCMS (ESI) [M+H] + =188.1.

[0551] Step 8: Preparation of 3-(1-(3-(1-methyl-1H-pyrazol-4-yl)propyl)pyrrolidin-3-yl)-1H-indazole: To a solution of 3-(pyrrolidin-3-yl)-1H-indazole (275 mg, 1.0 eq) and 3-(1-methyl-1H-pyrazol-4-yl)propanal (1.2 eq) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (1.4 eq) at room temperature and allowed to react for 24 hours. Dichloromethane (10 mL) was then added to the reaction solution, and saturated sodium bicarbonate solution (15 mL) was added dropwise under ice-cooling. After separation, the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then purified by prep-HPLC (C18, 0.05% formic acid in water:acetonitrile) to obtain the title compound (75.36 mg).

[0552] LCMS (ESI) [M+H] + =310.2; 1H NMR (400MHz, d6-DMSO) δ12.60 (s, 1H), 7.83 (d, J = 8.1Hz, 1H), 7.45 (t, J = 4.1Hz, 2H), 7.48-7.41 (m, 1H), 7.22 (s, 1H), 7.05 (t, J = 7.8Hz, 1H), 3.77-3. 68(m,4H),3.01(t,J=8.5Hz,1H),2.75-2.61(m,3H),2.55-2.51(m,1H),2. 47-2.41(m,3H),2.34-2.22(m,1H),2.16-2.06(m,1H),1.73-1.64(m,2H).

[0553] Example 70 (Compound 70)

[0554] Compound 70 was prepared by referring to the preparation method of Example 57:

[0555] LCMS (ESI) [M+H] + =335.2.

[0556] Example 71 (Compound 71)

[0557] Preparation of 3-(1-(3-(1-methyl-1H-pyrazol-4-yl)propyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole:

[0558] Step 1: Preparation of tert-butyl 3-hydroxy-3-(1-(4-methylphenylsulfonyl)-1H-indol-3-yl)pyrrolidine-1-carboxylate: Dissolve 3-iodo-1-(4-methylphenylsulfonyl)-1H-indole (15 g, 1.0 eq) in ultra-dry tetrahydrofuran (150 mL). Slowly add 1.6 M n-butyl lithium (1.2 eq) dropwise at -68°C. Incubate for 1 hour. Slowly add tert-butyl 3-oxopyrrolidine-1-carboxylate (1.1 eq) and continue stirring for 1 hour. Warm the mixture to room temperature, add water (500 mL), and extract with ethyl acetate (500 mL x 3). The organic phase is then dried to obtain a crude product. The crude product is purified by flash chromatography (Silica gel, PE:EA = 3:1) to obtain the title compound (7 g).

[0559] LCMS (ESI) [M-56-H2O+H] + =383.0.

[0560] Step 2: Preparation of 3-(2,5-dihydro-1H-pyrrol-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole: Dissolve tert-butyl 3-hydroxy-3-(1-(4-methylphenylsulfonyl)-1H-indol-3-yl)pyrrolidine-1-carboxylate (1 g, 1.0 eq) in dichloromethane (12 mL), add trifluoroacetic acid (2 mL), react at room temperature for 1 hour, and spin dry to obtain the target compound (800 mg, crude product).

[0561] LCMS (ESI) [M+H] + =339.1.

[0562] Step 3: Preparation of 3-(1-(3-(1-methyl-1H-pyrazol-4-yl)propyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole: 3-(2,5-dihydro-1H-pyrrol-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole (700 mg, 1 eq) and 3-(1-methyl-1H-pyrazol-4-yl)propanal (1.5 eq) were dissolved in tetrahydrofuran (10 mL). Sodium triacetoxyborohydride (2 eq) was added and the mixture was reacted at room temperature for 1 hour. Water (10 mL) and ethyl acetate (10 mL x 3) were added for extraction. The organic phase was dried to obtain the title compound (800 mg, crude product).

[0563] LCMS (ESI) [M+H] + =461.1.

[0564] Step 4: Preparation of 3-(1-(3-(1-methyl-1H-pyrazol-4-yl)propyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole: 3-(1-(3-(1-methyl-1H-pyrazol-4-yl)propyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole (500 mg, crude) was dissolved in tetrahydrofuran (5 mL), and methanol (1 mL), water (1 mL) and potassium hydroxide (304.34 mg) were added, and the mixture was stirred at 70°C for 1 hour. The reaction solution was spin-dried, extracted three times with water (10 mL) and dichloromethane (10 mL × 3), and the organic phases were combined to obtain a crude product. The crude product was purified by preparative TLC to obtain 120 mg of crude product. The crude product was separated and purified by prep-HPLC (C18, 0.1% formic acid in water: acetonitrile) to obtain the title compound (4.58 mg).

[0565] LCMS (ESI) [M+H] + =307.2; 1H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.21(s,1H),7.81(d,J=7.8Hz,1H),7.48(s,1H),7.40(dd,J=5.1,2.6Hz,2H),7.26(s,1H),7.11(d t,J=14.9,7.1Hz,2H),6.10(s,1H),3.90(s,2H),3.77(s,3H),3.71(s,2H),2.81-2.72(m,2H),2.46(d,J=7.6Hz,2H),1.88-1.66(m,2H).

[0566] Examples 72-73

[0567] Compounds 72-73 were prepared by referring to the preparation method of Example 29:

[0568] Compound 72: LCMS (ESI) [M+H] + =343.2; 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.14(s,1H),7.65-7.56(m,1H),7.45(s,1H),7. 30(s,1H),7.23(s,1H),7.12(d,J=10.1Hz,1H),6.84(t,J=9.2Hz,1H),4.78(d,J=9.9Hz ,1H),3.91(d,J=11.5Hz,1H),3.73(d,J=17.7Hz,4H),3.01(d,J=11.3Hz,1H),2.86(d,J =11.2Hz, 1H), 2.43 (dd, J = 13.7, 7.4Hz, 5H), 2.29 (t, J = 11.0Hz, 1H), 1.83-1.58 (m, 2H).

[0569] Compound 73: LCMS (ESI) [M+H] + =310.2.

[0570] Example 74 (Compound 74)

[0571] Preparation of 3-(1-(3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0572] Step 1: Preparation of 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyric acid hydrazide: 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyric acid methyl ester (3 g, 1.0 eq) was dissolved in ethanol (30 mL), and hydrazine hydrate (5.24 g, 10 eq) was added under nitrogen protection. The reaction was stirred at 60 ° C. for 12 hours. The reaction solution was concentrated to give the target compound (3 g, crude product), which was used directly in the next step.

[0573] LCMS (ESI) [M+H] + =287.1.

[0574] Step 2: Preparation of (E)-N'-(4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyryl)-N,N-dimethylformamide: 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyryl)hydrazide (3 g, crude product) was dissolved in methanol (30 mL), and N,N-dimethylformamide dimethyl acetal (3.12 g) was added. The mixture was stirred at 80°C under a nitrogen atmosphere for 6 hours, and then N,N-dimethylformamide dimethyl acetal (3.12 g) was added. The mixture was stirred at 80°C for 6 hours. The reaction solution was concentrated to obtain a crude product, which was purified by reverse phase chromatography to obtain the title compound (1 g).

[0575] LCMS (ESI) [M+H] + =342.2.

[0576] Step 3: Preparation of 3-(1-(3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: (E)-N'-(4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyryl)-N,N-dimethylformamide (300 mg, 1 eq) was dissolved in tetrahydrofuran (10 mL), and 1 M methylamine tetrahydrofuran (20 eq) was added under nitrogen. The reaction was stirred at 100°C for 12 hours. The reaction solution was concentrated to obtain a crude product. Water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by prep-HPLC (C18, 0.1% trifluoroacetic acid in water:acetonitrile), and then converted into a hydrochloride by adding 1% hydrochloric acid to obtain the title compound (47.22 mg).

[0577] LCMS (ESI) [M+H] + =310.2; 1H NMR (400MHz, DMSO-d6) δ11.44(s,1H),11.05(s,1H),9.35(s,1H),7.60(s,1H),7.35(dd,J=17.4,5.0Hz,2H),7.10(t,J=7.1Hz,1H) ,7.01(t,J=7.4Hz,1H),3.80(s,6H),3.34(d,J=6.6Hz,3H),3.11(t,J=7.4Hz,3H),2.47-2.42(m,1H),2.25(dt,J=14.5,7.3Hz,3H).

[0578] Examples 75-76

[0579] Compounds 75-76 were prepared by referring to the preparation method of Example 74:

[0580] Compound 75: LCMS (ESI) [M+H] + =296.1; 1 H NMR (400MHz, MeOD-d4) δ8.36(s,1H),7.56(d,J=7.8Hz,1H),7.32(d,J=8.1Hz,1H),7.11-7.04(m,2H),6.98(t,J=7.5Hz,1H),3.66(d,J=8.5H z, 4H), 3.26 (d, J = 8.2Hz, 1H), 3.09-2.95 (m, 5H), 2.82 (dd, J = 14.9, 9.0Hz, 1H), 2.73 (t, J = 8.9Hz, 1H), 2.45-2.32 (m, 1H), 2.15-2.01 (m, 1H).

[0581] Compound 76: LCMS (ESI) [M+H] + =370.2; 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.54(s,1H),7.56(d,J=7.9Hz,1H),7.3 4(d,J=8.0Hz,1H),7.19(d,J=2.2Hz,1H),7.06(t,J=7.5Hz,1H),6.97(t,J=7.3 Hz,1H),4.86-4.64(m,1H),4.37(dt,J=13.3,6.7Hz,1H),3.30(s,2H),3.25(s, 1H),3.11-2.98(m,2H),2.73(t,J=7.4Hz,2H),2.38(s,1H),2.06-1.94(m,2H), 1.89 (dd, J = 14.5, 7.2 Hz, 2H), 1.74-1.62 (m, 1H), 1.39 (dd, J = 6.6, 3.4 Hz, 6H). Compound 77: LCMS (ESI) [M+H] + =324.2.

[0582] Example 78 (Compound 78)

[0583] Preparation of 3-(8-(3-(4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)-8-azabicyclo[3.2.1]octan-6-yl)-1H-indole:

[0584] Step 1: Preparation of 8-benzyl-7-hydroxy-8-azabicyclo[3.2.1]octan-2-one: Dissolve 2,5-dimethoxy-2,5-dihydrofuran (50 g, 1 eq) and 3-oxoglutaric acid in 3 M aqueous hydrochloric acid (722 mL). Stir at room temperature overnight under nitrogen. Add 6 M aqueous sodium hydroxide (340 mL) to adjust the pH to 7. The reaction mixture is added to sodium acetate buffer (2000 mL) and stirred at room temperature overnight. Potassium carbonate (1.18 eq) and sodium chloride (2.8 eq) are added. Stirring is continued for 1 hour. Extraction is performed with dichloromethane (4 x 300 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by flash chromatography (Silica gel, PE:EA = 3:1) to obtain the title compound (14 g).

[0585] LCMS (ESI) [M+H] + =232.1.

[0586] Step 2: Preparation of 8-benzyl-8-azabicyclo[3.2.1]octan-6-ol: Add hydrazine hydrate (10 eq) to a solution of 8-benzyl-7-hydroxy-8-azabicyclo[3.2.1]octan-2-one (15 g, 1 eq) in diethylene glycol (250 mL). Stir at 120°C for 2 hours. Monitor the reaction by LCMS until the starting material disappears. Add potassium hydroxide (20 eq) in diethylene glycol in batches. Heat to 200°C and stir for 4 hours. Cool to room temperature. Add water (1 L) and stir for 1 hour. A large amount of white solid precipitates. Filter, wash the filter cake with water, collect the solid, and dry to obtain the title compound (27 g, crude product).

[0587] LCMS (ESI) [M+H] + =218.1.

[0588] Step 3: Preparation of 8-azabicyclo[3.2.1]octan-6-ol: Palladium on carbon (300 mg) was added to a solution of 8-benzyl-8-azabicyclo[3.2.1]octan-6-ol (3 g, crude product) in methanol (30 mL) and tetrahydrofuran (30 mL). The mixture was stirred at room temperature under Pd / C for 12 hours. The reaction mixture was filtered through celite, the filter cake was washed with tetrahydrofuran, the filtrate was collected, and the mixture was concentrated in vacuo to give the title compound (1.2 g).

[0589] LCMS (ESI) [M+H] + =128.3.

[0590] Step 4: Preparation of benzyl 6-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate: Benzyl chloroformate (1.1 eq) was added to 8-azabicyclo[3.2.1]octane-6-ol (1.2 g, 1 eq) and potassium carbonate (2 eq) / tetrahydrofuran (10 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was separated and purified by flash chromatography to give the title compound (1.47 g).

[0591] LCMS (ESI) [M+H] + =262.1.

[0592] Step 5: Preparation of 6-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester: Dess-Martin oxidant (3 eq) was added to 6-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester (1 g, 1 eq) in ethyl acetate (20 mL), and the mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated in vacuo. The title compound (650 mg) was obtained by purification through a reverse phase system (C18, 0.1% formic acid in water: acetonitrile).

[0593] LCMS (ESI) [M+H] + =260.1.

[0594] Step 6: Preparation of 6-hydroxy-6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester: 3-iodo-1-(4-methylbenzenesulfonyl)-1H-indole (1.5 eq) was dissolved in tetrahydrofuran (50 mL), and the atmosphere was replaced with nitrogen. 1.6 M n-butyllithium tetrahydrofuran solution (1.5 eq) was added dropwise at -78°C. After addition, the mixture was stirred at -78°C for 0.5 hours. Benzyl 6-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (5 g, 1 eq) was added to the reaction solution, and the mixture was stirred at -78°C for 1 hour. Saturated sodium carbonate solution (50 mL) was slowly added to the reaction solution at -78°C, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography to obtain the target compound (2.6 g).

[0595] LCMS (ESI) [M+Na] + =553.1.

[0596] Step 7: Preparation of benzyl 6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate: Benzyl 6-hydroxy-6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.8 g, 1 eq) was dissolved in dichloroethane (20 mL), and trifluoroacetic acid (10 eq) and triethylsilane (10 eq) were added. The atmosphere was replaced with nitrogen and stirred at 100° C. in a sealed container for 3 hours. Saturated sodium carbonate solution (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed once with saturated sodium bicarbonate solution and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to give the title compound (2.3 g, yield: 84.7%).

[0597] Step 8: Preparation of 3-(8-azabicyclo[3.2.1]octane-6-yl)-1-(4-methylbenzenesulfonyl)-1H-indole: Dissolve benzyl 6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.2 g, 1 eq) in methanol (20 mL), add palladium carbon (0.1 eq) and acetic acid (1 eq), replace the atmosphere with hydrogen, stir at room temperature for 16 hours, filter the reaction solution, and concentrate the mother liquor to obtain a crude product, which is purified to obtain the title compound (560 mg).

[0598] LCMS (ESI) [M+H] + =381.2.

[0599] Step 9: Preparation of methyl 4-(6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)butanoate: 3-(8-azabicyclo[3.2.1]octan-6-yl)-1-(4-methylbenzenesulfonyl)-1H-indole (550 mg, 1 eq) was dissolved in acetonitrile (10 mL), and methyl 4-bromobutyrate (1.2 eq) and potassium carbonate (1.5 eq) were added, and stirred at 80°C for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The mother liquor was concentrated to obtain a crude product, which was separated and purified by flash chromatography to obtain the title compound (560 mg).

[0600] LCMS (ESI) [M+H] + =481.2.

[0601] Step 10: Preparation of 4-(6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]oct-8-yl)butyric acid hydrazide: Methyl 4-(6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]oct-8-yl)butanoate (100 mg, 1 eq) was dissolved in ethanol (5 mL), hydrazine hydrate (10 eq) was added, and the mixture was stirred at 60°C for 16 hours. The reaction solution was concentrated to give the title compound (90 mg).

[0602] LCMS (ESI) [M+H] + =481.2.

[0603] Step 11: Preparation of (E)-N,N-dimethyl-N'-(4-(6-(1-toluenesulfonyl-1H-indol-3-yl)-8-azabicyclo[3.2.1]oct-8-yl)butyryl)formamide: 4-(6-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)-8-azabicyclo[3.2.1]oct-8-yl)butyric acid hydrazide (400 mg, 1 eq) was dissolved in methanol (10 mL), and N,N-dimethylformamide dimethyl acetal (10 eq) was added. The mixture was reacted at 80°C for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified to obtain the title compound (400 mg).

[0604] LCMS (ESI) [M+H] + =536.3.

[0605] Step 12: Preparation of 1-(4-methylbenzenesulfonyl)-3-(8-(3-(4-(propyl-2-yl)-4H-1,2,4-triazol-3-yl)propyl)-8-azabicyclo[3.2.1]octan-6-yl)-1H-indole:

[0606] (E)-N,N-Dimethyl-N'-(4-(6-(1-tosyl-1H-indol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)butanoyl)formamide (240 mg, 1 eq) was dissolved in acetic acid (5 mL), and propan-2-amine (10 eq) was added. The mixture was sealed and reacted at 110°C for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified to obtain the title compound (170 mg).

[0607] LCMS (ESI) [M+H] + =532.2.

[0608] Step 13: Preparation of 3-(8-(3-(4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)-8-azabicyclo[3.2.1]oct-6-yl)-1H-indole: 1-(4-methylbenzenesulfonyl)-3-(8-(3-(4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)-8-azabicyclo[3.2.1]oct-6-yl)-1H-indole (90 mg, 1 eq) was dissolved in tetrahydrofuran (THF) To the mixture of hydrofuran (5 mL), potassium hydroxide (249.5 eq) was added, followed by methanol (1 mL) and water (1 mL), and the mixture was stirred at 70°C for 6 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The mother liquor was concentrated to obtain a crude product, which was purified by prep-HPLC (C18, 0.05% ammonia solution in water: acetonitrile) to obtain the title compound (17.85 mg).

[0609] LCMS (ESI) [M+H] + =378.4; 1H NMR(400MHz,MeOD-d4)δ8.69(s,1H),8.48(s,1H),7.53(d,J=7.9Hz,1H),7.45-7.34(m ,2H),7.14(t,J=7.6Hz,1H),7.04(t,J=7.4Hz,1H),4.54-4.41(m,2H),4.19(s,2H),3.4 9(s,2H),3.14-2.98(m,2H),2.83(dd,J=20.3,13.1Hz,1H),2.52(dd,J=13.7,6.8Hz,1H ), 2.41 (s, 2H), 2.18 (s, 1H), 1.91 (d, J = 8.7Hz, 3H), 1.54 (d, J = 6.7Hz, 6H), 1.45 (s, 2H).

[0610] Examples 79-84

[0611] Compounds 79-84 were prepared by referring to the preparation methods of Examples 4, 5, 74, and 78:

[0612] Compound 79: LCMS (ESI) [M+H] + =338.2; 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.55(s,1H),8.22(s,1H),7.61(d,J=7.8Hz,1H),7.33(d,J=8 .1Hz,1H),7.17(d,J=2.2Hz,1H),7.06(t,J=7.5Hz,1H),6.96(t,J=7.4Hz,1H),4.40-4.29(m,1H),3 .61-3.51(m,1H),3.14(t,J=8.5Hz,1H),2.87(dd,J=16.3,7.6Hz,1H),2.79(dd,J=14.6,7.3Hz,3H) ,2.74-2.59(m,3H),2.28(ddd,J=21.5,10.4,6.6Hz,1H),2.00-1.87(m,3H),1.37(t,J=6.4Hz,6H).

[0613] Compound 80: LCMS (ESI) [M+H] + =356.2;

[0614] Compound 81: LCMS (ESI) [M+H] + =368.3; 1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.99(s,1H),7.24(s,1H),7.11(d,J=2.3Hz,1H), 7.02(d,J=2.2Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),4.39-4.22(m,1H),3.86(s,3H),3.74-3.5 9(m,1H),3.24(t,J=8.5Hz,1H),3.00(d,J=8.2Hz,1H),2.85(t,J=7.5Hz,4H),2.76(d,J=8.1 Hz, 2H), 2.44-2.34 (m, 1H), 2.12 (ddd, J = 21.0, 12.0, 6.6Hz, 3H), 1.46 (dd, J = 6.7, 4.8Hz, 6H).

[0615] Compound 82: LCMS (ESI) [M+H] + =368.2;

[0616] Compound 83: LCMS (ESI) [M+H] + =396.1; 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.51(s,1H),8.24(s,1H),7.60(dd,J=8.7,5.5Hz ,1H),7.18(d,J=2.0Hz,1H),7.11(dd,J=10.2,2.3Hz,1H),6.83(ddd,J=9.8,8.8,2.4Hz ,1H),5.12(q,J=9.2Hz,2H),3.61-3.51(m,1H),3.21(t,J=8.6Hz,1H),2.93(dt,J=14.8 ,7.4Hz,1H),2.88-2.68(m,6H),2.29(ddd,J=21.5,10.4,6.6Hz,1H),2.03-1.88(m,3H).

[0617] Compound 84: LCMS (ESI) [M+H] + =356.1; 1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),8.07(s,1H),7.62-7.54(m,1H),7.07-6.99(m,2H),6.91-6.81(m,1H),4.40-4.26(m,1H),3.66 (s,1H),3.18(s,1H),2.83(dd,J=34.4,26.9Hz,7H),2.39(s,1H),2.15(s,2H),2.04(dd,J=17.0,7.1Hz,1H),1.47(dd,J=6.6,5.6Hz,6H).

[0618] Example 85 (Compound 85)

[0619] Preparation of 3-(1-(3-(4-(difluoromethyl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0620] Step 1: Preparation of 4-(3-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)pyrrolidin-1-yl)butyronitrile: 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyronitrile (5 g, 1 eq) was dissolved in N,N-dimethylformamide (50 mL), potassium hydroxide (4 eq) was added, and the reaction system was stirred for 30 minutes. A solution of 4-methylbenzene-1-sulfonyl chloride (2.5 eq) in N,N-dimethylformamide (25 mL) was added dropwise. After the addition was complete, the reaction system was stirred for 12 hours, water (150 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography to obtain the target compound (5 g).

[0621] LCMS (ESI) [M+H] + =408.2.

[0622] Step 2: Preparation of 4-(3-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)pyrrolidin-1-yl)butyramide: 4-(3-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)pyrrolidin-1-yl)butyronitrile (4.5 g, 1 eq) was dissolved in methanol (45 mL), and 30% hydrogen peroxide (5 eq) and 1N sodium hydroxide (2 eq) were added in sequence. At this time, the solution was turbid. Dimethyl sulfoxide (4.5 mL) was added, and the reaction system was stirred at room temperature for 3 hours, extracted with ethyl acetate (50 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (4.1 g).

[0623] LCMS (ESI) [M+H]+ =426.3.

[0624] Step 3: Preparation of N-formyl-4-(3-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)pyrrolidin-1-yl)butanamide: 4-(3-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)pyrrolidin-1-yl)butanamide (3.6 g, 1 eq) was dissolved in a mixed solution of N,N-dimethylformamide dimethyl acetal (36 mL) and N,N-dimethylformamide (3.6 mL). The reaction system was stirred at 80°C for 12 hours. The reaction solution was concentrated to obtain a crude product, which was purified to obtain the target compound (3.2 g).

[0625] LCMS (ESI) [M+H] + =454.1.

[0626] Step 4: Preparation of 1-(4-methylbenzenesulfonyl)-3-(1-(3-(4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: N-formyl-4-(3-(1-(4-methylbenzenesulfonyl)-1H-indol-3-yl)pyrrolidin-1-yl)butanamide (3 g, 1 eq) was dissolved in acetic acid (30 mL), hydrazine hydrate (2 eq) was added under ice bath, the reaction system was stirred at 90 ° C for 2 hours, the reaction solution was concentrated to obtain a crude product, and the crude product was purified to obtain the title compound (2.2 g).

[0627] LCMS (ESI) [M+H] + =450.1.

[0628] Step 5: Preparation of 3-(1-(3-(4-(difluoromethyl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole: 1-(4-methylphenylsulfonyl)-3-(1-(3-(4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole (2 g, 1 eq) was dissolved in acetonitrile (20 mL) and saturated To an aqueous potassium fluoride solution (4 mL) was added (bromodifluoromethyl)trimethylsilane (5 eq), and the reaction system was stirred at room temperature for 16 hours. The reaction solution was concentrated, and water (20 mL) was added, followed by extraction with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by prep-HPLC (C18, 0.1% aqueous ammonia solution: acetonitrile) to obtain the title compound (200 mg).

[0629] LCMS (ESI) [M+H] + =500.2.

[0630] Step 6: Preparation of 3-(1-(3-(4-(difluoromethyl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(1-(3-(4-(difluoromethyl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole (200 mg, 1 eq) was dissolved in methanol (0.1 mL), tetrahydrofuran (THF) and 1% CO. To a mixed solution of oxalic acid (0.5 mL) and water (0.1 mL) was added potassium hydroxide (50 eq), the reaction system was stirred at 70 ° C for 3 hours, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by prep-HPLC (C18, 0.05% aqueous ammonia solution: acetonitrile) to obtain the title compound (18.73 mg).

[0631] LCMS (ESI) [M+H] + =345.9; 1 H NMR(400MHz,Chloroform-d)δ8.40(s,1H),7.96(s,1H),7.67(d,J=7.9Hz,1H), 7.37-7.32(m,1H),7.19(dd,J=8.9,6.2Hz,2H),7.10(t,J=7.5Hz,1H),7.03(s,1 H),3.69(dd,J=16.7,8.3Hz,1H),3.21(t,J=7.9Hz,1H),2.94(s,1H),2.87(t,J= 7.5Hz, 2H), 2.74-2.59 (m, 4H), 2.42-2.32 (m, 1H), 2.04 (dd, J = 14.2, 6.6Hz, 3H).

[0632] Example 86 (Compound 86)

[0633] Preparation of 3-(1-(3-(5-methyl-4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0634] Step 1: Preparation of (E)-N'-(4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyryl)-N,N-dimethylacetohydrazide amide: Dissolve 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyrylhydrazide (600 mg, 1.0 eq) in methanol (10 mL), add 1,1-dimethoxy-N,N-dimethylethan-1-amine (3.0 eq), and stir at 80°C for 3 hours. The reaction solution is concentrated to obtain a crude product, which is separated and purified by flash chromatography to obtain the title compound (240 mg).

[0635] LCMS (ESI) [M+H] + =356.2.

[0636] Step 2: Preparation of 3-(1-(3-(5-methyl-4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: (E)-N'-(4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butanoyl)-N,N-dimethylacetohydrazideamide (220 mg, 1.0 eq) was dissolved in acetic acid (5 mL), isopropylamine (10 eq) was added, and the mixture was stirred at 130°C for 48 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by prep-HPLC (C18, 0.05% formic acid in water:acetonitrile) to give the title compound (19.57 mg).

[0637] LCMS (ESI) [M+H] + =352.2; 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),8.17(s,1H),7.61(d,J=7.9Hz,1H),7.33(d,J= 8.2Hz,1H),7.17(s,1H),7.06(t,J=7.5Hz,1H),6.96(t,J=7.5Hz,1H),4.43(dd,J=14 .0,7.0Hz,1H),3.57(s,1H),3.14(s,1H),2.86(s,1H),2.82-2.75(m,3H),2.73-2.62 (m,3H),2.38(,3H),2.28(s,1H),1.94(dt,J=14.1,7.2Hz,3H),1.39(d,J=6.9Hz,6H).

[0638] Example 87 (Compound 87)

[0639] Preparation of 3-(1-(3-(4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0640] Step 1: Preparation of 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyric acid hydrazide: Methyl 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyrate (800 mg, 1 eq) was dissolved in ethanol (5 mL), hydrazine hydrate (1398.47 mg, 10 eq) was added, and the mixture was stirred at 60°C for 16 hours. The reaction solution was concentrated to obtain the target compound (720 mg, crude product), which was used directly in the next step.

[0641] LCMS (ESI) [M+H] + =287.1.

[0642] Step 2: Preparation of 2-(3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)propyl)-5-(trifluoromethyl)-1,3,4-oxadiazole: 4-(3-(1H-indol-3-yl)pyrrolidin-1-yl)butyric acid hydrazide (1.5 g, crude product) was dissolved in phosphorus oxychloride (10 mL), trifluoroacetic acid (0.9 g) was added, nitrogen was replaced, and the mixture was stirred at 80 ° C for 16 hours. The reaction solution was concentrated to remove phosphorus oxychloride, and then cooled to 0 ° C. The reaction solution was added to the mixture at 0 ° C. Saturated sodium carbonate solution (50 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was extracted with ethyl acetate (50 mL × 3), separated, and the organic phases were combined. The organic phase was washed once with saturated sodium carbonate solution (25 mL) and once with saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was separated and purified by prep-HPLC (C18, 0.1% formic acid in water: acetonitrile) to obtain the title compound (150 mg).

[0643] LCMS (ESI) [M+H] + =365.0.

[0644] Step 3: Preparation of 3-(1-(3-(4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: 2-(3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)propyl)-5-(trifluoromethyl)-1,3,4-oxadiazole (500 mg, 1 eq) was dissolved in acetic acid (10 mL), 2M methylamine tetrahydrofuran solution (10 eq) was added, and the mixture was stirred at 130°C in a sealed tube for 48 hours. The reaction mixture was stirred at 130°C for 48 hours. The acetic acid was removed by concentration, and a saturated sodium carbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed once with a saturated sodium carbonate solution (20 mL) and once with saturated brine (20 mL). The mixture was filtered and the mother liquor was concentrated to obtain a crude product. The crude product was first purified by prep-HPLC (C18, 0.1% formic acid in water: acetonitrile) and then by prep-HPLC (C18, 0.05% ammonia in water: acetonitrile) to obtain the title compound (53.63 mg).

[0645] LCMS (ESI) [M+H] + =378.2; 1H NMR(400MHz,MeOD-d4)δ7.56(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.10-7.04(m,2H),6.98(t,J=7.4Hz,1H),3.76(s,3H), 3.69-3.60(m,1H),3.27-3.20(m,1H),3.01-2.91(m,3H),2.77-2.62(m,4H),2.36(dt,J=17.2,7.9Hz,1H),2.12-2.00(m,3H).

[0646] Examples 88-89 (Compounds 88-89)

[0647] Compounds 88-89 were prepared by referring to the preparation methods of Examples 18 and 74:

[0648] Compound 88: LCMS (ESI) [M+H] + =382.2;

[0649] Compound 89: LCMS (ESI) [M+H] + =356.2; 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.55(s,1H),8.16(s,1H),7.56(d,J=7.8Hz,1H),7.36(d,J=8.1H z,1H),7.25(d,J=2.1Hz,1H),7.10(dd,J=11.0,4.0Hz,1H),7.00(dd,J=11.0,3.9Hz,1H),5.31-5.09(m ,1H),4.45-4.29(m,1H),3.73-3.54(m,1H),3.34(t,J=8.3Hz,1H),3.10(dd,J=24.3,11.7Hz,1H),2.84 -2.66(m,3H),2.61-2.53(m,2H),2.46(t,J=8.8Hz,1H),2.00-1.86(m,2H),1.39(dd,J=6.7,3.5Hz,6H).

[0650] Example 90 (Compound 90)

[0651] Preparation of 6-fluoro-3-(4-methyl-1-(3-(4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0652] Step 1: Preparation of tert-butyl 3-(6-fluoro-1H-indol-3-yl)-4-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate: tert-butyl 3-methyl-4-oxopyrrolidine-1-carboxylate (1.7 eq) and 6-fluoro-1H-indole (6 g, 1 eq) were dissolved in methanol (100 mL), potassium hydroxide (10 eq) was added, and the mixture was reacted at 70 ° C. for 16 hours. The methanol was spin-dried, water (50 mL) was added, and ethyl acetate (100 mL×3) was added for extraction. The organic phase was spin-dried to obtain a crude product, which was separated and purified by flash chromatography (Silica gel, PE:EA=5:1) to obtain the target compound (3 g, crude product).

[0653] LCMS (ESI) [M-56+MeCN+H] + =302.2.

[0654] Step 2: Preparation of tert-butyl 3-(6-fluoro-1H-indol-3-yl)-4-methylpyrrolidine-1-carboxylate: Dissolve tert-butyl 3-(6-fluoro-1H-indol-3-yl)-4-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate (2 g, 1 eq) in tetrahydrofuran (20 mL), add palladium carbon (500 mg, 10%) and stir at room temperature under a hydrogen atmosphere for 1 hour. Filter through celite and spin dry the filtrate to obtain the target compound (2 g, crude product).

[0655] LCMS (ESI) [M-56+MeCN+H] + =304.2.

[0656] Step 3: Preparation of 6-fluoro-3-(4-methylpyrrolidin-3-yl)-1H-indole: tert-Butyl 3-(6-fluoro-1H-indol-3-yl)-4-methylpyrrolidine-1-carboxylate (2 g, crude product) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the mixture was reacted at room temperature for 1 hour. The reaction was complete after LCMS detection. The reaction solution was spin-dried and purified by reverse phase separation (C18, 0.1% formic acid in water: acetonitrile) to obtain the title compound (1 g).

[0657] LCMS (ESI) [M+H] + =219.1.

[0658] Step 4: Preparation of methyl 4-(3-(6-fluoro-1H-indol-3-yl)-4-methylpyrrolidin-1-yl)butanoate: 6-Fluoro-3-(4-methylpyrrolidin-3-yl)-1H-indole (800 mg, 1 eq) was dissolved in acetonitrile (10 mL), methyl 4-bromobutyrate (0.8 eq) and sodium carbonate (4 eq) were added, and the mixture was reacted at 70 ° C. for 16 hours, preparative filtration was performed, and the filtrate was spin-dried to give a crude product, which was separated and purified by flash chromatography (Silica gel, DCM:MeOH=20:1) to give the title compound (400 mg, yield 34.3%).

[0659] LCMS (ESI) [M+H] + =319.3.

[0660] Step 5: Preparation of 4-(3-(6-fluoro-1H-indol-3-yl)-4-methylpyrrolidin-1-yl)butane hydrazide: 4-(3-(6-fluoro-1H-indol-3-yl)-4-methylpyrrolidin-1-yl)butanoic acid methyl ester (360 mg, 1 eq) was dissolved in ethanol (4 mL), hydrazine hydrate (10 eq) was added, and the mixture was reacted at 60 ° C for 4 hours. The disappearance of the starting material was monitored by TLC. LCMS showed that the reaction was successful. The title compound (360 mg, crude product) was obtained by spin drying.

[0661] LCMS (ESI) [M+H] + =319.2.

[0662] Step 6: Preparation of (E)-N'-(4-(3-(6-Fluoro-1H-indol-3-yl)-4-methylpyrrolidin-1-yl)butanoyl)-N,N-dimethyldiformamide: 4-(3-(6-Fluoro-1H-indol-3-yl)-4-methylpyrrolidin-1-yl)butanehydrazide (360 mg, crude) was dissolved in N,N-dimethylformamide (1 mL), and N,N-dimethylformamide dimethyl acetal (22.26 eq) was added. The mixture was reacted at 70°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was spin-dried and the crude product was purified by reverse phase system (C18, 0.1% NH3H2O ​​in water, MeOH) to give the title compound (250 mg).

[0663] LCMS (ESI) [M+H] + =374.5.

[0664] Step 7: Preparation of 6-fluoro-3-(4-methyl-1-(3-(4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: (E)-N'-(4-(3-(6-fluoro-1H-indol-3-yl)-4-methylpyrrolidin-1-yl)butanoyl)-N,N-dimethyldiformamide (250 mg, 1 eq) was dissolved in acetic acid (6 mL), and isopropylamine (10 eq) was added dropwise under ice bath. The mixture was reacted at 110 ° C. for 16 hours, and most of the acetic acid was removed by spin drying. Saturated potassium carbonate solution was added to adjust the pH to 10, and ethyl acetate (20 mL×3) was added to extract the aqueous phase. The organic phase was spin dried to obtain the crude product, which was separated and purified by prep-HPLC (C18, 0.05% NH3H2O ​​in water, MeCN) to obtain the title compound (33.13 mg).

[0665] LCMS (ESI) [M+H] + =370.6; 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),8.13(s,1H),7.50(dd,J=8.6,5.3Hz, 1H),7.10-6.95(m,2H),6.87(td,J=9.4,2.3Hz,1H),4.36(dt,J=13.4,6.8Hz,1H) ,3.76(d,J=8.1Hz,1H),3.23(s,2H),2.86(t,J=7.5Hz,2H),2.70(dd,J=14.7,7. 1Hz, 4H), 2.24 (s, 1H), 2.13 (s, 2H), 1.50 (d, J = 6.7Hz, 6H), 0.62 (d, J = 7.1Hz, 3H).

[0666] Examples 91-92 (Compounds 91-92)

[0667] Compounds 91-92 were prepared by referring to the preparation methods of Examples 18 and 74:

[0668] Compound 91: LCMS (ESI) [M+H] + =370.2;

[0669] Compound 92: LCMS (ESI) [M+H] + =368.1; 1H NMR (400MHz, DMSO-d6) δ8.19(s,2H),7.59(dd,J=8.7,5.4Hz,1H),7.03(dd,J=9.7,2.2Hz,1H),6.99(d,J=1.3Hz,1H),6.86(m,1H),4.59-4.46(m,1 H),3.65-3.54(m,1H),3.07(t,J=8.4Hz,1H),2.82(dt,J=15.3,8.1Hz,3H ),2.72-2.50(m,6H),2.38-2.29(m,3H),2.07-1.97(m,3H),1.89(m,2H).

[0670] Examples 93-96 (Compounds 93-96)

[0671] Compounds 93-96 were prepared by referring to the preparation methods of Examples 74 and 86:

[0672] Compound 93: LCMS (ESI) [M+H] + =342.2;

[0673] Compound 94: LCMS (ESI) [M+H] + =356.2;

[0674] Compound 95: LCMS (ESI) [M+H] + =378.2;

[0675] Compound 96: LCMS (ESI) [M+H] + =368.2.

[0676] Example 97 (Compound 97)

[0677] Preparation of 6-fluoro-3-(1-(3-fluoro-3-(5-methyl-4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0678] Step 1: Preparation of 3-fluorodihydrofuran-2(3H)-one: 3-hydroxydihydrofuran-2(3H)-one (14 g, 1 eq) was dissolved in dichloromethane (140 mL) under nitrogen protection, the temperature was lowered to 0°C, diethylaminosulfur trifluoride (1.5 eq) was slowly added dropwise, the temperature was raised to room temperature and the reaction was continued for 16 hours. The reaction was completed by TLC plate detection. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with dichloromethane (100 mL×3). The organic phase was spin-dried to give a crude product, which was separated and purified by flash chromatography to obtain the target compound (8 g).

[0679] Step 2: Preparation of methyl 4-bromo-2-fluorobutyrate: 3-Fluorodihydrofuran-2(3H)-one (8.4 g, 1 eq) was dissolved in dichloromethane (80 mL), 1 M tribromoborane (1.1 eq) was added under ice bath, the mixture was heated to room temperature and stirred for 16 hours, methanol (10 mL) was added and the reaction was continued for 2 hours. After monitoring the completion of the reaction, water (80 mL) was added for extraction, and the organic phase was washed with saturated sodium bicarbonate solution (100 mL*2), the organic phase was collected and dried, and the crude product was spin-dried to give the target compound (5.5 g).

[0680] Step 3: Preparation of methyl 2-fluoro-4-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)butanoate: 6-fluoro-3-(pyrrolidin-3-yl)-1H-indole (3.5 g, 1 eq) was dissolved in acetonitrile (40 mL), methyl 4-bromo-2-fluorobutyrate (1 eq) and sodium carbonate (3 eq) were added, and the mixture was stirred at 70 ° C for 5 hours. Acetonitrile was dried and water (150 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phase was dried to give a crude product, which was separated and purified by flash chromatography (Silica gel, PE:EA=1:9) to give the title compound (3.2 g).

[0681] LCMS (ESI) [M+H] + =323.0.

[0682] Step 4: Preparation of 2-fluoro-4-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)butyric acid hydrazide:

[0683] Methyl 2-fluoro-4-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)butanoate (3.2 g, 1 eq) was dissolved in ethanol (30 mL), hydrazine hydrate (1.49 g, 3 eq) was added, and the mixture was reacted at 50°C for 1 hour. The dried ethanol was spin-dried to give the target compound (3.2 g, crude product), which was used directly in the next step.

[0684] LCMS (ESI) [M+H] + =323.1.

[0685] Step 5: Preparation of (E)-N'-(2-fluoro-4-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)butanoyl)-N,N-dimethylacetohydrazide amide: 2-Fluoro-4-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)butanoylhydrazide (3.16 g, crude product) was dissolved in methanol (30 mL), and (1,1-dimethoxyethyl)dimethylamine (6.53 g) was added. The mixture was reacted at 70°C for 1 hour. The reaction solution was spin-dried and the crude product was purified to obtain the target compound (2 g).

[0686] LCMS (ESI) [M+H] + =392.2.

[0687] Step 6: Preparation of 6-fluoro-3-(1-(3-fluoro-3-(5-methyl-4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: (E)-N'-(2-fluoro-4-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)butanoyl)-N,N-dimethylacetohydrazide amide (300 mg, 1 eq) and acetic acid (5 mL), nitrogen was blown in, 2-aminopropane (20 eq) was added dropwise under ice bath, and the reaction was carried out at 110° C. for 48 hours. Saturated potassium carbonate solution was added to adjust the pH to 10, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was spin-dried to give a crude product, which was separated and purified by prep-HPLC (C18, 0.1% formic acid in water: acetonitrile) to give the title compound (19.52 mg).

[0688] LCMS (ESI) [M+H] + =388.2; 1 H NMR(400MHz,MeOD-d4)δ8.45(s,1H),7.57(dd,J=8.7,5.2Hz,1H),7.23(s,1H),7.07(dd,J=9 .9,2.2Hz,1H),6.84(td,J=9.5,2.3Hz,1H),5.99(ddd,J=48.9,8.7,3.4Hz,1H),4.77-4.66( m,1H),3.92(dd,J=13.3,7.0Hz,2H),3.63(dd,J=16.7,8.6Hz,3H),3.50(ddd,J=22.4,14.1, 9.7Hz,2H),2.86-2.66(m,2H),2.64-2.54(m,4H),2.43-2.25(m,1H),1.56(d,J=6.9Hz,6H).

[0689] Example 98-111 (Compound 98-111)

[0690] Compounds 98-111 were prepared by referring to the preparation methods of Examples 18 and 74:

[0691] Compound 98: LCMS (ESI) [M+H] + =352.1; 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),8.39(s,1H),7.61(d,J=7.9Hz,1H),7.32(d,J=8.1Hz ,1H),7.13(d,J=1.9Hz,1H),7.05(t,J=7.5Hz,1H),6.94(t,J=7.4Hz,1H),3.59-3.44(m,1H) ,2.95(dt,J=15.0,8.1Hz,3H),2.73(dd,J=15.2,7.6Hz,1H),2.63(dt,J=14.5,7.5Hz,2H),2 .55(t,J=7.8Hz,2H),2.29-2.16(m,1H),2.06-1.95(m,2H),1.93-1.83(m,1H),1.56(s,9H).

[0692] Compound 99: LCMS (ESI) [M+H] + =353.9; 1 H NMR(400MHz,MeOD-d4)δ8.38(s,1H),7.52(dd,J=8.7,5.3Hz,1H),7.06(s,1H),7.01 (dd,J=10.0,2.3Hz,1H),6.81-6.74(m,1H),3.62(dd,J=16.8,8.4Hz,1H),3.34(dd,J =7.3,4.0Hz,1H),3.24-3.18(m,1H),3.01-2.93(m,3H),2.70(ddt,J=17.7,14.3,7.5 Hz,4H),2.42-2.31(m,1H),2.12-1.99(m,3H),1.15-1.08(m,2H),1.07-1.00(m,2H).

[0693] Compound 100: LCMS (ESI) [M+H] + =424.2; 1H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.58(dd,J=8.6,5.4Hz,1H),7.03(dd,J=13.4,3.8Hz,2H),6.87(dd,J=12.8,5.5Hz,1H),4.64(dt,J=14.0,6 .9Hz,1H),3.65(s,1H),3.17(s,1H),2.98(t,J=7.4Hz,3H),2.77(d,J=32.3 Hz, 4H), 2.37 (s, 1H), 2.22 (s, 2H), 2.06 (d, J = 7.7Hz, 1H), 1.57-1.52 (m, 6H).

[0694] Compound 101: LCMS (ESI) [M+H] + =384.3; 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),7.58(ddd,J=11.1,8.8,5.6Hz,1H),7.14-7.06(m,2H),6 .84-6.77(m,1H),4.53-4.35(m,1H),3.47(dt,J=15.9,7.9Hz,1H),3.15-3.07(m,1H),2.90(td ,J=8.2,4.6Hz,1H),2.75-2.52(m,2H),2.47-2.30(m,6H),2.21(dt,J=21.9,7.4Hz,1H),2.02- 1.73(m,3H), 1.43(d,J=7.0Hz,3H), 1.31(dd,J=13.7,7.0Hz,3H), 1.23(dd,J=6.8,3.8Hz,3H).

[0695] Compound 102: LCMS (ESI) [M+H] + =366.2;

[0696] Compound 103: LCMS (ESI) [M+H] + =370.1; 1H NMR (400MHz, DMSO-d6) δ8.15(s,2H),7.65(dd,J=9.0,4.5Hz,1H),7.57(d,J=3.2Hz,1H),7.29(dd,J =9.9,2.5Hz,1H),6.95(td,J=9.2,2.5Hz,1H),6.43(d,J=3.1Hz,1H),5.12(dd,J=9.6,6.2Hz,1H),4 .40(dt,J=13.9,7.0Hz,1H),3.06(t,J=6.8Hz,1H),2.89(dd,J=8.7,4.6Hz,1H),2.79-2.73(m,3H), 2.68-2.52(m,2H),2.48-2.40(m,2H),2.37(s,3H),2.02-1.81(m,3H),1.38(dd,J=7.0,2.4Hz,6H).

[0697] Compound 104: LCMS (ESI) [M+H] + =384.1;

[0698] Compound 105: LCMS (ESI) [M+H] + =430.2;

[0699] Compound 106: LCMS (ESI) [M+H] + =366.2;

[0700] Compound 107: LCMS (ESI) [M+H] + =370.3; 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.27(s,1H),7.61(dd,J=8.7,5.5Hz,1H),7.20(d,J=1 .9Hz,1H),7.11(dd,J=10.2,2.3Hz,1H),6.83(ddd,J=9.8,8.8,2.4Hz,1H),4.41(d,J=7.0Hz ,2H),3.66-3.54(m,1H),3.28(d,J=8.3Hz,1H),2.96(d,J=7.0Hz,2H),2.79(dd,J=16.4,9.2 Hz, 5H), 2.38 (s, 3H), 2.35-2.26 (m, 1H), 1.97 (dd, J = 14.4, 7.0Hz, 3H), 1.39 (d, J = 7.0Hz, 6H).

[0701] Compound 108: LCMS (ESI) [M+H] + =418.2;

[0702] Compound 109: LCMS (ESI) [M+H] + =382.2;

[0703] Compound 110: LCMS (ESI) [M+H] + =384.2;

[0704] Compound 111: LCMS (ESI) [M+H] + =370.2.

[0705] Example 112 (Compound 112)

[0706] Preparation of 1-methyl-3-(1-(3-(5-methyl-4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0707] 3-(1-(3-(5-methyl-4-(propan-2-yl)-4H-1,2,4-triazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole (50 mg, 1 eq) was dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was cooled to 0°C, sodium hydride (2 eq) was added, and the temperature was maintained with stirring for 5 minutes. Iodomethane (1.1 eq) was added, and the temperature was warmed to room temperature with stirring for 1 hour. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by prep-HPLC (C18, 0.05% aqueous ammonia solution in acetonitrile) to obtain the title compound (12.8 mg).

[0708] LCMS (ESI) [M+H] + =366.2; 1 HNMR(400MHz,MeOD-d4)δ7.57(d,J=7.9Hz,1H),7.29(d,J=8.2Hz,1H),7.14(t,J =7.5Hz,1H),7.06-6.95(m,2H),4.53(m,1H),3.72(s,3H),3.68-3.57(m,1H),3.1 8(t,J=8.5Hz,1H),2.94(dd,J=15.3,8.0Hz,1H),2.90-2.82(m,2H),2.74-2.58( m,4H),2.49(s,3H),2.40-2.29(m,1H),2.08-1.92(m,3H),1.50(d,J=7.0Hz,6H).

[0709] Examples 113-121 (Compounds 113-121)

[0710] Referring to the preparation method of Example 74, Examples 113-121 were prepared:

[0711] Compound 113: LCMS (ESI) [M+H] + =378.1;

[0712] Compound 114: LCMS (ESI) [M+H] + =368.2;

[0713] Compound 115: LCMS (ESI) [M+H] + =386.2;

[0714] Compound 116: LCMS (ESI) [M+H] + =382.2;

[0715] Compound 117: LCMS (ESI) [M+H] + =363.2;

[0716] Compound 118: LCMS (ESI) [M+H] + =374.2;

[0717] Compound 119: LCMS (ESI) [M+H] + =424.2;

[0718] Compound 120: LCMS (ESI) [M+H] + =406.2;

[0719] Compound 121: LCMS (ESI) [M+H] + =363.2.

[0720] Example 122 (Compound 122)

[0721] Preparation of 3-(1-(3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propyl)pyrrolidin-3-yl))-1H-indole:

[0722] Step 1: Preparation of 3-(3,5-dimethyl-1,2,4-triazol-1-yl)propan-1-ol: Potassium carbonate (3.0 eq) was added to a solution of 3,5-dimethyl-4H-1,2,4-triazole (5 g, 1.0 eq) and 3-bromopropan-1-ol (1.2 eq) in acetonitrile (200 mL). The mixture was stirred at 50°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (6 g).

[0723] LCMS (ESI) [M+H] + =156.1.

[0724] Step 2: Preparation of 3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propanal: Dess-Martin reagent (1.5 eq) was added to a solution of 3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propan-1-ol (1.00 g, 1.0 eq) in dichloromethane (20 mL) and stirred at room temperature for 3 hours. The mixture was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (20 mL x 3). The aqueous phase was concentrated in vacuo, and the residue was added to dichloromethane (20 mL) and stirred for 10 minutes. The mixture was then filtered and the filtrate was concentrated in vacuo to obtain the title compound (200 mg, crude product).

[0725] LCMS (ESI) [M+H+18] + =172.2;

[0726] Step 3: Preparation of 3-(1-(3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propanal (150 mg, crude) and 3-(pyrrolidin-3-yl)-1H-indole (182 mg) were added to tetrahydrofuran (10 mL) and stirred for 10 minutes. Sodium triacetoxyborohydride (415 mg) and acetic acid (0.1 mL) were added to the system and stirred at room temperature for 2 hours. The mixture was quenched by adding saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated. The crude product was separated and purified by prep-HPLC (C18, 0.1% aqueous ammonia:acetonitrile) to obtain the title compound (20.9 mg).

[0727] LCMS (ESI) [M+H] + =324.2; 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),7.58(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.13( d,J=2.0Hz,1H),7.05(t,J=7.5Hz,1H),6.95(t,J=7.4Hz,1H),4.04(t,J=6.8Hz,2H),3.57 -3.46(m,1H),2.96(t,J=8.3Hz,1H),2.71(dd,J=14.9,7.9Hz,1H),2.57(dd,J=14.2,8.6H z,1H),2.49-2.33(m,3H),2.32(s,3H),2.27-2.18(m,1H),2.15(s,3H),1.95-1.83(m,3H).

[0728] Example 123

[0729] Compound 123 was prepared by referring to the preparation method of Example 74:

[0730] LCMS (ESI) [M+H] + =324.2.

[0731] Example 125 (Compound 125)

[0732] Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0733] Step 1: Preparation of 3-(2H-1,2,3-triazol-2-yl)propan-1-ol: 2H-1,2,3-triazole (500 mg, 1 eq) and 3-bromopropan-1-ol (1 eq) were dissolved in acetone (AC, 5 mL), potassium carbonate (1 eq) was added, and the mixture was stirred at 50°C for 6 hours. The reaction solution was filtered and the mother liquor was concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography (Silica gel, DCM:MeOH = 20:1) to obtain the title compound (300 mg).

[0734] LCMS (ESI) [M+H] + =128.2.

[0735] Step 2: Preparation of 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate: 3-(2H-1,2,3-triazol-2-yl)propan-1-ol (300 mg, 1 eq) was dissolved in dichloromethane (5 mL), triethylamine (2.4 eq) was added, and methanesulfonyl chloride (1.2 eq) was added dropwise at 0°C. After the addition, the mixture was stirred at 0°C for 1 hour. The reaction solution was concentrated to obtain a crude product, which was separated and purified by flash chromatography (Silica gel, DCM:MeOH=15:1) to obtain the target compound (230 mg).

[0736] LCMS (ESI) [M+H] + =206.1.

[0737] Step 3: Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (100 mg, 1 eq) and 3-(pyrrolidin-3-yl)-1H-indole (1 eq) were dissolved in acetonitrile (5 mL), potassium carbonate (1.5 eq) was added, and the mixture was stirred at 70°C for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was purified by Prep-HPLC (C18, 0.1% formic acid in water: acetonitrile) to obtain the target compound (40.36 mg).

[0738] LCMS (ESI) [M+H] + =296.2; 1 H NMR(400MHz,MeOD-d4)δ8.50(s,1H),7.70(s,2H),7.57(d,J=7.9Hz,1H),7.35(s,1H),7.1 9(s,1H),7.12(t,J=7.3Hz,1H),7.04(t,J=7.4Hz,1H),4.59(t,J=6.5Hz,2H),3.92-3.79( m,2H),3.60-3.52(m,2H),3.36(t,J=9.6Hz,1H),3.30(d,J=1.5Hz,1H),3.27(d,J=8.2Hz, 1H), 2.54 (td, J=13.3, 6.6Hz, 1H), 2.45-2.37 (m, 2H), 2.30 (ddd, J=17.4, 10.9, 6.5Hz, 1H).

[0739] Examples 124 and 126-129 (Compounds 124 and 126-129)

[0740] Compounds 124 and 126-129 were prepared by referring to the preparation methods of Examples 122 and 125:

[0741] Compound 124: LCMS (ESI) [M+H] + =296.1;

[0742] Compound 126: LCMS (ESI) [M+H] + =310.2;

[0743] Compound 127: LCMS (ESI) [M+H] + =340.2;

[0744] Compound 128: LCMS (ESI) [M+H] + =354.2;

[0745] Compound 129: LCMS (ESI) [M+H] + =322.2.

[0746] Examples 130-131 (Compounds 130-131)

[0747] Compounds 130-131 were prepared by referring to the preparation methods of Examples 1 and 5:

[0748] Compound 130: LCMS (ESI) [M+H] + =352.1;

[0749] Compound 131: LCMS (ESI) [M+H] + =336.2; 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.02(dd,J=4.9,1.6Hz,1H),7.61(d,J=7.9Hz,1H),7.56(dd,J=7 .1,1.4Hz,1H),7.35(d,J=8.1Hz,1H),7.22(d,J=2.1Hz,1H),7.08(s,1H),6.98(s,1H),6.93(dd,J=7.1 ,5.0Hz,1H),3.87(s,3H),3.67-3.63(m,1H),3.41(d,J=8.4Hz,1H),3.10(dd,J=18.7,10.9Hz,2H),2.9 4-2.82(m,3H),2.63-2.58(m,2H),2.39-2.29(m,1H),2.02(dd,J=12.4,8.2Hz,1H),1.92-1.82(m,2H).

[0750] Example 132 (Compound 132)

[0751] Preparation of 3-(1-(3-(4-methoxypyrimidin-5-yl)propyl)pyrrolidin-3-yl)-1H-indole:

[0752] Step 1: Preparation of 3-(4-methoxypyrimidin-5-yl)propanal: Ethyl 3-(4-methoxypyrimidin-5-yl)propionate (700 mg, 1.0 eq) was dissolved in dichloromethane (10 mL), the temperature was lowered to -78°C, and diisobutylaluminum hydride toluene solution (2.0 eq) was slowly added dropwise. The reaction was continued at -78°C for 1 hour. The reaction was completed by TLC detection. Water (2 mL) was added to quench the reaction. Dichloromethane was added and stirred for 5 minutes. Anhydrous sodium sulfate was added, the mixture was filtered, the filtrate was concentrated, and the title compound (250 mg) was obtained by purification.

[0753] LCMS (ESI) [M+H] + =167.1.

[0754] Step 2: Preparation of 3-(1-(3-(4-methoxypyrimidin-5-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(4-methoxypyrimidin-5-yl)propanal (1.1 eq) and 3-(pyrrolidin-3-yl)-1H-indole (150 mg, 1.0 eq) were dissolved in tetrahydrofuran (10 mL), acetic acid (0.5 mL) was added, sodium triacetoxyborohydride (3.0 eq) was added, and the mixture was reacted at room temperature for 1 hour. Water was added to quench the mixture, and ethyl acetate (10 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The organic phase was separated and purified by prep-HPLC (C18, 0.05% TFA / water, MeCN). After concentration to dryness, aqueous hydrochloric acid solution (4 mL, 1%) was added to obtain the target compound (36.02 mg).

[0755] LCMS (ESI) [M+H] + =337.3; 1H NMR(400MHz,MeOD-d4)δ9.16(s,1H),8.73(s,1H),7.60(d,J=8.0Hz,1H),7.37(d,J=8.1Hz,1H ),7.23(s,1H),7.12(d,J=7.5Hz,1H),7.05(d,J=7.7Hz,1H),4.29(d,J=3.3Hz,3H),4.15-4.00 (m,1H),3.87(dd,J=18.9,7.9Hz,2H),3.72(t,J=8.0Hz,1H),3.52-3.33(m,3H),3.22(t,J=11 .1Hz,1H),2.84(t,J=7.2Hz,2H),2.66-2.53(m,1H),2.47-2.28(m,1H),2.16(d,J=3.8Hz,2H).

[0756] Example 133 (Compound 133)

[0757] Compound 133 was prepared by referring to the preparation methods of Examples 20 and 132:

[0758] LCMS (ESI) [M+H] + =370.3; 1 H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 2.9Hz, 1H), 7.63-7.54 (m, 2H), 7.35(d,J=8.1Hz,1H),7.29(d,J=2.3Hz,1H),7.07(t,J=7.5Hz,1H),6.98(t,J=7.4Hz,1H),4. 75(d,J=8.5Hz,1H),3.93-3.83(m,4H),3.70(t,J=10.3Hz,1H),2.98(d,J=10.6Hz,1H),2.82( d,J=10.7Hz,1H),2.61-2.55(m,2H),2.40(d,J=23.6Hz,3H),2.23(s,1H),1.82-1.70(m,2H).

[0759] Examples 134-138 (Compounds 134-138)

[0760] Compounds 134-138 were prepared by referring to the preparation methods of Examples 1, 5, 140, 146, and 147:

[0761] Compound 134: LCMS (ESI) [M+H] +=347.1;

[0762] Compound 135: LCMS (ESI) [M+H] + =365.1;

[0763] Compound 136: LCMS (ESI) [M+H] + =377.2;

[0764] Compound 137: LCMS (ESI) [M+H] + =393.2;

[0765] Compound 138: LCMS (ESI) [M+H] + =323.2.

[0766] Example 139 (Compound 139)

[0767] Preparation of 7-((3-(1H-indol-3-yl)pyrrolidin-1-yl)methyl)-3-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine:

[0768] Step 1: Preparation of methyl 6-methoxy-2,3,4,5-tetrahydropyridine-4-carboxylate: To a solution of methyl 2-oxopiperidine-4-carboxylate (2 g, 1 eq) in DCE (90 mL) was added trimethyloxonium tetrafluoroborate (1.2 eq) at room temperature, followed by heating to 60°C for 24 hours. Saturated potassium carbonate solution (40 mL) was slowly added to the reaction mixture under ice-cooling. After stirring for 10 minutes, the mixture was separated. The organic phase was washed with water (10 mL x 2) and dried over anhydrous sodium sulfate. Filtered and spun down to obtain the title compound (2 g, crude product).

[0769] LCMS (ESI) [M+H] + =172.0.

[0770] Step 2: Preparation of methyl 3-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate: To a solution of methyl 6-methoxy-2,3,4,5-tetrahydropyridine-4-carboxylate (2 g, crude) in methanol (60 mL) was added isobutyrylhydrazide (1.1 g) at room temperature and heated to 80°C for 24 hours. The reaction mixture was then spin-dried to obtain the title compound (2.6 g, crude).

[0771] LCMS (ESI) [M+H] + =224.2.

[0772] Step 3: Preparation of 3-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxaldehyde: To a solution of methyl 3-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (1.4 g, crude) in dichloromethane (10 mL) was slowly added dropwise at -78°C under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and allowed to react overnight. Water (5 mL) was then added to the reaction mixture under an ice bath to quench the reaction, which was then diluted with ethyl acetate (20 mL). The mixture was then dried over anhydrous magnesium sulfate and filtered. The filter cake was washed with ethyl acetate (30 mL), and the filtrate was evaporated to dryness to yield the title compound (1.1 g, crude).

[0773] Step 4: Preparation of 7-((3-(1H-indol-3-yl)pyrrolidin-1-yl)methyl)-3-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine: To a solution of 3-(pyrrolidin-3-yl)-1H-indole (198 mg, 1.0 eq) in 1,2-dichloroethane (5 mL) at room temperature were added 3-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (410 mg, crude) and sodium triacetoxyborohydride (1.4 eq). After reacting at room temperature for 24 hours, the reaction mixture was diluted with acetonitrile (10 mL). Subsequently, the product was filtered, and the filter cake was washed with acetonitrile (15 mL). The filtrate was spin-dried and purified by prep-HPLC (C18, 0.05% formic acid in water:acetonitrile) to obtain the title compound (32.49 mg).

[0774] LCMS (ESI) [M+H] + =364.2; 1 H NMR (400MHz, CDCl3) δ8.08(s,1H),7.70(t,J=8.2Hz,1H),7.36(d,J=8.1Hz,1H),7.19(t,J=7.6 Hz,1H),7.11(t,J=7.5Hz,1H),7.03(s,1H),4.06-3.97(m,1H),3.81-3.70(m,1H),3.70-3.60(m ,1H),3.29-3.21(m,1H),3.11-2.91(m,2H),2.83-2.62(m,3H),2.58-2.49(m,2H),2.41-2.26(m ,2H),2.18-2.00(m,2H),1.78-1.65(m,2H),1.41(d,J=6.9Hz,3H),1.36(dd,J=6.9,2.1Hz,3H).

[0775] Example 140 (Compound 140)

[0776] Preparation of 3-(1-(2-(3-(propan-2-yl)-5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)ethyl)pyrrolidin-3-yl)-1H-indole:

[0777] Step 1: Preparation of 3-(2-nitroethyl)dihydrofuran-2(3H)-one: 3-Methylenedihydrofuran-2(3H)-one (25 g, 1 eq) was dissolved in nitromethane (240 mL). DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (0.13 eq) was added. The reaction system was stirred at room temperature for 12 hours. TLC indicated the reaction was complete. The reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (240 mL) and washed sequentially with 3M hydrochloric acid (240 mL × 3), water (240 mL × 3), saturated aqueous sodium bicarbonate solution (240 mL × 3), and brine (240 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography to obtain the title compound (18.5 g).

[0778] Step 2: Preparation of 3-(2-hydroxyethyl)pyrrolidin-2-one: 3-(2-nitroethyl)dihydrofuran-2(3H)-one (17.5 g, 1 eq) was dissolved in methanol (350 mL), and Raney nickel (2 eq) and magnesium sulfate (1 eq) were added in sequence. The reaction solution was stirred at 30 ° C. under a hydrogen atmosphere for 12 hours. TLC showed that the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was slurried with dichloromethane, filtered, and the filtrate was concentrated to obtain the target compound (14 g).

[0779] Step 3: Preparation of 2-(2-oxopyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate: 3-(2-hydroxyethyl)pyrrolidin-2-one (5 g, 1 eq) was dissolved in dichloromethane (5 mL), and 4-methylbenzene-1-sulfonyl chloride (1.1 eq), N,N-dimethylpyridin-4-amine (0.2 eq), and triethylamine (1.2 eq) were added in sequence. The reaction system was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by flash chromatography to obtain the target compound (7.5 g, yield 68.4%).

[0780] LCMS (ESI) [M+H] + =284.0.

[0781] Step 4: Preparation of 2-(5-methoxy-3,4-dihydro-2H-pyrrol-4-yl)ethyl 4-methylbenzenesulfonate: 2-(2-oxopyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate (1 g, 1 eq) was dissolved in dichloromethane (10 mL), and trimethyloxonium tetrafluoroborate (1.5 eq) was added. The reaction system was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified to obtain the target compound (800 mg).

[0782] LCMS (ESI) [M+H] + =298.1.

[0783] Step 5: Preparation of N'-(4-(2-hydroxyethyl)-3,4-dihydro-2H-pyrrol-5-yl)-2-methylpropane hydrazide: 2-(5-methoxy-3,4-dihydro-2H-pyrrol-4-yl)ethyl 4-methylbenzenesulfonate (300 mg, 1 eq) was dissolved in methanol (3 mL), and isobutyric hydrazide (1.1 eq) was added. The reaction system was stirred at 85° C. for 12 hours. The reaction solution was concentrated to obtain a crude product, which was purified by reverse phase separation (C18, 0.1% ammonia in water: acetonitrile) to obtain the title compound (150 mg).

[0784] LCMS (ESI) [M+H] + =214.0.

[0785] Step 6: Preparation of 2-(3-(propan-2-yl)-5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)ethan-1-ol: Dissolve N'-(4-(2-hydroxyethyl)-3,4-dihydro-2H-pyrrol-5-yl)-2-methylpropane hydrazide (150 mg, 1 eq) in water (2 mL), add sodium bicarbonate (10 eq), and stir the reaction system at 100°C for 16 hours. The reaction solution is separated and purified to obtain the title compound (30 mg).

[0786] LCMS (ESI) [M+H] + =196.3.

[0787] Step 7: Preparation of 2-(3-(Propan-2-yl)-5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)ethyl 4-methylbenzenesulfonate: 2-(3-(Propan-2-yl)-5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)ethane-1-ol (30 mg, 1 eq) was dissolved in dichloromethane (1 mL), and 4-methylbenzenesulfonate was added successively. Benzene-1-sulfonyl chloride (1.2 eq), triethylamine (1.5 eq), N,N-dimethylpyridin-4-amine (0.1 eq), the reaction was stirred at room temperature for 1 hour, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then purified by reverse phase separation (C18, 0.1% trifluoroacetic acid in water: acetonitrile) to obtain the title compound (30 mg).

[0788] LCMS (ESI) [M+H] + =350.0

[0789] Step 8: Preparation of 3-(1-(2-(3-(Propan-2-yl)-5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)ethyl)pyrrolidin-3-yl)-1H-indole: 3-(Pyrrolidin-3-yl)-1H-indole (13.32 mg, 1 eq) and 2-(3-(Propan-2-yl)-5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)ethyl)pyrrolidin-3-yl)-1H-indole were added. oxazol-7-yl) ethyl ester (1 eq) was dissolved in N,N-dimethylformamide (1 mL), potassium carbonate (2 eq) was added, and the reaction system was stirred at 70°C for 12 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by prep-HPLC (C18, 0.05% aqueous ammonia solution: acetonitrile) to obtain the title compound (4.8 mg).

[0790] LCMS (ESI) [M+H] + =364.3; 1H NMR(400MHz,MeOD-d4)δ7.57(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.09-7.05(m,2H),6 .98(t,J=7.5Hz,1H), 4.11(tdd,J=8.6,4.3,2.1Hz,1H), 4.00(ddd,J=7.3,6.5,2.4Hz,1H), 3.70-3.63(m,1H),3.29-3.23(m,2H),3.15-3.08(m,1H),3.03-2.84(m,3H),2.77-2.63(m, 3H), 2.51-2.34 (m, 2H), 2.14-2.04 (m, 2H), 1.93-1.84 (m, 1H), 1.33 (dd, J = 7.0, 3.4Hz, 6H).

[0791] Example 141 (Compound 141)

[0792] Compound 141 was prepared by referring to the preparation method of Example 5:

[0793] LCMS (ESI) [M+H] + =334.1.

[0794] Example 142 (Compound 142)

[0795] Preparation of 3-(1-(2-((1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole:

[0796] Step 1: Preparation of 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)-N'-(pyridin-2-yl)propanoic acid: 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)propanoic acid (500 mg, 1.0 eq) and 2-hydrazinopyridine (1.2 eq) were dissolved in N,N-dimethylformamide (10 mL), HATU (1.2 eq) was added, and diisopropylethylamine (2.0 eq) was added dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 4 hours. LCMS showed that the reaction of the raw material was complete. The product was separated and purified by flash chromatography (C18, 0.05% formic acid in water: acetonitrile) to give the title compound (350 mg).

[0797] LCMS (ESI) [M+H] + =350.2.

[0798] Step 2: Preparation of 3-(1-(2-((1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole: 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)-N'-(pyridin-2-yl)propionohydrazide (200 mg, 1.0 eq) was dissolved in phosphorus oxychloride (10 mL) and reacted at 100° C. for 16 hours. The phosphorus oxychloride was spin-dried, and dichloromethane and methanol were added to dissolve the solution. Saturated sodium carbonate was added to adjust the pH to neutral, filtered, and the filtrate was spin-dried. The title compound (4.46 mg) was separated and purified by prep-HPLC (C18, 0.1% formic acid in water: acetonitrile) to obtain the title compound (4.46 mg).

[0799] LCMS (ESI) [M+H] + =332.1; 1 H NMR(400MHz,MeOD-d4)δ8.48(s,1H),8.39(d,J=7.0Hz,1H),7.75(d,J=9.4Hz,1H),7.58 (d,J=7.9Hz,1H),7.49(dd,J=9.0,6.8Hz,1H),7.35(d,J=8.1Hz,1H),7.19(s,1H),7.07( ddd,J=21.6,15.5,7.6Hz,3H),3.86(dt,J=18.0,8.0Hz,2H),3.72(d,J=7.1Hz,2H),3.5 7(dd,J=15.7,8.3Hz,4H),3.35(s,1H),2.57(dd,J=12.8,5.5Hz,1H),2.39-2.24(m,1H).

[0800] Example 143 (Compound 143)

[0801] Preparation of 3-(2-(3-(1H-indol-3-yl)pyrrolidin-1-yl)ethyl)thiazolo[2,3-c][1,2,4]triazole:

[0802] Step 1: Preparation of 2-hydrazino-1,3-thiazole: Dissolve 1,3-thiazol-2-amine (1 g, 1.0 eq) in concentrated hydrochloric acid (36%, 10 mL), add water (10 mL), add sodium nitrite (1.0 eq) at -10°C, stir at -10°C for 10 minutes, add a solution of dichlorotin (2.0 eq) in hydrochloric acid (10 mL), stir at -10°C for 0.5 hours, filter the reaction solution, and dry the residue to obtain the target compound (1.1 g).

[0803] LCMS (ESI) [M+H] + =116.1.

[0804] Step 2: Preparation of 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)-N'-(1,3-thiazol-2-yl)propanoylhydrazide: 2-Hydrazino-1,3-thiazole (500 mg, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), and 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)propionic acid (1.0 eq) and HATU (1.5 eq) were added. Diisopropylethylamine (3.0 eq) was added dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 4 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The mother liquor was concentrated to obtain a crude product, which was separated and purified by flash chromatography to obtain the target compound (344 mg).

[0805] LCMS (ESI) [M+H] + =356.2.

[0806] Step 3: Preparation of 3-(2-(3-(1H-indol-3-yl)pyrrolidin-1-yl)ethyl)thiazolo[2,3-c][1,2,4]triazole: 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)-N'-(1,3-thiazol-2-yl)propionohydrazide (320 mg, 1.0 eq) was dissolved in phosphorus oxychloride (13 mL) and reacted at 100°C for 16 hours. The phosphorus oxychloride was spin-dried, and dichloromethane and methanol were added to dissolve the solution. Saturated sodium carbonate was added to adjust the pH to neutral, filtered, and the filtrate was spin-dried. The target compound (27.32 mg) was obtained by separation and purification by prep-HPLC (C18, 0.1% formic acid in water: acetonitrile).

[0807] LCMS (ESI) [M+H] + =338.1; 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.17(s,1H),7.98(d,J=4.4Hz,1H),7.51(d,J=8.2Hz,1H),7 .38(d,J=4.3Hz,1H),7.31(d,J=8.1Hz,1H),7.11(s,1H),7.04(t,J=7.4Hz,1H),6.93(d,J=7.8Hz,1 H),3.53-3.48(m,1H),3.19(d,J=7.3Hz,2H),3.10(d,J=8.2Hz,1H),2.93(dd,J=13.2,7.0Hz,2H),2 .81(d,J=8.7Hz,1H),2.72(d,J=5.6Hz,1H),2.63-2.58(m,1H),2.23(s,1H),1.89(d,J=7.7Hz,1H).

[0808] Example 144 (Compound 144)

[0809] Referring to the preparation method of Example 5, Example 144 was prepared:

[0810] LCMS (ESI) [M+H] + =335.1.

[0811] Example 145 (Compound 145)

[0812] Preparation of 3-(1-((3-cyclopropyl-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)pyrrolidin-3-yl)-1H-indole:

[0813] Step 1: Preparation of 3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid methyl ester: Dissolve 6-methoxy-2,3,4,5-tetrahydropyridine-4-carboxylic acid methyl ester (2.8 g, 1 eq) in methanol (30 mL), add cyclopropylcarboxylic acid hydrazide (1.2 eq), stir at 85 ° C for 16 hours, spin dry the solvent, and separate and purify by flash chromatography to obtain the target compound (2.5 g).

[0814] LCMS (ESI) [M+H] + =222.0.

[0815] Step 2: Preparation of 3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxaldehyde: Methyl 3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (200 mg, 1.0 eq) was dissolved in dichloromethane (8 mL), and diisobutylaluminum hydride (1 M / Hexanes, 1.8 mL, 2 eq) was slowly added dropwise at -70°C. The reaction was continued at this temperature for 1 hour, and an appropriate amount of dichloromethane was added to dilute it. Water (0.4 mL) was slowly added dropwise to quench the mixture. The mixture was stirred at room temperature for 15 minutes, an appropriate amount of anhydrous magnesium sulfate was added, and stirring was continued for 15 minutes. The mixture was filtered, and the filtrate was concentrated to obtain the title compound (100 mg).

[0816] LCMS (ESI) [M+H] + =192.0.

[0817] Step 3: Preparation of 3-(1-((3-cyclopropyl-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)pyrrolidin-3-yl)-1H-indole: 3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (100 mg, 1.0 eq) was dissolved in tetrahydrofuran (8 mL), 3-(pyrrolidin-3-yl)-1H-indole (1.0 eq) was added, and 2 drops of acetic acid were added dropwise. The mixture was stirred at room temperature for 20 minutes, sodium triacetoxyborohydride (2 eq) was added, and the reaction was continued by stirring for 1 hour. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by prep-HPLC (C18, 0.05% formic acid in water:acetonitrile) to give the title compound (21.07 mg).

[0818] LCMS (ESI) [M+H] + =362.2; 1HNMR (400MHz, DMSO-d6) δ10.77(s,1H),7.62(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7.16(s,1H),7.06(t,J=7 .5Hz,1H),6.96(t,J=7.4Hz,1H),4.16-4.06(m,1H),3.83(dt,J=11.7,5.5Hz,1H),3.55(dd,J=16.3,8.2Hz,1H) ,3.09(s,1H),3.04-2.94(m,1H),2.83(s,1H),2.73(s,1H),2.58(dd,J=16.9,8.5Hz,3H),2.40(dd,J=16.4,10 .3Hz,1H),2.34-2.22(m,1H),2.16(d,J=12.5Hz,2H),1.98-1.84(m,2H),1.70-1.58(m,1H),0.98-0.78(m,4H).

[0819] Example 146 (Compound 146)

[0820] Preparation of 7-((3-(1H-indol-3-yl)pyrrolidin-1-yl)methyl)-3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine:

[0821] Step 1: Preparation of 2,2-difluoroacetohydrazide: Ethyl 2,2-difluoroacetate (5 g, 1.0 eq) was dissolved in methanol (25 mL), hydrazine hydrate (10.0 eq) was added, and the mixture was stirred at 80°C for 16 hours. The reaction solution was concentrated to obtain the target compound (4.2 g).

[0822] 1 H NMR (400MHz, DMSO-d6) δ6.19 (t, J=53.5Hz, 1H).

[0823] Step 2: Preparation of methyl 6-methoxy-2,3,4,5-tetrahydropyridine-4-carboxylate: methyl 2-oxopiperidine-4-carboxylate (500 mg, 1.0 eq) was dissolved in dichloromethane (5 mL), and trimethyloxonium tetrafluoroborate (1.5 eq) was added. The mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (370 g).

[0824] LCMS (ESI) [M+H] + =172.1.

[0825] Step 3: Preparation of methyl 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate: 6-methoxy-2,3,4,5-tetrahydropyridine-4-carboxylate (2 g, 1.0 eq) and 2,2-difluoroacetohydrazide (1.1 eq) were dissolved in methanol (20 mL), stirred at 85 ° C for 24 hours, and the reaction solution was concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography to obtain the target compound (700 mg).

[0826] LCMS (ESI) [M+H] + =232.0.

[0827] Step 4: Preparation of 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxaldehyde: 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid methyl ester (700 mg, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and solid lithium aluminum tetrahydride (1.5 eq) was added at -40 ° C. The mixture was stirred at -40 ° C. under nitrogen for 2 hours. The reaction solution was quenched with water to quench the lithium aluminum tetrahydride, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography (C18, 0.05% trifluoroacetic acid in water: acetonitrile) to obtain the title compound (100 mg).

[0828] LCMS (ESI) [M+H] + =202.1.

[0829] Step 5: Preparation of 7-((3-(1H-indol-3-yl)pyrrolidin-1-yl)methyl)-3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine: 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (80 mg, 1.0 eq) and 3-(pyrrolidin-3-yl)-1H-indole (1.5 eq) were dissolved in tetrahydrofuran (5 mL). Acetic acid (0.1 eq) was added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.5 eq) was added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The mother liquor was concentrated to obtain a crude product, which was separated and purified by prep-HPLC (C18, 0.05% aqueous ammonia solution: acetonitrile) to obtain the title compound (7.12 mg).

[0830] LCMS (ESI) [M+H] + =372.1; 1H NMR(400MHz,MeOD-d4)δ7.61(d,J=7.9Hz,1H),7.31(d,J=8.1Hz,1H),7.20-6.89( m,4H),4.37(d,J=12.6Hz,1H),4.15-4.01(m,1H),3.71-3.60(m,1H),3.25(s,1H), 3.17(t,J=8.4Hz,1H),2.93(td,J=9.0,2.8Hz,1H),2.75(ddd,J=15.0,8.7,2.4Hz ,1H),2.70-2.53(m,4H),2.41-2.19(m,3H),2.14-1.99(m,1H),1.84-1.68(m,1H).

[0831] Example 147 (Compound 147)

[0832] Preparation of 6-fluoro-3-(1-(2-(5-methoxy-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole:

[0833] Step 1: Preparation of 2-hydrazino-6-methoxypyridine:

[0834] 2-Chloro-6-methoxypyridine (10 g, 1 eq) was added to hydrazine hydrate (35 mL) and reacted at 100°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated in vacuo, and the residue was added with water (100 mL). The mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia solution: acetonitrile) to afford 2-hydrazino-6-methoxypyridine (1.8 g) as a brown oil.

[0835] LCMS (ESI) [M+H] + =140.1.

[0836] Step 2: Preparation of 3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione: 6-fluoro-1H-indole (20 g, 1 eq) was dissolved in acetic acid (200 mL), 2,5-dihydro-1H-pyrrole-2,5-dione (2.5 eq) was added, and the reaction system was stirred at 120 ° C for 48 hours. The reaction solution was concentrated, diluted with a small amount of ethyl acetate and a large amount of water, and the pH was adjusted to 10 with 15% sodium hydroxide. It was extracted with ethyl acetate (500 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, and the crude product was slurried with petroleum ether: ethyl acetate (3:1), filtered, and dried to obtain the target compound (18 g).

[0837] LCMS (ESI) [M+H]+ =233.2.

[0838] Step 3: Preparation of 6-fluoro-3-(pyrrolidin-3-yl)-1H-indole: At 0°C, lithium aluminum tetrahydride (5eq) was added in batches to 3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (24g, 1eq) in tetrahydrofuran (300mL), the temperature was raised to 80°C and stirred for 3 hours. The reaction solution was cooled to 0°C, and water (20mL) and 15% sodium hydroxide solution (20mL) were slowly added. After the addition of water (60mL) was completed, anhydrous sodium sulfate was added and dried, filtered, and the filter cake was washed with tetrahydrofuran (100mL). The filtrate was collected and concentrated in vacuo to obtain the target compound (18.3g, crude product), which was directly used in the next reaction.

[0839] LCMS (ESI) [M+H] + =205.2.

[0840] Step 4: Preparation of methyl 3-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)propanoate:

[0841] Methyl 3-bromopropionate (6.54 g, 1 eq) was added to 6-fluoro-3-(pyrrolidin-3-yl)-1H-indole (8 g, crude product) and sodium carbonate (3 eq) in acetonitrile (100 mL), and stirred at 70 ° C for 16 hours. The reaction solution was cooled to room temperature, and water (150 mL) was added and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was separated and purified to obtain the target compound (7.5 g).

[0842] LCMS (ESI) [M+H] + =291.1.

[0843] Step 5: Preparation of 3-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)propanoic acid: Lithium hydroxide (1 eq) was added to a solution of methyl 3-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)propanoate (6 g, 1 eq) in tetrahydrofuran (40 mL) and water (20 mL), and the mixture was stirred at room temperature for 16 hours. Acetic acid was added to adjust the pH to 7, and the reaction solution was concentrated in vacuo. The residue was separated and purified by reverse phase separation (C18, 0.1% formic acid in water:acetonitrile) to obtain the title compound (1.84 g).

[0844] LCMS (ESI) [M+H] + =277.2.

[0845] Step 6: Preparation of 3-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)-N'-(6-methoxypyridin-2-yl)propane hydrazide: HATU (1.5 eq) and DIEA (3 eq) were added to 3-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)propanoic acid (1.6 g, 1 eq) and 2-hydrazino-6-methoxypyridine (1.2 eq) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were collected, washed with saturated brine, dried, and concentrated in vacuo. The residue was separated and purified by reverse phase system (C18, 0.05% aqueous ammonia solution: acetonitrile) to give the title compound (1.28 g).

[0846] LCMS (ESI) [M+H] + =398.2.

[0847] Step 7: Preparation of 3-(1-(2-(5-chloro-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-6-fluoro-1H-indole: 3-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)-N'-(6-methoxypyridin-2-yl)propane hydrazide (600 mg, 1 eq) was added to phosphorus oxychloride (10 mL), stirred at 100° C. for 16 hours, concentrated in vacuo, and the residue was separated and purified to give the title compound (230 mg).

[0848] LCMS (ESI) [M+H] + =384.4.

[0849] Step 8: Preparation of 6-fluoro-3-(1-(2-(5-methoxy-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole: Under ice-cooling, sodium methoxide (1.5 eq) was added to a solution of 3-(1-(2-(5-chloro-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-6-fluoro-1H-indole (200 mg, 1 eq) in methanol (5 mL), and the mixture was stirred at 80°C for 1 hour. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated in vacuo. The residue was separated and purified by prep-HPLC (C18, 0.05% ammonia in water:acetonitrile) to give the title compound (26.30 mg).

[0850] LCMS (ESI) [M+H] + =380.1; 1H NMR(400MHz,Chloroform-d)δ8.20(s,1H),7.56(dd,J=8.6,5.4Hz,1H),7.31(d,J=9.1Hz,1H ),7.15(dd,J=9.1,7.3Hz,1H),7.06-6.99(m,2H),6.85(td,J=9.5,2.2Hz,1H),5.91(d,J=7. 2Hz,1H),4.03(s,3H),3.66(dt,J=23.9,7.8Hz,3H),3.26(t,J=8.1Hz,1H),3.21-3.05(m,2H ), 3.01 (d, J = 6.6Hz, 1H), 2.88-2.74 (m, 2H), 2.45-2.35 (m, 1H), 2.02 (td, J = 14.3, 7.7Hz, 1H).

[0851] Example 148 (Compound 148)

[0852] Preparation of 6-fluoro-3-(1-(2-(8-fluoro-5-methoxy-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)azetidin-3-yl)-1H-indole:

[0853] Step 1: Preparation of 3,6-difluoro-2-hydrazinopyridine: Add hydrazine hydrate (2.5 eq) to 2,3,6-trifluoropyridine (1 g, 1 eq) and triethylamine (3 eq) in N-methylpyrrolidone (10 mL) and stir at 100°C for 1 hour. The reaction mixture was cooled to room temperature, added with water (20 mL), and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the title compound (850 mg).

[0854] LCMS (ESI) [M+H] + =146.2.

[0855] Step 2: Preparation of tert-butyl 3-(6-fluoro-1H-indol-3-yl)-3-hydroxyazetidine-1-carboxylate: Potassium hydroxide (1.1 eq) was added to 6-fluoro-1H-indole (15 g, 1 eq) in methanol (300 mL), stirred to dissolve, and then tert-butyl 3-oxoazetidine-1-carboxylate (20.9 g, 1.1 eq) was added. The mixture was stirred at 50°C for 12 hours, cooled to room temperature, and ethyl acetate (500 mL) was added. The mixture was washed with water (300 mL × 3) and saturated brine (500 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was separated and purified to give the title compound (8.6 g).

[0856] LCMS(ESI)[M+H-18-Boc] + =189.1.

[0857] Step 3: Preparation of tert-butyl 3-(6-fluoro-1H-indol-3-yl)azetidine-1-carboxylate: At 0°C, triethylsilane (10eq) was added to tert-butyl 3-(6-fluoro-1H-indol-3-yl)-3-hydroxyazetidine-1-carboxylate (11g, 1eq) in dichloromethane (150mL). After the reaction solution became turbid, trifluoroacetic acid (3eq) was added, and the mixture was stirred at 0°C for 3 hours. Saturated sodium bicarbonate solution (300mL) was added, and the mixture was extracted with dichloromethane (300mL×3). The organic phase was collected, dried, and concentrated. The residue was separated and purified to obtain the target compound (4g).

[0858] LCMS (ESI) [M-56+42] + =276.2.

[0859] Step 4: Preparation of 3-(azetidin-3-yl)-6-fluoro-1H-indole: Add trifluoroacetic acid (10 mL) to tert-butyl 3-(6-fluoro-1H-indol-3-yl)azetidine-1-carboxylate (4 g, 1 eq) in dichloromethane (30 mL) and stir at room temperature for 3 hours. The reaction mixture is concentrated in vacuo to give the title compound (4 g, crude product).

[0860] LCMS (ESI) [M+H] + =191.2.

[0861] Step 5: Preparation of methyl 3-(3-(6-fluoro-1H-indol-3-yl)azetidin-1-yl)propanoate: Methyl 3-bromopropanoate (3.51 g, 1 eq) was added to 3-(azetidin-3-yl)-6-fluoro-1H-indole (4 g, crude product) and sodium carbonate (5 eq) in acetonitrile (40 mL) and stirred at 70°C for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated in vacuo. The residue was separated and purified to obtain the title compound (4.17 g).

[0862] LCMS (ESI) [M+H] + =277.1.

[0863] Step 6: Preparation of 3-(3-(6-fluoro-1H-indol-3-yl)azetidin-1-yl)propanoic acid: Lithium hydroxide (5 eq) was added to methyl 3-(3-(6-fluoro-1H-indol-3-yl)azetidin-1-yl)propanoate (4.17 g, 1 eq) in tetrahydrofuran (30 mL) and water (10 mL), stirred at room temperature for 16 hours, acetic acid was added to adjust the pH to 7, and concentrated in vacuo. The residue was separated and purified by reverse phase system (C18, 0.1% formic acid in water: acetonitrile) to give the title compound (3.2 g).

[0864] LCMS (ESI) [M+H] + =263.2.

[0865] Step 7: Preparation of N'-(3,6-difluoropyridin-2-yl)-3-(3-(6-fluoro-1H-indol-3-yl)azetidin-1-yl)propane hydrazide: HATU (1.5 eq) was added to a solution of 3-(3-(6-fluoro-1H-indol-3-yl)azetidin-1-yl)propanoic acid (3 g, 1 eq) in N,N-dimethylformamide (30 mL), and 3,6-difluoro-2-hydrazinopyridine (1.2 eq) and DIEA (3 eq) were added. The mixture was stirred at room temperature for 4 hours. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were collected, washed with saturated brine, dried, and concentrated in vacuo. The residue was separated and purified to give the title compound (3.73 g).

[0866] LCMS (ESI) [M+H] + =390.1.

[0867] Step 8: Preparation of 3-(1-(2-(5,8-difluoro-(1,2,4)triazolo[4,3-a]pyridin-3-yl)ethyl)azetidin-3-yl)-6-fluoro-1H-indole: N'-(3,6-difluoropyridin-2-yl)-3-(3-(6-fluoro-1H-indol-3-yl)azetidin-1-yl)propane hydrazide (3.73 g, 1 eq) was added to phosphorus oxychloride (30 mL), stirred at 100° C. for 16 hours, and the liquid was concentrated in vacuo. The residue was separated and purified by a reverse phase system (C18, 0.05% aqueous ammonia solution: acetonitrile) to give the title compound (2.5 g) as a colorless oil.

[0868] LCMS (ESI) [M+H] + =372.1.

[0869] Step 9: Preparation of 6-fluoro-3-(1-(2-(8-fluoro-5-methoxy-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)azetidin-3-yl)-1H-indole: Sodium methoxide (1.5 eq) was added to 3-(1-(2-(5,8-difluoro-(1,2,4)triazolo[4,3-a]pyridin-3-yl)ethyl)azetidin-3-yl)-6-fluoro-1H-indole (220 mg, 1 eq) in methanol (10 mL), stirred at 80°C for 1 hour, the reaction solution was concentrated in vacuo, and the residue was purified by prep-HPLC (C18, 0.05% ammonia in water:acetonitrile) to give the title compound (86.63 mg).

[0870] LCMS (ESI) [M+H] + =384.2; 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.57(dd,J=8.6,5.6Hz,1H),7.21(t,J=9.4Hz,2H),7.10(dd,J=10.2,2.2Hz,1H),6.85-6.75 (m,1H),6.15(dd,J=8.2,3.0Hz,1H),4.04(s,3H),3.73(t,J=9.1Hz,3H),3.29(d,J=7.0Hz,2H),3.17(s,2H),2.92(d,J=7.3Hz,2H).

[0871] Example 149 (Compound 149)

[0872] Preparation of 6-fluoro-3-(1-(2-(8-fluoro-(1,2,4)triazolo[4,3-a]pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole:

[0873] Step 1: Preparation of 3-(3-(6-Fluoro-1H-indol-3-yl)pyrrolidin-1-yl)-N'-(3-fluoropyridin-2-yl)propanoic acid hydrazide: 3-(3-(6-Fluoro-1H-indol-3-yl)pyrrolidin-1-yl)propanoic acid (3.5 g, 1 eq) was dissolved in DMF (N,N-dimethylformamide) (30 mL). (3-Fluoropyridin-2-yl)hydrazine (1 eq) and HATU (1.2 eq) were added. After stirring for 5 minutes, N,N-diisopropylethylamine (2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was isolated and purified using a reverse phase column (C18, 0.1% ammonia in water:acetonitrile) to obtain the desired product (700 mg).

[0874] LCMS (ESI) [M+H] + =386.1.

[0875] Step 2: Preparation of 6-fluoro-3-(1-(2-(8-fluoro-(1,2,4)triazolo[4,3-a]pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole: 3-(3-(6-fluoro-1H-indol-3-yl)pyrrolidin-1-yl)-N'-(3-fluoropyridin-2-yl)propanoylhydrazide (300 mg, 1 eq) was dissolved in acetic acid (10 mL) and replaced with nitrogen three times. The reaction was stirred in an oil bath at 110°C for 16 hours. The solvent was dried, water (20 mL) was added, and the pH was adjusted to 10 with saturated sodium carbonate solution. The product was extracted with ethyl acetate (3×80 mL) and dried to obtain the crude product, which was separated and purified by prep-HPLC (C18, 0.05% ammonia in water: acetonitrile) to give the title compound (60 mg).

[0876] LCMS (ESI) [M+H] + =368.1; 1 HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.37(d,J=6.9Hz,1H),7.47(dd,J=8.5,5.7Hz, 1H),7.24(dd,J=11.1,7.4Hz,1H),7.13-7.02(m,2H),6.99-6.84(m,1H),6.74(td,J=9 .8,2.3Hz,1H),3.55-3.40(m,1H),3.35(t,J=7.2Hz,2H),3.11-2.90(m,3H),2.76(t,J =10.6Hz, 2H), 2.61 (d, J = 8.5Hz, 1H), 2.21 (tt, J = 13.2, 6.6Hz, 1H), 1.90-1.77 (m, 1H).

[0877] Example 150 (Compound 150)

[0878] Compound 150 was prepared by referring to the preparation method of Example 149:

[0879] LCMS (ESI) [M+H] + =368.1.

[0880] Example 151 (Compound 151)

[0881] Preparation of 6-fluoro-3-(1-(((3-trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridin-7-yl)methyl)pyrrolidin-3-yl)-1H-indole:

[0882] Step 1: Preparation of methyl 6-methoxy-2,3,4,5-tetrahydropyridine-4-carboxylate: methyl 2-oxopiperidine-4-carboxylate (1.5 g, 1 eq) was dissolved in dichloromethane (20 mL), and trimethyloxonium tetrafluoroborate (1.5 eq) was added. The mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the target compound (1.46 g).

[0883] LCMS (ESI) [M+H] + =172.1.

[0884] Step 2: Preparation of methyl 3-(trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridine-7-carboxylate: Dissolve methyl 6-methoxy-2,3,4,5-tetrahydropyridine-4-carboxylate (800 mg, 1 eq) in methanol (10 mL), add 2,2,2-trifluoroacetylhydrazine (1.1 eq), stir at 85 ° C for 24 hours, and concentrate the reaction solution to obtain a crude product. The crude product is purified to obtain the target compound (180 mg).

[0885] LCMS (ESI) [M+H] + =250.1.

[0886] Step 3: Preparation of 3-(trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridin-7-yl)methanol: 3-(trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridine-7-carboxylic acid methyl ester (300 mg, 1 eq) was dissolved in tetrahydrofuran (5 mL), replaced with nitrogen, cooled to -60 °C, and 1 M tetrahydrofuran was slowly added. To a tetrahydrofuran solution of lithium aluminum hydride (2 eq), stir at -60 ° C for 2 hours to generate the target compound. Slowly drop 1 mL of water into the reaction solution. After the lithium aluminum hydride is quenched, the reaction solution is warmed to room temperature, water (20 mL) is added, and extracted with ethyl acetate (20 mL × 3). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor is concentrated to obtain a crude product. The crude product is purified to obtain the target compound (260 mg).

[0887] LCMS (ESI) [M+H] + =222.0;

[0888] Step 4: Preparation of (3-(trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridin-7-yl)methyl methanesulfonate: 3-(trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridin-7-yl)methanol (270 mg, 1 eq) was dissolved in dichloromethane (5 mL), triethylamine (2.2 eq) was added, the temperature was lowered to 0°C, methanesulfonyl chloride (1.1 eq) was slowly added dropwise, and the mixture was stirred at 0°C for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for 5 minutes. Water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the target compound (280 mg, crude product) which was used directly in the next step.

[0889] LCMS (ESI) [M+H] + =300.0.

[0890] Step 5: Preparation of 6-fluoro-3-(1-(((3-trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridin-7-yl)methyl)pyrrolidin-3-yl)-1H-indole: Dissolve (3-(trifluoromethyl)-5H,6H,7H,8H-(1,2,4)triazolo[4,3-a]pyridin-7-yl)methyl methanesulfonate (270 mg, 1 eq) in N,N-dimethylformamide (5 mL) , add 6-fluoro-3-(pyrrolidin-3-yl)-1H-indole (1 eq) and potassium carbonate (1.5 eq), stir at 70 ° C for 72 hours, add water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the mother liquor to obtain a crude product, which was purified by prep-HPLC (C18, 0.05% formic acid in water: acetonitrile) to obtain the target compound (17.5 mg).

[0891] LCMS (ESI) [M+H] + =408.3; 1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.17(s,1H),7.67-7.57(m,1H),7.16(s,1H),7.10(dd, J=10.2,2.1Hz,1H),6.82(t,J=9.3Hz,1H),4.22(d,J=10.5Hz,1H),4.11-4.02(m,1H),3.54(dd ,J=16.1,7.9Hz,1H),3.20-3.11(m,1H),3.10-3.02(m,1H),2.85-2.69(m,2H),2.58(dt,J=16 .6,8.8Hz,4H),2.34-2.12(m,3H),1.90(dq,J=14.7,7.5Hz,1H),1.74(dd,J=18.0,6.2Hz,1H).

[0892] Example 152 (Compound 152)

[0893] Compound 152 was prepared by referring to the preparation method of Example 149:

[0894] LCMS (ESI) [M+H] + =332.2.

[0895] Example 153 (Compound 153)

[0896] Preparation of 3-(1-(2-(5-(trifluoromethyl)-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole:

[0897] Step 1: Preparation of 2-hydrazino-6-(trifluoromethyl)pyridine: 2-chloro-6-(trifluoromethyl)pyridine (5 g, 1 eq) was dissolved in ethanol (50 mL), hydrazine hydrate (5 eq) was added, and the mixture was reacted at 80 ° C for 16 hours. The ethanol was dried and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain the target compound (3.5 g).

[0898] LCMS (ESI) [M+H] + =178.1.

[0899] Step 2: Preparation of 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)-N'-(6-(trifluoromethyl)pyridin-2-yl)propanoic acid hydrazide: 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)propionic acid (1 g, 1 eq) and (6-(trifluoromethyl)pyridin-2-yl)hydrazine (1.2 eq) were dissolved in ethyl acetate (10 mL), pyridine (5 eq) and 50% propylphosphoric tricyclic anhydride (T3P) / ethyl acetate solution (16.22 eq) were added, and the mixture was reacted at 50° C. for 1 hour. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was spin-dried to give the target compound (800 mg) by purification.

[0900] LCMS (ESI) [M+H] + =418.2.

[0901] Step 3: Preparation of 3-(1-(2-(5-(trifluoromethyl)-(1,2,4)triazolo(4,3-a)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-1H-indole: Dissolve 3-(3-(1H-indol-3-yl)pyrrolidin-1-yl)-N'-(6-(trifluoromethyl)pyridin-2-yl)propanohydrazide (300 mg, 1 eq) in phosphorus oxychloride (5 mL), protect with nitrogen, react at 100°C for 16 hours, prepare, separate and purify to obtain the target compound (15.31 mg).

[0902] LCMS (ESI) [M+H] + =400.3; 1 H NMR(400MHz,MeOD-d4)δ8.31(d,J=41.3Hz,2H),8.10(d,J=9.2Hz,1H),7.73(d, J=6.9Hz,1H),7.65-7.51(m,2H),7.37(d,J=8.1Hz,1H),7.24(s,1H),7.18-7.10 (m,1H),7.09-6.98(m,1H),4.02(dt,J=18.5,7.5Hz,4H),3.75(s,2H),3.63(dd, J=24.3, 17.7Hz, 3H), 2.64 (dd, J=12.7, 6.8Hz, 1H), 2.42 (dt, J=9.0, 6.5Hz, 1H).

[0903] Example 154 (Compound 154)

[0904] Compound 154 was prepared by referring to the preparation method of Example 153:

[0905] LCMS (ESI) [M+H] + =346.2.

[0906] Example 155 (Compound 155)

[0907] Preparation of 3-(4-(2-(imidazo(1,5-a)pyridin-3-yl)ethyl)morpholin-2-yl)-1H-indole:

[0908] Step 1: Preparation of ethyl 2-(((pyridin-2-yl)methyl)carbamoyl)acetate: Dissolve 1-(pyridin-2-yl)methanamine (10 g, 1 eq) in ultra-dry tetrahydrofuran (100 mL). Add ethyl 3-chloro-3-oxopropanoate (1 eq) dropwise under nitrogen in an ice bath, followed by triethylamine (1.5 eq). The temperature was raised to room temperature and the reaction was allowed to proceed for 2 hours. Water (150 mL) and ethyl acetate (100 mL x 3) were added for extraction. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate to obtain the title compound (14 g).

[0909] LCMS (ESI) [M+H] + =223.2.

[0910] Step 2: Preparation of ethyl 2-(imidazo(1,5-a)pyridin-3-yl)acetate: Dissolve ethyl 2-(((pyridin-2-yl)methyl)carbamoyl)acetate (13 g, 1 eq) in phosphorus oxychloride (100 mL), react at 100 ° C under nitrogen protection for 16 hours, spin-dry to remove most of the phosphorus oxychloride, quench, wash to obtain a crude product, and separate and purify to obtain the target compound (9 g).

[0911] LCMS (ESI) [M+H] + =205.2.

[0912] Step 3: Preparation of 2-imidazo(1,5-a)pyridin-3-ylethanol: Dissolve ethyl 2-(imidazo(1,5-a)pyridin-3-yl)acetate (2 g, 1 eq) in tetrahydrofuran (20 mL), add lithium aluminum tetrahydride (2 eq) in batches under an ice bath, warm to room temperature and react for 2 hours, add water (1 mL) to quench, add 15% NaOH (1 mL), water (1 mL), add anhydrous sodium sulfate and stir for 30 minutes, and filter to obtain the target compound (1.5 g, crude product).

[0913] LCMS (ESI) [M+H] + =163.0.

[0914] Step 4: Preparation of 2-(imidazo(1,5-a)pyridin-3-yl)ethyl methanesulfonate:

[0915] 2-Imidazolo(1,5-a)pyridin-3-ylethanol (800 mg, crude product) was dissolved in dichloromethane (10 mL), triethylamine (1497.35 mg) was added, and methanesulfonyl chloride (847.52 mg) was slowly added dropwise. The mixture was reacted at room temperature for 2 hours. Water (10 mL) and dichloromethane (10 mL × 3) were added to extract the aqueous phase, washed with saturated brine, and dried over anhydrous sodium sulfate to obtain the crude product. The target compound (700 mg) was separated and purified.

[0916] LCMS (ESI) [M+H] + =241.1.

[0917] Step 5: Preparation of 1-(1H-indol-3-yl)-2-iodoethane-1-one: 1-(1H-indol-3-yl)ethane-1-one (1 g, 1 eq) was dissolved in methanol (10 mL), and copper oxide (1.1 eq) and iodine (1.1 eq) were added. The mixture was reacted at 70°C for 3 hours. The reaction was cooled to room temperature, and water (30 mL) was added to the reaction solution. The mixture was stirred for 20 minutes, and the filter cake obtained by filtration was completely dissolved in tetrahydrofuran (50 mL). The copper oxide was removed by filtration, and the filtrate was dried to obtain the title compound (1.7 g).

[0918] LCMS (ESI) [M+H] + =286.0.

[0919] Step 6: Preparation of 2-(2-hydroxyethylamino)-1-(1H-indol-3-yl)ethane-1-one: To the stirred ethanol-1-amine (80 mL, 24.9 eq) was added 1-(1H-indol-3-yl)-2-iodoethane-1-one (15 g, 1 eq) in batches under ice bath, and the mixture was reacted under ice bath for 30 minutes. Water (100 mL) was added to precipitate a solid, which was filtered to obtain a crude product, which was slurried with acetonitrile to obtain the target compound (3.2 g).

[0920] LCMS (ESI) [M+H] + =219.1.

[0921] Step 7: Preparation of 2-((2-hydroxyethyl)amino)-1-(1H-indol-3-yl)ethane-1-ol: 2-(2-hydroxyethylamino)-1-(1H-indol-3-yl)ethane-1-one (1.3 g, 1 eq) was dissolved in methanol (10 mL), and sodium borohydride (5 eq) was slowly added under ice bath, and the reaction was heated to room temperature for 16 hours. 4 M hydrochloric acid methanol (15 mL) was added under ice bath to quench the reaction until the pH value was neutral. The salt was filtered off and the filtrate was used directly in the next step.

[0922] LCMS (ESI) [M-18+H] + =203.2.

[0923] Step 8: Preparation of 3-(morpholin-2-yl)-1H-indole:

[0924] To 2-((2-hydroxyethyl)amino)-1-(1H-indol-3-yl)ethane-1-ol (the reaction solution after quenching in the previous step) was added 4 M methanolic hydrochloric acid solution (10 mL) under an ice bath until the pH value was 2. The mixture was stirred at room temperature for 30 minutes, dried by rotary evaporation, filtered, and rinsed to obtain a crude product. The crude product was dissolved in methanol, and aqueous ammonia was added dropwise until the pH value was 9. The mixture was filtered and dried to obtain the title compound (1.5 g).

[0925] LCMS (ESI) [M+H] + =203.1.

[0926] Step 9: Preparation of 3-(4-(2-(imidazo(1,5-a)pyridin-3-yl)ethyl)morpholin-2-yl)-1H-indole: 3-(Morpholin-2-yl)-1H-indole (300 mg, 1 eq) and 2-(imidazo(1,5-a)pyridin-3-yl)ethyl methanesulfonate (1 eq) were dissolved in acetonitrile (10 mL) and N,N-dimethylformamide (5 mL), potassium carbonate (3 eq) was added, and the mixture was reacted at 70°C for 24 hours. The acetonitrile was dried by spin drying, and ethyl acetate (10 mL×3) and water (20 mL) were added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give the crude product, which was separated and purified by prep-HPLC to obtain the target compound (21.03 mg).

[0927] LCMS (ESI) [M+H] + =347.1; 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.19(d,J=7.0Hz,1H),7.61(d,J=7.9Hz,1H),7.49(d,J=9.1Hz,1H),7.34(d, J=8.1Hz,1H),7.30-7.24(m,2H),7.07(t,J=7.3Hz,1H),6.98(t,J=7.2Hz,1H),6.70(dd,J=9.0,6.4Hz,1H),6.61(t, J=6.3Hz,1H),4.72(d,J=8.1Hz,1H),3.89(d,J=11.5Hz,1H),3.68(dd,J=11.1,9.1Hz,1H),3.19(t,J=7.5 Hz, 2H), 3.04 (d, J = 11.1Hz, 1H), 2.84 (dt, J = 14.4, 9.5Hz, 3H), 2.40 (d, J = 10.7Hz, 1H), 2.33-2.25 (m, 1H).

[0928] Example 156 (Compound 156)

[0929] Preparation of 3-(4-(2-imidazo[1,2-a]pyridin-3-yl)ethyl)morpholin-2-yl)-1H-indole:

[0930] Step 1: Preparation of 2-(Imidazolo[1,2-a]pyridin-3-yl)ethane-1-ol: Dissolve ethyl 2-imidazo[1,2-a]pyridin-3-yl)acetate (1 g, 1 eq) in tetrahydrofuran (30 mL). Cool the reaction mixture to -10°C and slowly add lithium aluminum tetrahydride (2 eq) in portions. Slowly warm to room temperature and stir for 3 hours. Add water (0.4 mL) and 15% sodium hydroxide solution (0.4 mL), followed by water (1.2 mL). Stir at room temperature for 15 minutes. Add an appropriate amount of anhydrous magnesium sulfate and continue stirring for 15 minutes. Filter and spin-dry the filtrate to obtain the title compound (790 mg).

[0931] LCMS (ESI) [M+H] + =163.1.

[0932] Step 2: Preparation of 2-(imidazo[1,2-a]pyridin-3-yl)ethyl methanesulfonate: Dissolve 2-(imidazo[1,2-a]pyridin-3-yl)ethane-1-ol (600 mg, 1 eq) in dichloromethane (15 mL), add triethylamine (3 eq), cool the reaction solution to 0°C, slowly add methylsulfonyl chloride (1.2 eq) dissolved in dichloromethane (3 mL) dropwise, stir at room temperature for 1 hour, add water (30 mL), extract with dichloromethane (3×50 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the target compound (600 mg, crude product), which is directly used in the next reaction.

[0933] LCMS (ESI) [M+H] + =241.1.

[0934] Step 3: Preparation of 3-(4-(2-imidazo[1,2-a]pyridin-3-yl)ethyl)morpholin-2-yl)-1H-indole: Dissolve 2-(imidazo[1,2-a]pyridin-3-yl)ethyl methanesulfonate (500 mg, crude) in N,N-dimethylformamide (20 mL). Add 3-morpholin-2-yl-1H-indole (420.86 mg, 1 eq) and potassium carbonate (3 eq). Stir in an oil bath at 70°C for 16 hours. Add water (100 mL) and extract with ethyl acetate (3 × 100 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated and purified by prep-HPLC (C18, 10 mmol ammonia in water:acetonitrile) to obtain the title compound (95.41 mg).

[0935] LCMS (ESI) [M+H] + =347.2; 1 HNMR(400MHz,MeOD-d4)δ8.31(t,J=8.1Hz,1H),7.65(d,J=7.8Hz,1H),7.53(d,J=9.1Hz,1H), 7.44(d,J=3.8Hz,1H),7.38-7.20(m,3H),7.09(t,J=7.5Hz,1H),6.98(dt,J=12.4,6.8Hz,2H), 4.90(d,J=10.3Hz,1H),4.02(d,J=11.5Hz,1H),3.95-3.76(m,1H),3.18(dd,J=16.6,8.5Hz,3 H), 2.99 (d, J = 9.7Hz, 1H), 2.90-2.75 (m, 2H), 2.65-2.52 (m, 1H), 2.45 (dd, J = 11.3, 7.9Hz, 1H).

[0936] Examples 157-165

[0937] Compounds 157-165 were prepared by referring to the preparation methods of Examples 1, 5, and 156:

[0938] Compound 157: LCMS (ESI) [M+H] + =365.1;

[0939] Compound 158: LCMS (ESI) [M+H] + =364.2;

[0940] Compound 159: LCMS (ESI) [M+H] + =374.1;

[0941] Compound 160: LCMS (ESI) [M+H] + =358.2;

[0942] Compound 161: LCMS (ESI) [M+H] + =374.2;

[0943] Compound 162: LCMS (ESI) [M+H] + =332.2;

[0944] Compound 163: LCMS (ESI) [M+H] + =332.2;

[0945] Compound 164: LCMS (ESI) [M+H] + =378.2;

[0946] Compound 165: LCMS (ESI) [M+H] + =375.1.

[0947] Example 166 (Compound 166)

[0948] Compound 166 was prepared by referring to the preparation methods of Examples 20, 29, and 132:

[0949] LCMS (ESI) [M+H] + =375.1; 1 H NMR (400MHz, MeOD-d4) δ7.98 (dd, J=4.8, 1.1Hz, 1H), 7.64 (d, J=7.9Hz, 1H), 7.35 (t, J=8.1Hz, 2H),7.23(dd,J=8.9,4.2Hz,2H),7.09(dd,J=11.2,4.0Hz,1H),7.01(t,J=7.1Hz,1H),4.87(d, J=2.1Hz,1H),3.97(dd,J=11.5,1.8Hz,1H),3.89-3.80(m,4H),3.05(d,J=11.6Hz,1H),2.86(t ,J=7.7Hz,3H),2.47(dt,J=22.1,9.2Hz,3H),2.29(td,J=11.5,3.4Hz,1H),1.97-1.86(m,2H).

[0950] Examples 167-169 (Compounds 167-169)

[0951] Compounds 167-169 were prepared by referring to the preparation methods of Examples 1 and 5:

[0952] Compound 167: LCMS (ESI) [M+H] + =296.1;

[0953] Compound 168: LCMS (ESI) [M+H] + =351.2;

[0954] Compound 169: LCMS (ESI) [M+H] + =351.2.

[0955] Example 170 (Compound 170)

[0956] Preparation of 3-(1-(3-(1,2,4-oxadiazol-3-yl)propyl)azetidin-3-yl)-1H-indole:

[0957] Step 1: Preparation of 4-(3-(1H-indol-3-yl)azetidin-1-yl)butanenitrile: 4-Bromobutanenitrile (0.9 eq) was added to a solution of 3-(azetidin-3-yl)-1H-indole (4.85 g, 1 eq) and potassium carbonate (1 eq) in acetonitrile (50 mL), and the mixture was stirred at 70°C for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by flash chromatography (Silica gel, PE / EA = 1 / 1) to obtain the title compound (1 g).

[0958] LCMS (ESI) [M+H] + =240.1.

[0959] Step 2: Preparation of (Z)-N'-hydroxy-4-(3-(1H-indol-3-yl)azetidin-1-yl)butanemidine: Potassium carbonate (3 eq) was added to a solution of 4-(3-(1H-indol-3-yl)azetidin-1-yl)butanenitrile (1 g, 1 eq), hydroxylamine hydrochloride (3.5 eq) in ethanol (10 mL) and water (5 mL), and the mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse phase chromatography (C18, 0.1% NH3.H2O / water, MeCN) to afford the title compound (260 mg).

[0960] LCMS (ESI) [M+H] + =273.1.

[0961] Step 3: Preparation of 3-(1-(3-(1,2,4-oxadiazol-3-yl)propyl)azetidin-3-yl)-1H-indole: (Z)-N'-hydroxy-4-(3-(1H-indol-3-yl)azetidin-1-yl)butanemidine (250 mg, 1 eq) was added to triethyl orthoformate (5 mL) and a catalytic amount of trifluoroacetic acid. The mixture was stirred at room temperature for 10 minutes and at 60°C for 0.5 hours. The reaction mixture was concentrated in vacuo, and the residue was added with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-HPLC (C18, 0.1% NH3.H2O / water, MeCN) to obtain the title compound (60.47 mg).

[0962] LCMS (ESI) [M+H] + =283.1. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.49(s,1H),7.60(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7.21(d,J=2.2Hz,1H),7.09-7.03(m,1H),6.99-6.9 4(m,1H),3.79(dd,J=14.9,7.2Hz,1H),3.71(t,J=7.0Hz,2H),3.14(q,J=6 .7Hz,2H),2.80(t,J=7.5Hz,2H),2.53(d,J=7.0Hz,2H),1.78-1.68(m,2H).

[0963] Example 171 (Compound 171) and Example 172 (Compound 172)

[0964] Preparation of (R)-3-(1-[3-(1,2,4-oxadiazol-3-yl)propyl]pyrrolidin-3-yl)-1H-indole (Compound 171) and (S)-3-(1-[3-(1,2,4-oxadiazol-3-yl)propyl]pyrrolidin-3-yl)-1H-indole (Compound 172):

[0965] Compound 49 (2.7 g) was subjected to chiral separation to give compounds 171 and 172. Chiral separation conditions: temperature: room temperature; mobile phase: CO2 / MeOH [0.1% ammonia in methanol (7 M) = 86 / 14]; flow rate: 130 mL / min; detection wavelength: 214 nm. The target compound P1 (171 or 172) (t major=3.108min,ee>99%,1.274g) and P2 (172 or 171) (t major =3.75 7min, ee>96%, 0.933g).

[0966] Example 173 (Compound 173)

[0967] Preparation of 3-(1-(3-(1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indol-4-ol:

[0968] Step 1: Preparation of 4-(3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidin-1-yl)butyronitrile: 4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole (5 g, 1 eq) was dissolved in acetonitrile (50 mL). 4-bromobutyronitrile (0.9 eq) and sodium carbonate (3 eq) were added and reacted at 70°C for 16 hours. The mixture was filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was dried and purified by flash chromatography (silica gel, DCM:MeOH = 30:1) to give the title compound (5.5 g).

[0969] LCMS (ESI) [M+H] + =360.2.

[0970] Step 2: Preparation of (Z)-4-(3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidin-1-yl)-N'-hydroxybutyramidine: 4-(3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidin-1-yl)butyronitrile (5.4 g, 1 eq) was dissolved in water (50 mL) and ethanol (50 mL), and hydroxylamine hydrochloride (3 eq) and potassium carbonate (3 eq) were added. The mixture was reacted at 80°C for 16 hours. The ethanol was dried by spin-drying, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried by spin-drying to obtain the crude product, which was separated and purified by reverse phase separation (C18, 0.1% FA / water, MeCN) to obtain the title compound (3.2 g).

[0971] LCMS (ESI) [M+H] + =393.2.

[0972] Step 3: Preparation of 4-(benzyloxy)-3-(1-(3-(1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: (Z)-4-(3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidin-1-yl)-N'-hydroxybutyramidine (700 mg, 1 eq) was dissolved in triethyl orthoformate (6 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was allowed to react at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate (3 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3) and water (30 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give the crude product, which was separated and purified by flash chromatography (Silica gel, DCM:MeOH = 30:1) to obtain the title compound (200 mg).

[0973] LCMS (ESI) [M+H] + =403.2.

[0974] Step 4: Preparation of 3-(1-(3-(1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol: 4-(benzyloxy)-3-(1-(3-(1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole (200 mg, 1 eq) was dissolved in ultra-dry dichloromethane (20 mL), the temperature was lowered to -70 °C, and a 1 M dichloromethane solution of boron tribromide (2.5 mL) was slowly added dropwise. mL, 5 eq) and reacted at -70°C for 30 minutes. LCMS detected the formation of the product. Saturated sodium bicarbonate solution (20 mL) was added dropwise at -70°C to quench the reaction. The mixture was warmed to room temperature and stirred for 15 minutes. Water (20 mL) and dichloromethane (20 mL × 3) were added for extraction, and the obtained organic phase was spin-dried. The target compound (10.74 mg) was obtained by separation and purification by Prep-HPLC (C18, 0.1% FA / water, MeCN).

[0975] LCMS (ESI) [M+H] + =313.2; 1 H NMR(400MHz,MeOD-d4)δ9.17(s,1H),8.54(s,1H),7.02(s,1H),6.97-6.81(m,2H),6.39(d,J=7.2Hz,1H),4.09-3.98(m,1H),3.81 (d,J=9.1Hz,1H),3.53(dd,J=20.6,10.3Hz,3H),3.31-3.22(m,2H),2.93(t,J=7.0Hz,2H),2.52-2.37(m,2H),2.26-2.15(m,2H).

[0976] Example 174 (Compound 174)

[0977] Preparation of 3-(1-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indol-4-ol:

[0978] Step 1: Preparation of (Z)-4-(3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidin-1-yl)-N'-(isobutyryloxy)butyramidine: 2-Methylpropionic acid (134.69 mg, 1 eq) was dissolved in dichloromethane (10 mL). HATU (1 eq) and N,N-diisopropylethylamine (1.3 eq) were added and stirred at room temperature for 30 minutes. (Z)-4-(3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidin-1-yl)-N'-hydroxybutyramidine (1 eq) was added and the reaction continued for 2 hours. Water (20 mL) and dichloromethane (10 mL x 3) were added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give the crude product, which was isolated and purified by flash chromatography (silica gel, DCM:MeOH = 20:1) to obtain the title compound (400 mg).

[0979] LCMS (ESI) [M+H] + =463.2.

[0980] Step 2: Preparation of 4-(benzyloxy)-3-(1-(3-(5-(propan-2-yl)-1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole: (Z)-4-(3-(4-(benzyloxy)-1H-indol-3-yl)pyrrolidin-1-yl)-N'-(isobutyryloxy)butyramidine (350 mg, 1 eq) was dissolved in ethanol (20 mL) and water (10 mL), and sodium acetate (5 eq) was added. The mixture was reacted at 80°C for 16 hours. The ethanol was dried and extracted with water (20 mL) and ethyl acetate (15 mL x 3). The crude product was separated and purified by flash chromatography (Silica gel, DCM:MeOH = 15:1) to obtain the title compound (250 mg).

[0981] LCMS (ESI) [M+H] + =445.2.

[0982] Step 3: Preparation of 3-(1-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol: 4-(benzyloxy)-3-(1-(3-(5-(propan-2-yl)-1,2,4-oxadiazol-3-yl)propyl)pyrrolidin-3-yl)-1H-indole (75 mg, 1 eq) was dissolved in ultra-dry dichloromethane (20 mL), the temperature was lowered to -70 ° C, and 1 M boron tribromide in dichloromethane was slowly added dropwise. The mixture was stirred for 5 minutes, and the temperature was raised to room temperature. Saturated sodium bicarbonate was added to adjust the pH to 9. Water (20 mL) and dichloromethane (20 mL × 3) were added to extract the obtained organic phase, which was spin-dried and purified by Prep-HPLC (C18, 0.1% FA / water, MeCN) to obtain the target compound (8.36 mg).

[0983] LCMS (ESI) [M+H] + =355.2; 1 H NMR (400MHz, MeOD-d4) δ8.52(s,1H),7.03(s,1H),6.96-6.77(m,2H),6.39(d,J=7.3Hz,1H),4.03(d,J=8.3Hz,1H),3.82(s,1H),3.6 8-3.44(m,3H),3.31(s,2H),3.27-3.16(m,1H),2.86(t,J=6.9Hz,2H),2.59-2.38(m,2H),2.32-2.11(m,2H),1.37(d,J=6.9Hz,6H).

[0984] Example 175 (Compound 175)

[0985] Preparation of 3-(3-(-3-(1H-indazol-3-yl)pyrrolidin-1-yl)propyl)-5-isopropyl-1,2,4-oxadiazole:

[0986] Step 1: Preparation of 4-(3-(1H-indazol-3-yl)pyrrolidin-1-yl)butyronitrile: 3-(Pyrrolidin-3-yl)-1H-indazole (1.6 g, 1 eq) was dissolved in acetonitrile (20 mL) and N,N-dimethylformamide (10 mL). 4-bromobutyronitrile (1 eq) and potassium carbonate (3 eq) were added and reacted at 80°C for 5 hours. The acetonitrile was evaporated, and the mixture was extracted with water (30 mL) and ethyl acetate (40 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain the title compound (2 g).

[0987] LCMS (ESI) [M+H] + =255.2.

[0988] Step 2: Preparation of (Z)-N'-hydroxy-4-(3-(1H-indazol-3-yl)pyrrolidin-1-yl)butyramidine: 4-(3-(1H-indazol-3-yl)pyrrolidin-1-yl)butyronitrile (2.2 g, 1 eq) was dissolved in water (20 mL) and ethanol (30 mL), and hydroxylamine hydrochloride (3 eq) and potassium carbonate (3 eq) were added. The mixture was reacted at 70°C for 16 hours. The ethanol was dried by spin-drying, and the mixture was extracted with ethyl acetate (30 mL x 3) and water (30 mL). The organic phase was dried by spin-drying to obtain a crude product, which was separated and purified by reverse phase separation (C18, 0.1% TFA / water, MeCN) to obtain the title compound (2 g).

[0989] LCMS (ESI) [M+H] + =288.2.

[0990] Step 3: Preparation of (Z)-N'-(isobutyryloxy)-4-(3-(1H-indazol-3-yl)pyrrolidin-1-yl)butyramidine: 2-Methylpropionic acid (306.62 mg, 1 eq) was dissolved in dichloromethane (20 mL). HATU (1 eq) and N,N-diisopropylethylamine (1.3 eq) were added and stirred at room temperature for 30 minutes. (Z)-N'-hydroxy-4-(3-(1H-indazol-3-yl)pyrrolidin-1-yl)butyramidine (1 eq) was added and the reaction continued for 2 hours. Water (30 mL) and dichloromethane (20 mL x 3) were added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give the crude product, which was separated and purified by flash chromatography (silica gel, DCM:MeOH = 20:1) to obtain the title compound (250 mg).

[0991] LCMS (ESI) [M+H] + =358.2.

[0992] Step 4: Preparation of 3-(3-(-3-(1H-indazol-3-yl)pyrrolidin-1-yl)propyl)-5-isopropyl-1,2,4-oxadiazole: (Z)-N'-(isobutyryloxy)-4-(3-(1H-indazol-3-yl)pyrrolidin-1-yl)butyramidine (150 mg, 1 eq) was dissolved in ethanol (5 mL) and water (5 mL), and sodium acetate (3 eq) was added. The mixture was reacted at 80°C for 16 hours. The ethanol was dried and extracted with water (20 mL) and ethyl acetate (15 mL x 3) to give a crude product, which was separated and purified by Prep-HPLC (C18, 0.1% FA / water, MeCN) to give the title compound (11.6 mg).

[0993] LCMS (ESI) [M+H] + =340.2; 1 H NMR(400MHz,MeOD-d4)δ8.56(s,1H),7.79(d,J=8.1Hz,1H),7.49(d,J=8.4Hz,1H),7.38(t ,J=7.7Hz,1H),7.14(t,J=7.5Hz,1H),4.13-4.00(m,1H),3.74-3.63(m,1H),3.56-3.46(m ,1H),3.43-3.34(m,2H),3.18(dd,J=16.4,9.2Hz,3H),2.85(t,J=7.3Hz,2H),2.58(dd,J= 13.5, 6.9Hz, 1H), 2.35 (dd, J = 13.4, 7.0Hz, 1H), 2.22-2.06 (m, 2H), 1.37 (d, J = 7.0Hz, 6H).

[0994] Example 176 (Compound 176)

[0995] Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)azetidin-3-yl)-1H-indole:

[0996] Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)azetidin-3-yl)-1H-indole: 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (596 mg, 1 eq) was added to 3-(azetidin-3-yl)-1H-indole (1 eq) and potassium carbonate (6 eq) in acetonitrile (10 mL) and stirred at 70°C for 16 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was isolated and purified by prep-HPLC (C18, 0.1% NH3.H2O / water / MeCN) to give the title compound (50.34 mg).

[0997] LCMS (ESI) [M+H] + =282.4; 1H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 7.76 (s, 2H), 7.60 (d, J = 7.9Hz, 1H), 7.33 (d,J=8.1Hz,1H),7.19(d,J=2.1Hz,1H),7.06(t,J=7.5Hz,1H),6.96(t,J=7.4H z,1H),4.47(t,J=7.0Hz,2H),3.77(dd,J=14.9,7.4Hz,1H),3.68(t,J=6.9Hz,2 H), 3.09 (t, J = 6.9 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 1.89 (dd, J = 13.9, 7.0 Hz, 2H).

[0998] Example 177 (Compound 177) and Example 178 (Compound 178)

[0999] Preparation of (R)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole (Compound 177) and (S)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole (Compound 178):

[1000] Compound 125 (200 mg) was subjected to chiral separation to obtain target compounds 177 and 178. Chiral separation conditions: temperature: room temperature; mobile phase: CO2 / MeOH [0.1% DEA = 75 / 25]; flow rate: 120 mL / min; detection wavelength: 214 nm, to obtain the target compounds (P3 (177 or 178) (t major =1.905min, ee>97%, 15.8mg), P4 (178 or 177) (t major =2.437min, ee>95%, 14.5mg).

[1001] Example 179 (Compound 179)

[1002] Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole:

[1003] Step 1: Preparation of 3-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole: 1H-indole (5 g, 1 eq) was dissolved in isopropanol (50 mL), and 1-benzylpiperidin-3-one (2 eq) and potassium hydroxide (10 eq) were added and stirred at 80°C for 16 hours. The isopropanol was dried, and the product was dissolved in dichloromethane and filtered. The filtrate was dried to give a crude product, which was then separated and purified by flash chromatography (Silica gel, dichloromethane:ethyl acetate = 5:1) to obtain the title compound (4.5 g).

[1004] LCMS (ESI) [M+H] + =289.3.

[1005] Step 2: Preparation of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole: 3-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole (450 mg, 1 eq) was dissolved in dichloromethane (10 mL). 1-Chloroethylcarbonyl chloride (ACE-Cl) (1.1 eq) was added under nitrogen. The mixture was allowed to react at room temperature for 5 hours. LCMS analysis indicated the disappearance of the starting material. Methanol (10 mL) was added and the reaction continued at 70°C for 5 hours. The solvent was then dried and purified by reverse phase purification (C18, 0.1% TFA / water, MeCN) to obtain the title compound (70 mg).

[1006] LCMS (ESI) [M+H] + =199.1.

[1007] Step 3: Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole: 3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole (60 mg, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), and 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (1 eq) and potassium carbonate (2 eq) were added. The mixture was reacted at 60°C for 16 hours. Water (30 mL) and ethyl acetate (30 mL × 2) were added for washing. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried. The title compound (6.46 mg) was obtained by separation and purification by Prep-HPLC (C18, 10 mmol / L NH4HCO3 / water, MeCN).

[1008] LCMS (ESI) [M+H] + =308.2; 1H NMR(400MHz,MeOD-d4)δ7.78(d,J=8.0Hz,1H),7.70(s,2H),7.37(d,J=8.1Hz, 1H),7.28(s,1H),7.12(t,J=7.5Hz,1H),7.06(d,J=7.2Hz,1H),6.26(d,J=3.8H z,1H),4.58(t,J=6.7Hz,2H),3.67(d,J=1.7Hz,2H),2.98(t,J=6.0Hz,2H),2. 86 (dd, J = 9.2, 6.6 Hz, 2H), 2.52 ( d, J = 3.7 Hz, 2H), 2.37 ( dd, J = 15.2, 7.2 Hz, 2H).

[1009] Example 180 (Compound 180)

[1010] Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indol-4-ol:

[1011] Step 1: Preparation of 4-(benzyloxy)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole: 4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole (400 mg, 1 eq) and potassium carbonate (3 eq) were added to acetonitrile (20 mL), followed by 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (1 eq). The mixture was reacted at 70°C for 16 hours. The mixture was filtered, the filtrate was dried, and the compound was isolated and purified by flash chromatography (Silica gel, dichloromethane:methanol = 10:1, volume ratio) to give the compound (400 mg).

[1012] LCMS (ESI) [M+H] + =402.2.

[1013] Step 2: Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol: 4-(benzyloxy)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole (320 mg, 1 eq) was dissolved in methanol (10 mL). Acetic acid (1 mL), 10% palladium on carbon (50 mg), and 20% palladium hydroxide on carbon (50 mg) were added. The mixture was reacted at room temperature under a hydrogen atmosphere for 1 hour. The product was filtered and dried to give a crude product, which was then separated and purified by Prep-HPLC (C18, 0.1% FA / water, MeCN) to give the title compound (59.45 mg).

[1014] LCMS (ESI) [M+H] + =312.1; 1 H NMR(400MHz,MeOD-d4)δ8.49(s,1H),7.70(s,2H),7.02(s,1H),6.87(dd,J=18.8,7.7Hz,2H),6.39(d,J=7.3Hz,1H),4 .59(t,J=6.4Hz,2H),4.10-3.95(m,1H),3.84-3.72(m,1H),3.62-3.45(m,3H),3.29-3.21(m,2H),2.52-2.33(m,4H).

[1015] Example 181 (Compound 181) and Example 182 (Compound 182)

[1016] Preparation of (R)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol (Compound 181) and (S)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol (Compound 182):

[1017] Step 1: Preparation of (R)-4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole and (S)-4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole: 4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole (7 g) was subjected to chiral separation. Chiral separation conditions were as follows: temperature: room temperature; mobile phase: CO2 / IPA [0.1% ammonia solution in ethanol (7 M) = 85 / 15]; flow rate: 120 mL / min; detection wavelength: 214 nm. Compound P5 (t major =1.770 min, ee>99%, 3.32 g) and P6 (t maj or=2.276min, ee>99%, 3.26g).

[1018] Step 2: Preparation of (R)-4-(benzyloxy)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole and (S)-4-(benzyloxy)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole: Compound P5 (400 mg, 1 eq) obtained in the first step and potassium carbonate (3 eq) were added to acetonitrile (20 mL), followed by 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (1 eq). The mixture was reacted at 70°C for 16 hours. The mixture was filtered, and the filtrate was dried and purified by flash chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain compound P5-1 (450 mg). P5-1: LCMS (ESI) [M+H] + =402.2. Using the same preparation method, compound P6 (400 mg, 1 eq) was substituted for compound P5 to obtain compound (P6-1: 440 mg). P6-1: LCMS (ESI) [M+H] + =402.2.

[1019] Step 3: Preparation of (R)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol and (S)-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol: The compound prepared in the second step (P5-1: 400 mg, 1 eq) was dissolved in methanol (10 mL), and acetic acid (1 mL), 10% palladium carbon (50 mg) and 20% palladium hydroxide on carbon (50 mg) were added. The mixture was reacted at room temperature for 1 hour under a hydrogen atmosphere. The reaction was completed by LCMS detection. The mixture was filtered and dried to obtain a crude product, which was separated and purified by Prep-HPLC (C18, 0.1% FA / water, MeCN) to obtain the target compound (181 or 182: 125 mg). (181 or 182): LCMS (ESI) [M+H] + =312.2.

[1020] Using the same preparation method, compound P6-1 (400 mg, 1 eq) was substituted for compound P5-1, and the target compound (182 or 181: 120 mg) was obtained. (182 or 181): LCMS (ESI) [M+H] + =312.2.

[1021] Example 183 (Compound 183)

[1022] Preparation of 2-methyl-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indol-4-ol:

[1023] Step 1: Preparation of 4-(Benzyloxy)-2-methyl-1H-indole: Dissolve 2-methyl-1H-indole-4-ol (900 mg, 1 eq) and potassium carbonate (2.5 g, 3 eq) in N,N-dimethylformamide (15 mL). Add benzyl bromide (1.5 eq) dropwise and react at room temperature for 16 hours. Extract with water (40 mL) and ethyl acetate (40 mL x 2). The organic phase is washed with saturated brine (30 mL x 3) and dried over anhydrous sodium sulfate to obtain a crude product. Purify the crude product by flash chromatography (Silica gel, DCM:MeOH = 15:1) to obtain the title compound (1.5 g, crude product).

[1024] LCMS (ESI) [M+H] + =238.1.

[1025] Step 2: Preparation of 3-(4-(Benzyloxy)-2-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione: 4-(Benzyloxy)-2-methyl-1H-indole (1.5 g, crude) and 2,5-dihydro-1H-pyrrole-2,5-dione (1.53 g) were dissolved in acetic acid (20 mL) and reacted at 125°C for 16 hours. The acetic acid was dried by spin-drying, and water (30 mL) was added. The pH was adjusted to 9 by adding saturated sodium carbonate, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was spin-dried and slurried with dichloromethane to obtain the title compound (1 g).

[1026] LCMS (ESI) [M+H] + =335.1.

[1027] Step 3: Preparation of 4-(Benzyloxy)-2-methyl-3-(pyrrolidin-3-yl)-1H-indole: Dissolve 3-(4-(Benzyloxy)-2-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione (1 g, 1 eq) in tetrahydrofuran (20 mL). Slowly add lithium aluminum tetrahydride (5 eq) under ice-cooling. Raise the temperature to 75°C and continue the reaction for 16 hours. Return to room temperature, add water (1 mL), 15% NaOH solution (1 mL), and water (3 mL) dropwise under ice-cooling. Add anhydrous sodium sulfate, stir for 20 minutes, and filter. Rinse the filter cake with tetrahydrofuran, and spin dry the filtrate to obtain the crude product. Purify the crude product by reverse-phase separation (C18, 0.1% TFA / water, MeCN) to obtain the title compound (600 mg).

[1028] LCMS (ESI) [M+H] +=307.1.

[1029] Step 4: Preparation of 4-(benzyloxy)-2-methyl-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole: 4-(benzyloxy)-2-methyl-3-(pyrrolidin-3-yl)-1H-indole (210 mg, 1 eq) was dissolved in acetonitrile (10 mL), and 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (1 eq) and potassium carbonate (3 eq) were added. The mixture was reacted at 70°C for 16 hours. The mixture was filtered, and the filtrate was dried and purified by flash chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain the title compound (160 mg).

[1030] LCMS (ESI) [M+H] + =416.2.

[1031] Step 5: Preparation of 2-methyl-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol: 4-(benzyloxy)-2-methyl-3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole (150 mg, 1 eq) was dissolved in methanol (10 mL). Acetic acid (0.5 mL), 10% palladium on carbon (10 mg), and 20% palladium hydroxide on carbon (10 mg) were added. The mixture was reacted at room temperature under a hydrogen atmosphere for 20 minutes. The mixture was filtered, dried, and separated and purified by Prep-HPLC (C18, 0.1% FA / water, MeCN) to obtain the title compound (32.44 mg).

[1032] LCMS (ESI) [M+H] + =326.1; 1 H NMR (400MHz, MeOD-d4) δ8.53(s,1H),7.72(s,2H),6.85(t,J=7.8Hz,1H),6.81-6.75(m,1H),6.39(dd,J=7.5,0.8Hz,1H),4.61(t,J=6. 5Hz,2H),3.83(dd,J=11.4,7.8Hz,2H),3.66-3.47(m,3H),3.30-3.21(m,2H),2.62-2.48(m,1H),2.46-2.38(m,2H),2.37-2.27(m,4H).

[1033] Example 184 (Compound 184)

[1034] Preparation of 6-fluoro-3-(1-[3-(2H-1,2,3-triazol-2-yl)propyl]pyrrolidin-3-yl)-1H-indol-4-ol:

[1035] Step 1: Preparation of 4-fluoro-2-phenylmethoxybenzaldehyde: The raw material 4-fluoro-2-hydroxybenzaldehyde (25 g, 1 eq) was dissolved in N,N-dimethylformamide (300 mL), and benzyl bromide (1.1 eq) and potassium carbonate (1.5 eq) were added and stirred at 80°C for 6 hours. LCMS showed that the raw material reaction was complete and a large amount of target compound was generated. The reaction solution was slowly poured into ice water (2 L) and a gray solid was generated. The mixture was stirred for 20 minutes and filtered. The filter cake was washed twice with water (2 x 100 mL). The filter cake solid was collected and dissolved in ethyl acetate (800 mL). The organic phases were combined, washed with saturated brine (3 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (two parallel batches) (70 g).

[1036] LCMS (ESI) [M+H] + =231.0.

[1037] Step 2: Preparation of ethyl 2-azido-3-(2-(benzyloxy)-4-fluorophenyl)prop-2-enoate: Sodium ethoxide (295.57 g, 5 eq, 20 wt% in ethanol) was dissolved in ethanol (500 mL). The reaction mixture was cooled to -20°C and ethyl 2-azidoacetate (5 eq) was slowly added. The reaction mixture was stirred at this temperature for 20 minutes. 4-Fluoro-2-phenylmethoxybenzaldehyde (40 g, 1 eq) was slowly added dropwise over 60 minutes. The reaction mixture was allowed to react at -8°C for 3 hours. TLC monitoring of the reaction revealed the disappearance of the starting material spot and the formation of a less polar spot. The reaction mixture was slowly added to ice water and filtered. The filter cake was washed with water (3 x 200 mL). The solid (45 g, crude) was collected, dissolved in xylene (1200 mL) and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and used directly in the next step without further purification.

[1038] Step 3: Preparation of ethyl 4-(benzyloxy)-6-fluoro-1H-indole-2-carboxylate: Dissolve ethyl 2-azido-3-(2-(benzyloxy)-4-fluorophenyl)prop-2-enoate (45 g, crude) in xylene (1000 mL). The reaction mixture was incubated at 150°C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated, and a small amount of xylene was added to the solid, followed by filtration. The filter cake was rinsed with xylene and dried to yield the title compound (20 g).

[1039] LCMS (ESI) [M+H] + =314.1.

[1040] Step 4: Preparation of 4-(benzyloxy)-6-fluoro-1H-indole-2-carboxylic acid: 4-(benzyloxy)-6-fluoro-1H-indole-2-carboxylic acid ethyl ester (12 g, 1 eq) was dissolved in ethanol / tetrahydrofuran / water (30 mL / 30 mL / 30 mL) and sodium hydroxide (5 eq) was added. The reaction was stirred for 10 hours. The reaction was completed after LCMS monitoring. The pH was adjusted to 2 with 1N hydrochloric acid solution, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the title compound (9 g).

[1041] LCMS (ESI) [M+H] + =286.1.

[1042] Step 5: Preparation of 4-(benzyloxy)-6-fluoro-1H-indole: 4-(benzyloxy)-6-fluoro-1H-indole-2-carboxylic acid (9 g, 1 eq) was dissolved in N-methylpyrrolidone (200 mL) and activated copper powder (4 eq) was added. The mixture was replaced with nitrogen three times and stirred in an oil bath at 200°C for 10 hours. LCMS showed that the target compound was generated. The mixture was cooled to room temperature, ice water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography (Silica gel, PE:EtOAc=10:1) to obtain the target compound (7 g).

[1043] LCMS (ESI) [M+H] + =242.1.

[1044] Step 6: Preparation of 3-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione: 4-(benzyloxy)-6-fluoro-1H-indole (6.7 g, 1 eq) was dissolved in acetic acid (80 mL) and maleimide (4 eq) was added. The mixture was stirred in an oil bath for 72 hours. The reaction was monitored by LCMS to complete the reaction. The mixture was cooled to room temperature, the solvent was dried, water (80 mL) was added to dilute the mixture, and the pH was adjusted to 9 with saturated sodium carbonate solution (40 mL). Ethyl acetate (100 mL×3) was added for extraction, and the organic phase was dried to obtain a crude product. An appropriate amount of anhydrous ether (30 mL) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with ether (3×5 mL). The filter cake was collected and dried to obtain the target product (5 g).

[1045] LCMS (ESI) [M+H] + =339.1.

[1046] Step 7: Preparation of 4-(benzyloxy)-6-fluoro-3-(pyrrolidin-3-yl)-1H-indole: Dissolve 3-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (4.5 g, 1 eq) in tetrahydrofuran (15 mL), cool the reaction solution to -10 ° C, slowly add lithium aluminum tetrahydride (5 eq) in batches, slowly raise to 70 ° C, stir for 3 hours, LCMS shows that the raw materials have reacted, cool to -10 ° C, slowly add ice water solution (2.5 mL), add 15% sodium hydroxide solution (2.5 mL), then add water (8 mL) and stir at room temperature for 15 minutes, add an appropriate amount of anhydrous magnesium sulfate, and continue stirring for 15 minutes. The crude product was slurried in anhydrous ether (20 mL) and stirred at room temperature for 10 minutes. The product was filtered and the filter cake was washed three times with ether (3 x 5 mL). The filter cake was collected and dried to obtain the desired product (2.5 g).

[1047] LCMS (ESI) [M+H] + =311.1.

[1048] Step 8: 4-(Benzyloxy)-6-fluoro-3-(1-[3-(2H-1,2,3-triazol-2-yl)propyl]pyrrolidin-3-yl)-1H-indole

[1049] Preparation of: 4-(Benzyloxy)-6-fluoro-3-(pyrrolidin-3-yl)-1H-indole (900 mg, 1 eq) was dissolved in acetonitrile (30 mL), sodium carbonate (3 eq) and 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (1 eq) were added, the atmosphere was replaced with nitrogen three times, and the reaction was stirred in an oil bath at 70°C for 3 hours. LCMS showed the formation of the target compound. The reaction mixture was cooled to room temperature, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3x80 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography (Silica gel, DCM:MeOH=10:1) to obtain the target compound (400 mg).

[1050] LCMS (ESI) [M+H] + =420.2.

[1051] Step 9: Preparation of 6-fluoro-3-(1-[3-(2H-1,2,3-triazol-2-yl)propyl]pyrrolidin-3-yl)-1H-indole-4-ol: 4-(benzyloxy)-6-fluoro-3-(1-[3-(2H-1,2,3-triazol-2-yl)propyl]pyrrolidin-3-yl)-1H-indole (120 mg, 1 eq) was dissolved in methanol (10 mL). Palladium on carbon (0.1 eq, 10% purity) and palladium hydroxide on carbon (0.1 eq, 10% purity) were added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. LCMS indicated complete reaction. The mixture was filtered, and the filtrate was dried to give the crude product, which was then concentrated. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 / water, MeCN) to give the title compound (19.41 mg).

[1052] LCMS (ESI) [M+H] + =330.2; 1 H NMR (400MHz, CDCl3) δ13.58(s,1H),7.80(d,J=26.1Hz,1H),7.59(s,2H),6.77(d,J=2.3 Hz,1H),6.51(dd,J=9.0,2.2Hz,1H),6.31(dd,J=11.7,2.2Hz,1H),4.64-4.44(m,2H),3 .59(dd,J=15.0,9.3Hz,1H),3.37(dd,J=14.6,6.8Hz,1H),3.17(d,J=9.6Hz,1H),2.62( dt,J=19.2,9.8Hz,2H),2.52(s,1H),2.43-2.26(m,3H),2.19(s,1H),2.15-2.04(m,1H); 19 F NMR (377MHz, CDCl3) δ-119.97 (s).

[1053] Example 185 (Compound 185) and Example 186 (Compound 186)

[1054] Preparation of (R)-3-(1-(3-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol (Compound 185) and (S)-3-(1-(3-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol (Compound 186):

[1055] Compound 127 (300 mg) was subjected to chiral separation to obtain the target compounds 185 and 186. Chiral separation conditions: temperature: room temperature; mobile phase: CO2 / IPA [0.1% ammonia in methanol (7M) = 80 / 20]; flow rate: 120 mL / min; detection wavelength: 214 nm. P7 (185 or 186) (t major =2.611 min, ee>99%, 57 mg) and P8 (186 or 185) (t major =3.490min, ee>99%, 66.5mg)

[1056] Example 187 (Compound 187)

[1057] Preparation of 3-(1-(3-(4-methyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indol-4-ol:

[1058] Step 1: Preparation of 4-(benzyloxy)-3-(1-(3-(4-methyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(4-methyl-2H-1,2,3-triazol-2-yl)propyl methanesulfonate (300 mg, 1 eq) was added to 4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole (1 eq) and potassium carbonate (3 eq) in acetonitrile (10 mL) and stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was collected. The filtrate was concentrated in vacuo, and the residue was purified by reverse phase chromatography (C18, 0.1% FA / water, MeCN) to give the title compound (300 mg).

[1059] LCMS (ESI) [M+H] + =416.2.

[1060] Step 2: Preparation of 3-(1-(3-(4-methyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol: Palladium on carbon (20 mg) and palladium hydroxide on carbon (20 mg) were added to a solution of 4-(benzyloxy)-3-(1-(3-(4-methyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole (200 mg, 1 eq) in methanol (5 mL) and water (5 mL), and stirred at 25 ° C for 0.5 hours under a hydrogen atmosphere.

[1061] The reaction was monitored by LCMS. The reaction mixture was filtered through celite, and the filtrate was adjusted to pH 9 with saturated sodium bicarbonate solution and concentrated in vacuo. The residue was slurried in dichloromethane (20 mL), filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (C18, 0.1% FA / water, MeCN) to obtain the title compound (12.98 mg).

[1062] LCMS (ESI) [M+H] + =326.2; 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.22(s,1H),7.50(s,1H),6.95(d,J=2.3Hz,1H),6.81(t, J=7.8Hz,1H),6.73(dd,J=8.0,0.9Hz,1H),6.25(dd,J=7.5,0.8Hz,1H),4.40(t,J=7.0Hz,2H),3 .69(d,J=9.0Hz,1H),3.01(t,J=7.4Hz,1H),2.79(d,J=6.5Hz,2H),2.60-2.53(m,2H),2.45(s,1 H), 2.33-2.26 (m, 1H), 2.22 (s, 3H), 2.08 (dt, J = 14.1, 7.2Hz, 2H), 1.85 (dt, J = 15.7, 8.6Hz, 1H).

[1063] Example 188 (Compound 188)

[1064] Preparation of 3-(1-(3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indol-4-ol:

[1065] Step 1: Preparation of 1-benzyl-4-cyclopropyl-1H-1,2,3-triazole: Add acetylene cyclopropane (1.5 eq) to (azidomethyl)benzene (6 g, 1 eq), sodium ascorbyl acetate (0.1 eq), and copper sulfate pentahydrate (0.01 eq) in tert-butanol (50 mL) and water (50 mL). Stir at room temperature for 16 hours. The reaction is monitored by LCMS. Water (50 mL) is added, and the mixture is extracted with ethyl acetate (100 mL x 3). The organic phases are combined, washed with saturated brine (200 mL), dried, and concentrated. The residue is purified by flash chromatography (Silica gel, PE / EA = 3 / 1) to afford the title compound (8.93 g).

[1066] LCMS(ESI)[M+H+ACN] + =241.2.

[1067] Step 2: Preparation of 4-cyclopropyl-2H-1,2,3-triazole: Palladium on carbon (1 g) and palladium hydroxide on carbon (1 g) were added to a solution of 1-benzyl-4-cyclopropyl-1H-1,2,3-triazole (8 g, 1 eq) in methanol (40 mL) and water (40 mL). The mixture was stirred at 60°C under a hydrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The reaction mixture was filtered through celite, and the filtrate was adjusted to pH 9 with saturated sodium bicarbonate solution and concentrated in vacuo. The residue was slurried in dichloromethane (50 mL), filtered, and the filtrate was concentrated to obtain the title compound (4.05 g).

[1068] LCMS (ESI) [M+H] + =110.1.

[1069] Step 3: Preparation of 3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propan-1-ol: 3-Bromopropanol (5.09 g, 1 eq) was added to 4-cyclopropyl-2H-1,2,3-triazole (4 g, 1 eq) and potassium carbonate (1.5 eq) in acetone (50 mL). The mixture was stirred at 50°C for 8 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (Silica gel, DCM / MeOH = 10 / 1) to afford the title compound (3.12 g).

[1070] LCMS (ESI) [M+H] + =168.1.

[1071] Step 4: Preparation of 3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propyl methanesulfonate: Methanesulfonyl chloride (1.2 eq) was added dropwise to a solution of 3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propan-1-ol (500 mg, 1 eq) and triethylamine (1.2 eq) in dichloromethane (10 mL) at 0°C. The mixture was stirred at room temperature for 10 minutes. The reaction was monitored by LCMS. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to yield the title compound (634 mg, crude product).

[1072] LCMS (ESI) [M+H] + =246.5.

[1073] Step 5: Preparation of 4-(benzyloxy)-3-(1-(3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole: 3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propyl methanesulfonate (537 mg, 1 eq) was added to 4-(benzyloxy)-3-(pyrrolidin-3-yl)-1H-indole (1 eq) and potassium carbonate (3 eq) in acetonitrile (10 mL). The mixture was stirred at 70°C for 16 hours and the reaction was monitored by LCMS. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by flash chromatography (silica gel, DCM / MeOH = 10 / 1) to obtain the title compound (588 mg).

[1074] LCMS (ESI) [M+H] + =442.7.

[1075] Step 6: Preparation of 3-(1-(3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole-4-ol: Palladium on carbon (50 mg) and palladium hydroxide on carbon (50 mg) were added to a solution of 4-(benzyloxy)-3-(1-(3-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indole (500 mg, 1 eq) in methanol (5 mL) and water (5 mL), acetic acid (0.1 mL) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LCMS, and the reaction solution was filtered. Saturated sodium bicarbonate solution was added to the filtrate to adjust the pH to 9, and dichloromethane (15 mL×2) was added for extraction. The organic phases were combined and concentrated in vacuo. The residue was purified by prep-HPLC (C18, 0.1% NH3.H2O / water, MeCN) to give the target compound (101.69 mg).

[1076] LCMS (ESI) [M+H] + =352.3; 1H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.58(s,1H),7.48(s,1H),6.93(d,J=2.3Hz,1H),6.82(t,J=7.8Hz,1H), 6.73(dd,J=8.0,0.9Hz,1H),6.25(dd,J=7.5,0.9Hz,1H),4.41-4.33(m,2H),3.72-3.61(m,1H),2.97(dd,J=8.5, 6.6Hz,1H),2.75(dd,J=9.1,3.9Hz,1H),2.68(t,J=8.8Hz,1H),2.51(d,J=1.5Hz,1H),2.47(s,1H),2.40-2.23( m,2H),2.12-2.00(m,2H),1.93(tt,J=8.4,5.0Hz,1H),1.88-1.75(m,1H),0.95-0.87(m,2H),0.72-0.67(m,2H).

[1077] Example 189 (Compound 189)

[1078] Preparation of 3-(1-(3-(2H-1,2,3-triazol-2-yl)propyl)pyrrolidin-3-yl)-1H-indazole:

[1079] 3-(Pyrrolidin-3-yl)-1H-indazole (350 mg, 1 eq) and potassium carbonate (3 eq) were dissolved in acetonitrile (15 mL) and N,N-dimethylformamide (3 mL). 3-(2H-1,2,3-triazol-2-yl)propyl methanesulfonate (1 eq) was added and the mixture was reacted at 70°C for 16 hours. Water (30 mL) and ethyl acetate (20 mL x 3) were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then purified by flash chromatography (silica gel, DCM:MeOH = 20:1) to obtain a crude product, which was then purified by Prep-HPLC (C18, 0.1% FA / water, MeCN) to obtain the title compound (92.44 mg).

[1080] LCMS (ESI) [M+H] + =297.1; 1H NMR(400MHz,MeOD-d4)δ8.47(s,1H),7.78(d,J=8.2Hz,1H),7.71(s,2H),7.50(d,J =8.5Hz,1H),7.45-7.33(m,1H),7.21-7.08(m,1H),4.61(t,J=6.5Hz,2H),4.20-4.0 7(m,1H),3.79(dd,J=11.2,7.9Hz,1H),3.69(dd,J=11.2,7.4Hz,1H),3.49(dd,J=14 .7,7.4Hz,2H),3.29-3.23(m,2H),2.61(dt,J=14.9,7.3Hz,1H),2.48-2.30(m,3H).

[1081] Biological Examples

[1082] Experimental Example 1: 5-HT 2A Receptor isotope competition affinity testing

[1083] Incubation of a radiolabeled ligand (agonist or antagonist) with a receptor protein can form a receptor-ligand complex. Adding the test compound to the complex can compete with the isotope-labeled ligand for binding to the receptor, ultimately forming a relative steady-state equilibrium. The affinity of the test compound for the receptor can be indirectly assessed by measuring the dissociation of the isotope-labeled ligand from the receptor.

[1084] Experimental procedures

[1085] Prepare 100x serial dilutions of the compound in DMSO, starting at 1mM, 4-fold serial dilutions, 10 concentration points. Use a pipette to transfer 1μL of the compound to a 96-well assay plate (final concentration is 10μM starting, 4-fold serial dilutions, 10 concentration points), and first add 49μL of 10 μM prepared in assay buffer (50mM Tris-HCl, pH 7.4) to each well. 2 μg / mL 5-HT 2A Receptor protein (final concentration 5 μg / well). Then add 50 μL of 2nM isotope-labeled [ 3 [H]-Ketanserin (2x final concentration), seal the membrane, and incubate on a shaker at room temperature for 1 hour. Filter the reaction mixture through a Unifilter-96GF / C filter plate pretreated with 0.3% PEI. Rinse the filter plate with 4°C precooled assay buffer and dry it in a 50°C incubator. After adding scintillation fluid, read the value using a MicroBeta2 instrument. Calculate the percentage inhibition rate using the formula: % inhibition rate = (Count 高信号对照 -Count 样品孔 ) / (Count 高信号对照 -Count低信号对照 )*100, perform four-parameter fitting to calculate IC 50 Values, high signal control: no compound group (same volume of DMSO instead), low signal control: non-isotope labeled Ketanserin group with 2X final concentration.

[1086] Table 1: 5-HT 2A Receptor isotope competition affinity test results Ki value Note: Ki: +++≤100nM, 100nM<++≤500nM, +>500nM.

[1087] Experimental Example 2: 5-HT 2A β-arrestin recruitment experiments

[1088] Co-expression of ProLink in human osteosarcoma cells (U2OS) TM The cells are labeled with a GPCR receptor (PK) and an enzyme receptor (EA) labeled with β-arrestin. Activation of the GPCR-PK induces the recruitment of the β-arrestin-EA, forcing the two enzyme fragments to complement each other. The resulting functional enzyme hydrolyzes the substrate, generating a chemiluminescent signal. These cells have been modified with a proprietary compound that has no significant impact on assay performance to prevent their long-term proliferation and expansion.

[1089] Cell preparation: Preheat AssayComplete Cell Plating Reagent in a 37°C water bath for 15 minutes. Transfer 11.5 mL of preheated AssayComplete Cell Plating Reagent to a new sterile 15 mL centrifuge tube. Remove 5-HT from -80°C or liquid nitrogen. 2A U2OS cells should be placed on dry ice before thawing. Immediately thaw the cells by adding 0.5 mL of prewarmed AssayComplete Cell Plating Reagent to the cryovial. Transfer 0.6 mL of the thawed cell suspension to a microcentrifuge tube containing 23.5 mL of prewarmed AssayComplete Cell Plating Reagent, gently mix the cells, and transfer them to a disposable sterile sample reservoir. Add 20 μL of cell suspension to each well of a 384-well plate. Incubate the 384-well plate in an incubator at 37°C, 5% CO2 for 48 hours.

[1090] β-Arrestin2 assay: Dilute the compound using Cell Plating Reagent 0 in a dilution plate, 4-fold dilution, 10 points. The concentration corresponding to each point should be 5 times the final concentration. Add 5 μL of 5× compound to each well of the 384-well plate containing the cell suspension, and incubate the plate at 37°C for 90 minutes. Prepare the detection reagent by adding 19 parts Cell Assay Buffer, 5 parts Substrate Reagent 1, and 1 part Substrate Reagent 2 to a 15 mL centrifuge tube and mix thoroughly. Add 12.5 μL of detection reagent to each well of the plate. Incubate the plate in the dark at room temperature for 1 hour. Read the plate (Envision).

[1091] Day 1: Seed cells into 10 cm culture dishes:

[1092] HEK293 cells were seeded in 10 cm culture dishes at a density of 4×10^6 cells / dish and cultured in DMEM medium containing 10% dialyzed FBS and 1% PS.

[1093] Day 2: Transfection plasmid:

[1094] Plasmid A (5-HT 2A ) and plasmid B (β-arrestin-2);

[1095] Continue to add fuGENE HD reagent to the above Opti-MEM medium and let it stand at room temperature for 15 minutes;

[1096] The above mixture was added to a 10 cm culture dish of HEK293 cells and mixed gently;

[1097] The culture dish was incubated at 37°C, 5% CO2 for 24 h.

[1098] Day 3: Compound treatment and cell harvest:

[1099] The test compound was prepared in DMSO and diluted with assay buffer to different concentration gradients before being added to a 384-well assay plate.

[1100] Cells were collected from a 10 cm culture dish 24 h after transfection, washed twice with serum-free DMEM medium, and resuspended to adjust the cell concentration to 5×10^5 cells / mL.

[1101] Aspirate 20 μL of cell suspension (containing 1×10^4 cells) and inoculate into a 384-well assay plate containing the compound. Centrifuge the plate at 1000 rpm for 5 seconds and then incubate at 37°C, 5% CO2 for 24 hours.

[1102] Day 4: Chemiluminescence detection:

[1103] Prepare the required amount of recombinant Nano-Glo Live Cell Reagent. Mix Nano-Glo Live Cell Substrate with Nano-Glo LCS Dilution Buffer at a 1:19 volume ratio (20x dilution). Add 5 μL / well of the diluted detection reagent to a 384-well assay plate.

[1104] Read the chemiluminescent signal of the assay plate and calculate the percentage activity:

[1105] % activity = (RLU sample well - RLU low signal control) / (RLU high signal control - RLU low signal control) * 100, fitting calculation EC 50 Values, low signal control: DMSO group without compound, high signal control: 1 μM Yangshen 5-HT group.

[1106] Experimental Example 3: 5-HT 2A R calcium influx activation test

[1107] 1. Experimental Materials

[1108] 1.1 Culture medium

[1109] DMEM medium (Invitrogen, catalog #11965)

[1110] Dialyzed fetal bovine serum (BI, catalog #040111A)

[1111] Hygromycin (Invitrogen, cat. #10687010)

[1112] 1.2 Reagents

[1113] Fluo-4 Direct Kit (Invitrogen, Cat. No. F10471)

[1114] 1.3 Instruments

[1115] 384-well cell plate (Greiner, Cat. No. 781090)

[1116] 384-well compound plate (Greiner, Cat. No. 781280)

[1117] FLIPR instrument (Molecular Device)

[1118] EHCO Instruments (Labcyte)

[1119] Cell counter (Beckman, Vi-cell XR)

[1120] 2. Compound Detection

[1121] 2.1 Cell Preparation

[1122] 1) For cultured cells (stable expression of human 5-HT 2A The HEK293 cells of the recipient were washed twice with preheated DPBS, and then digested with appropriate amount of trypsin at 37℃ for 1 minute; then the appropriate amount of culture medium was added to terminate the digestion, and 1 ml was taken out and used Vi-CELL TM Count and determine viability.

[1123] 2) Centrifuge the cells at 1000 rpm for 5 minutes.

[1124] 3) Gently discard the supernatant without touching the cell mass at the bottom.

[1125] 4) Dilute the cells to 1×10 6 Cells / mL (20,000 cells / 20 μL) were seeded in 384-well poly-lysine-coated cell plates and cultured at 37° C. with 5% CO 2 for 16-20 hours.

[1126] 2.2 Reagent Preparation

[1127] 1) Prepare 250 mM probenecid solution: According to the kit instructions, add 1 mL of FLIPR buffered saline to 77 mg of probenecid and prepare it immediately before use.

[1128] 2) Fluo-4 Direct TM (2×, 8μM) loading buffer preparation: According to the kit instructions, add the required amount of Fluo-4 Direct TM Remove and thaw, add 10mL FLIPR buffered saline and 0.2mL 250mM Pro benecid solution to each tube, vortex in the dark for >5 minutes, and prepare before use.

[1129] 2.3 Compound detection methods

[1130] 1) Preparation of reference and test compound plates: Use Echo to perform a 10-point gradient dilution, and transfer 750 nL to the corresponding compound plates.

[1131] 2) Add 30 μL of experimental buffer solution to the corresponding compound plate and centrifuge at 1000 rpm for 1 minute;

[1132] 3) Take the cell plate prepared the day before out of the incubator and add 20 μL 2×Fluo-4 Direct TM Buffer, the total volume is 40 μL.

[1133] 4) Incubate in a 5% CO2, 37°C incubator for 50 minutes, then place at room temperature for 10 minutes.

[1134] 5) Place the compound plate, cell plate, and pipette tip into the instrument;

[1135] 6) Run the FLIPR instrument software and, following the pre-programmed protocol, add 10 μL of the test compound and reference compound at the designated concentration to the cell plate and read the fluorescence signal. After reading, export the data using the "Max-Min" and "Read 1 to 90" methods in the software.

[1136] 7) Analyze the data:

[1137] Activation% = (RLU-DMSO) / (HC-DMSO)*100

[1138] RLU: relative absorbance, reading from 1 to 90;

[1139] HC: average fluorescence signal at the highest agonist concentration;

[1140] DMSO: average fluorescence signal of DMSO group;

[1141] 8) Data were fitted using Prism 5.0.

[1142] For agonists: Fit EC using "log(agonist) vs. response --Variable slope" 50 ;

[1143] Table 2: 5-HT 2A R calcium influx activation test

[1144] Through the compound to 5-HT 2A The results of the R calcium flow activation test showed that the compounds of the present invention have a moderate activation effect on calcium flow, thereby exerting antidepressant effects. The control compound has no calcium flow activity, indicating no activation effect.

[1145] Experimental Example 4: Evaluation of the efficacy of the compounds of the present invention in the mouse head-shake model and depression model

[1146] 1. Experimental conditions and materials:

[1147] 1.1 Animal Source: Mice (C57BL / 6 strain, purchased from Shanghai Lingchang Biotechnology Co., Ltd., 8-9 weeks old, 20-24 g, male)

[1148] 1.2 Conditions: Temperature (20-25°C), relative humidity (40-70%), photoperiod (12-h photoperiod (7:00-19:00)), free access to food and water

[1149] 1.3 Labeling: Animal tail labeling method

[1150] 2. Experimental steps:

[1151] Experiment 1: Effects of compounds in the head impulse test

[1152] a) Acclimation: Animals were acclimated to the test room starting on the second day of their arrival, and were soothed and acclimated for seven consecutive days to reduce stress. b) Grouping: Prior to testing, animals were placed in the testing room for one hour to acclimate. On the day of testing, animals were randomly divided into groups based on weight. Each group consisted of 12 animals. c) Dosing: Animals were weighed and administered the compound according to group, with a dosing volume of 10 mL / kg. d) Testing: Following dosing, animals were placed in a transparent observation box, and head shaking behavior was recorded for 60 minutes. e) Testing indicator: The total number of head shakings observed within 60 minutes after dosing.

[1153] Experimental results: The mouse head shaking test (HTR) reflects the hallucinogenic effect of the compound. DOI is a positive tool drug. After administration, the mice showed obvious head shaking, which has hallucinogenic effects. Psilocybin is a reference drug. After administration, the mice also showed obvious head shaking, which has hallucinogenic effects.

[1154] Compounds 49, 180, and 182, administered at doses higher than that of psilocybin, did not induce significant head shaking in mice and therefore did not exhibit hallucinogenic effects. The results are shown in Figure 1.

[1155] Experiment 2: Compounds in Antidepressant effects in mice 7 days after a single administration

[1156] a) Acclimation: Animals were acclimated by handling starting on the second day of treatment and continued to be soothed for seven consecutive days to reduce stress. b) Behavioral Testing: FST: Compound and psilocybin groups (15 animals per group) were housed for an additional 7 days after administration. On day 7, the ketamine group (15 animals per group) was placed in a forced swim chamber along with the compound and psilocybin groups 30 minutes after administration. The chambers were recorded for 6 minutes, and the duration of immobility during the last 4 minutes was calculated. c) Experimental Testing Parameter: The duration of immobility during the forced swim period of 2-6 minutes was measured.

[1157] The experimental results show that compared with the solvent control group, compound 180 can significantly shorten the immobility time in the forced swim test of mice (p<0.05), as shown in Figure 2; moreover, in both experiments, compared with the solvent group, compound 180 can significantly shorten the immobility time in the forced swim test of mice (p<0.05), and the effect is stable.

Claims

1. A compound represented by the following formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof: in, Indicates a single bond or a double bond, one and only one is a double bond; X1 is selected from N or NH, CR X1 ; X2 is selected from N, CR X2 ; X3 is selected from N, CR X3 ; X4 is selected from N, CR X4 ; And X1, X2, X3, and X4 are not N at the same time; Y1 is selected from O, S, NR Y11 , CR Y12 ; Y2 is selected from N, CR Y22 ; Y3 is selected from N, C; When Y3 is N, there is a single bond between Y3 and Y2; when Y3 is C, there is a double bond between Y3 and Y2; R X1 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thioalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; R X2 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thioalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; R X3 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thioalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; R X4 is selected from hydrogen, deuterium, halogen, or optionally substituted C 1-4 Alkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; R Y11 is selected from hydrogen, deuterium, optionally substituted C 1-3 Alkyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; R Y12 is selected from hydrogen, deuterium, optionally substituted C 1-3 Alkyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; R Y22 is selected from hydrogen, deuterium, halogen, optionally substituted C 1-3 Alkyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; L is -Z-L'-, -L'-Z-, -L'-Z-L'-; L' is selected from the following optionally substituted groups: -C 1-4 Alkylene-, -C 1-4 Oxyalkylene-, -C 1-4 Thioalkylene-, -C 1-4 Azaalkylene-, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 substituted by a haloalkoxy substituent; Z is optionally replaced by a R A Substituted: 4-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl; wherein each R A Independently selected from Deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 substituted by an alkoxy substituent; Ring B is C 6-14 Aryl, 5-16 membered heterocyclyl, 5-16 membered heteroaryl; Each R B independently selected from deuterium, halogen, -OH, -CN, -NH2, oxo, optionally substituted with: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Oxaalkyl, C 1-4 Thioalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Substituted by a haloalkyl substituent; a is selected from 0, 1, 2, 3; b is selected from 0, 1, 2, 3, 4; Unless otherwise specified, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; The condition is that Z is not When Y1 is NH and X4 is N, L is not 2. The compound of claim 1, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: X1, X2, X3, and X4 are not N; or, X1 is N, X2 is CR X2 , X3 is CR X3 , X4 is CR X4 ;or, X2 is N, X1 is CR X1 , X3 is CR X3 , X4 is CR X4 ;or, X3 is N, X1 is CR X1 , X2 is CR X2 , X4 is CR X4 ;or, X4 is N, X1 is CR X1 , X2 is CR X2 , X3 is CR X3 ;or, X2 and X4 are N, and X1 is CR X1 , X3 is CR X3 ;or, X1 and X3 are N, and X2 is CR X2 , X4 is CR X4 .

3. The compound according to any one of claims 1 to 2, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: Y1 is CR Y12 , Y2 is CR Y22 , Y3 is N; or Y1 is NR Y11 , Y2 is selected from N or CR Y22 , Y3 is C; or Y1 is NR Y11 , Y2 is selected from CR Y22 , Y3 is C; or Y1 is O, Y2 is N, and Y3 is C.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: R X1 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Oxaalkyl, C 1- 4-thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; Preferably, R X1 Selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH2, or the following optionally substituted groups: methoxy, ethoxy, methylthio; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; More preferably, R X1 Selected from hydrogen, -F, -OH, -OCH3; R X2 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Oxaalkyl, C 1- 4-thiaalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; Preferably, R X2 Selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH2, or the following optionally substituted groups: methoxy, ethoxy, methylthio; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; More preferably, R X2 is selected from hydrogen, -F, -OCH3; R X3 is selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Oxaalkyl, C 1-4 Thioalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; More preferably, R X2 is selected from hydrogen, -F, -OCH3; More preferably, R X2 Selected from hydrogen; R X3 Selected from hydrogen, deuterium, -F, -Cl, -Br, -OH, -CN, -NH2, or the following optionally substituted groups: methoxy, ethoxy, methylthio; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; Preferably, R X3 is selected from hydrogen, -F, -OCH3; More preferably, R X3 Selected from hydrogen; R X4 is selected from hydrogen, deuterium, halogen, or the following optionally substituted groups: methyl, ethyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; Preferably, R X4 Selected from hydrogen, deuterium, -F, -Cl, -Br; More preferably, R X4 Selected from hydrogen.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: R Y11 is selected from the group consisting of hydrogen, deuterium, and optionally substituted groups: methyl, ethyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, -CN, -OH, -NH2; preferably, R Y11 is selected from hydrogen, methyl; Preferably, R Y11 is selected from hydrogen; R Y22 is selected from the group consisting of hydrogen, deuterium, -F, -Cl, -Br, optionally substituted groups: methyl, ethyl, wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, -CN, -OH, -NH2; More preferably, R Y22 is selected from hydrogen, -Br, methyl; More preferably, R Y22 Selected from hydrogen.

6. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, Wherein L is -Z-L'-, -L'-Z-, -L'-Z-L'-; L' is an optionally substituted group: -C 1-4 Alkylene-, -C 1-4 wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 substituted by an alkyl substituent; Preferably, L' is ** is the B ring connection site; * is the Z ring connection site; Z is optionally replaced by a R A Substituted: 4-10 membered heterocyclyl, 4-10 membered heterocycloalkenyl; wherein R A Selected from deuterium, halogen, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy; Preferably, Z is optionally replaced by a R A Replaces: * is connected to the L' end; or Preferably, Z is More preferably, L is ** is the B ring attachment site.

7. The compound according to any one of claims 1 to 6, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: Ring B is phenyl, 5-12 membered heterocyclic group, 5-12 membered heteroaryl group; for example, ring B is phenyl, 5-membered monocyclic heteroaryl group; Preferably, ring B is Preferably, ring B is Preferably, ring B is Among them, each R B independently selected from deuterium, halogen, -OH, -CN, -NH2, oxo, optionally substituted with: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thioalkyl, C 3-6 Cycloalkyl, wherein optionally substituted means unsubstituted or substituted by one or more selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Substituted by a haloalkyl substituent; Preferably, each R B are independently selected from F, CN, oxo, methyl, cyclopropane, cyclobutane, methoxy, trifluoromethyl, 8. The compound according to any one of claims 1 to 7, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: b is selected from 0, 1, 2, 3; preferably, b is selected from 0, 1, 2; and / or a is selected from 0, 1, and 2; preferably, a is selected from 0 and 1; more preferably, a is selected from 0.

9. The compound according to any one of claims 1 to 8, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein the compound is a compound represented by the following formula (II): in, X1, X2, X3, X4, Y1, Y2, Y3, L', Ring B, R B , R A , a, b are as described in the compound of formula (I) of claim 1-8; W is -CH2-, -O-, -S-, or -NH-; Each R A independently selected from deuterium, halogen, -OH, oxo, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 substituted by an alkoxy substituent; m is selected from 0, 1, 2, and 3.

10. The compound according to any one of claims 1 to 9, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein the compound is a compound represented by the following formula (III-1) to (III-8): in, L', Ring B, R B , b, W, R A , a, m are as described in the compounds of formula (I) and (II) as claimed in claims 1-9; R is selected from deuterium, halogen, -OH, -CN, -NH2, or an optionally substituted group: C 1-4 Alkyl, C 1-4 Oxaalkyl, C 1-4 Thioalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; n is 0, 1, 2, 3.

11. The compound according to any one of claims 1 to 10, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein the compound is a compound represented by the following formula (A1) to (A16): in, L', Ring B, R B , b, R A , a) as described in the compounds of formula (I), (II), (III-1) to (III-8) in claims 1-10; Preferably, ring B is phenyl, 5-membered monocyclic heteroaryl; or, ring B is 12. The compound according to any one of claims 1 to 10, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein the compound is a compound represented by the following formula (a)-(b): in, R, L', Ring B, R A , R B , n, a, b are as described in the compounds of formula (I), (II), (III-2) in claims 1-10; Preferably, R is selected from -OH, methoxy; preferably, L' is selected from the following optionally substituted groups: -propylene-; preferably, ring B is phenyl, Or preferably ring B is phenyl, For example 13. The compound according to any one of claims 1 to 10, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein the compound is a compound represented by the following formula (c)-(d): in, R, L', Ring B, R A , R B , n, a, b are as described in the compounds of formula (I), (II), (III-2) in claims 1-10; w1, w2, w3, w4 are independently selected from CH, N; W is -CH, -CH2-, -O-, -S-; represents a single bond or a double bond, but not both; when When it is a double bond, W is -CH-.

14. A compound, a stereoisomer of the compound or a mixture thereof, a pharmaceutically acceptable salt of the compound, wherein the compound is selected from:

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof.

16. Use of the compound according to any one of claims 1 to 14, or its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, or the pharmaceutical composition according to claim 15 as a 5-HT2A receptor agonist in the preparation of a medicament for treating a central nervous system disease, preferably depression.

17. The compound according to any one of claims 1 to 14, or its stereoisomer, pharmaceutically acceptable salt, or mixture thereof, or the pharmaceutical composition according to claim 15, for use as a 5-HT2A receptor agonist in the treatment of central nervous system diseases, preferably depression.

18. A method for treating a central nervous system disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition according to claim 15, wherein the central nervous system disease is preferably depression.

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