Polysubstituted tetrahydrocarbazole compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a polysubstituted tetrahydrocarbazole compound as well as a preparation method, a pharmaceutical composition and application thereof. Relates to a novel tetrahydrocarbazole compound shown in a general formula (I), pharmaceutically acceptable salts, isomers, solvates, metabolites and metabolic precursors of the tetrahydrocarbazole compound, a pharmaceutical composition containing the tetrahydrocarbazole compound and the pharmaceutical composition which has a relatively good inhibition effect on a transient potential channel TRPM7, and is used for preventing, treating or adjunctively treating various diseases related to the TRPM7. Such as tumors, nervous system diseases, immune and inflammation and cardiovascular diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention discloses a class of polysubstituted tetrahydrocarbazole compounds and their preparation methods, pharmaceutical compositions and uses. The invention relates to novel tetrahydrocarbazole compounds represented by general formula (I), pharmaceutically acceptable salts, isomers, solvates, metabolites, metabolic precursors, drug combinations containing them and such compounds, which have good inhibitory effects on transient potential channel TRPM7 and are used for preventing, treating or assisting in treating various diseases related to TRPM7, such as tumors, nervous system diseases, immune and inflammatory diseases and cardiovascular diseases. Background Art

[0002] TRPM7 (Transient Receptor Potential Melastatin 7) belongs to the TRPM subfamily and is a bifunctional transmembrane protein with an ion channel domain and a kinase domain. The human TRPM7 gene is located on the long arm of chromosome 15 and consists of 39 exons with a total length of 134.34 kb. The human TRPM7 protein encodes 1865 amino acids with a molecular weight of 210 kDa. TRPM7 usually exists in the form of a heterotetramer. Each subunit includes an amino (N) terminus, a carboxyl (C) terminus, and six transmembrane segments (S1-S6) in the cell membrane. Each transmembrane segment is about 21 amino acids long, and there is a pore region (P) between S5 and S6 that forms an ion-permeable channel. The N-terminus of TRPM7 contains four homologous domains of the TRPM family, and the C segment includes a highly conserved TRP domain, a CC domain, a serine / threonine-rich region, an exchange segment, a kinase domain, and an ATP binding region. The functional core parts of TRPM7 are the channel pore region, the serine / threonine-rich region and the α-type serine / threonine protein kinase domain.

[0003] TRPM7 is widely distributed in mammalian tissues and has been identified to be expressed in heart, liver, spleen, lung, kidney, digestive tract and other tissues and organs. As a non-selective cation channel, TRPM7 responds to cations including Ca 2+ Mg 2+ , K + 、Na +TRPM7 is permeable to many divalent and monovalent cations, including ; as a protein kinase, TRPM7 can phosphorylate itself and substrates through serine / threonine. TRPM7 plays an important role in physiological processes such as cell proliferation, adhesion, migration, differentiation, and phenotypic transformation. Embryos of TRPM7 homozygous knockout mice died at day 7.5, and zebrafish carrying TRPM7 loss-of-function mutations showed severe growth retardation and changes in bone development, indicating that TRPM7 is indispensable for the body to participate in different physiological processes and maintain the normal growth and development of living organisms. In addition, when cell volume, osmotic pressure, pH, etc. change, or when encountering oxidative stress, TRPM7 can respond to various physiological processes by regulating the influx of intracellular cations and kinase activity, thereby affecting ion homeostasis and phosphorylation events.

[0004] TRPM7 plays an important role in many human diseases, and its dysfunction can cause neurological diseases, cancer, cardiovascular diseases, etc. For example, it plays an important role in neuronal damage caused by cerebral ischemia. TRPM7 permeable Ca 2+ and Zn 2+ The content of TRPM7 increased in ischemic cortical and hippocampal tissues, inducing mitochondrial dysfunction and causing neuronal damage. In the hippocampus of rats with cerebral hypoperfusion, the mRNA and protein levels of TRPM7 increased significantly and were correlated with intracellular Ca 2+ It is positively correlated with the level of reactive oxygen species (ROS). TRPM7 modulators have shown good regulatory effects in a variety of in vitro and in vivo models. Waixenicin A inhibits TRPM7 currents in vitro in primary cultures of mouse hippocampal neurons, enhances neurite growth and maturation, reduces brain damage during ischemia and hypoxia, inhibits malarial parasites from invading red blood cells, and reduces hyperglycemia-induced neuronal damage. The results suggest that inhibiting or downregulating TRPM7 channels may help alleviate ischemic neuronal damage, and TRPM7 can be used as a potential target for neuroprotection during stroke. It was also found in an in vivo model of epilepsy that inhibiting TRPM7 channels can significantly reduce the death of apoptotic neurons after epileptic seizures, thus exerting a neuroprotective effect.

[0005] TRPM7 plays multiple functions in cancer cells, affecting the survival, proliferation, growth, migration, invasion and cell cycle of cancer cells. TRPM7 expression levels have increased significantly in breast cancer, glioblastoma and lung cancer cell lines and tissues. The expression levels of TRPM7 transcripts and proteins in human glioblastoma cells are significantly higher than those in normal human astrocyte NHA cells. Blocking the expression of TRPM7 can significantly reduce the invasion and metastasis of tumor cells, and midazolam can block TRPM7 and inhibit the growth of glioma cells. Therefore, the TRPM7 channel is also considered to be a potential molecular biomarker and therapeutic target for certain types of cancer.

[0006] TRPM7 is the main calcium regulation channel in human and mouse cardiac fibroblasts. Compared with atrial myoblasts of healthy subjects, TRPM7 expression in atrial myoblasts of patients with atrial fibrillation increased by 3 to 5 times, and the calcium current mediated by it increased significantly, inducing upregulation of transforming growth factor β1 expression, increasing fibroblast differentiation and fibrosis, and ultimately leading to atrial fibrillation. After downregulating or silencing TRPM7, Ca 2+ The influx of TRPM7 was significantly reduced, inhibiting the differentiation of fibroblasts. More and more studies have shown that TRPM7 is a new player in immune cell regulation and inflammation. The activation of TRPM7 can lead to dysregulated immune responses and inflammation. Inhibition of TRPM7 can help alleviate proinflammatory diseases and immune hypersensitivity reactions.

[0007] In summary, TRPM7 is a potential drug target for a variety of diseases, and TRPM7 inhibitors may provide new treatments for tumors, neurological diseases, immune and inflammatory diseases, and cardiovascular-related diseases. However, the TRPM7 channel-selective small molecule modulators that have been discovered have problems such as small number, weak effect, poor specificity, and difficulty in drug development. In addition, most of the existing small molecule inhibitors were originally regulators of other channels and diseases, including CCT128930, which was originally an Akt2 kinase inhibitor. Therefore, the discovery of new TRPM7 small molecule inhibitors is of great significance. Summary of the invention

[0008] The purpose of the present invention is to provide a TRPM7 small molecule inhibitor.

[0009] The first aspect of the present invention provides a compound of the structure shown in general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:

[0010]

[0011] in,

[0012] X is selected from the group consisting of O, S or NR 3 ;

[0013] Y is selected from the following group: O, S, C=O, SO2, N, CR 4 or NR 4 ;

[0014] m and n are each independently selected from the group consisting of 0, 1, 2, 3 or 4;

[0015] R 1 For 1, 2, 3 or 4 substituents on the ring, and the R 1 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10 Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amine group, NH2, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group, or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 1 The group can form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring with the atoms to which it is connected, and the carbocyclic or heterocyclic ring can be saturated or partially unsaturated;

[0016] R 2 For 1, 2, 3 or 4 substituents on the ring, and the R 2 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched chain alkyl, substituted or unsubstituted C2~C 10 Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 substituted or unsubstituted C6~C 10Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amine group, NH2, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group, or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 2 The group can form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring with the atoms to which it is connected, and the carbocyclic or heterocyclic ring can be saturated or partially unsaturated;

[0017] The ring is selected from the following groups: substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl; and when the A ring is phenyl, the R 1 At least one of the groups is not H; preferably, the A ring is selected from a substituted or unsubstituted fragment selected from the following group:

[0018]

[0019] The ring is selected from the following groups: substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl; preferably, the B ring is selected from substituted or unsubstituted fragments selected from the following group:

[0020]

[0021] Among them, each of the above X 2 and X 3 Each independently selected from the following group: O, S, C=O, CHR 5 or NR 5 ;

[0022] X 4 Selected from the following group: N, CR 5 ;

[0023] R 3 , R 4 and R 5 Each of them is independently selected from the following group: hydrogen, C1-C6 alkylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with aryl or heteroaromatic ring, C1-C6 alkyl substituted with cycloalkane or heterocyclic group, C3-C8 saturated or partially unsaturated carbocyclic group, C3-C8 halogenated saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered heterocyclic group;

[0024] The bond is a single bond or a double bond;

[0025] wherein the heteroaryl or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0026] Unless otherwise specified, the substitution means that the corresponding group is substituted by 1 to 3 substituents selected from the following groups: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group and 5- to 12-membered heteroaryl;

[0027] The halogen is F, Cl, Br or I; the cycloalkane, heterocyclic group, aryl or heteroaryl is a monocyclic ring, a condensed ring, a spirocyclic ring or a bridged ring; the aryl or heteroaryl is a monocyclic ring or a condensed ring; the heterocyclic group or heteroaryl has one or more heteroatoms selected from the following group: N, S or O.

[0028] In another preferred embodiment, the compound has a structure shown in the following formula Ia or Ib:

[0029]

[0030] In another preferred embodiment, the compound has a structure shown in the following formula Ic or Id:

[0031]

[0032] Wherein, Y1, Y2, Y3, and Y4 are each independently selected from the following group: N or CH, and the H on the CH can be replaced by R 2 Replacement (in which case the CH is C).

[0033] In another preferred embodiment, m is 1.

[0034] In another preferred embodiment, n is 0 or 1.

[0035] In another preferred embodiment, Y is N or NH.

[0036] In another preferred embodiment, R 1 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-10 membered heterocyclic group, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, NH2, substituted or unsubstituted C1-C6 alkyl-NH-, substituted or unsubstituted C1-C6 alkyl)2-N-, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 1 The group and the atoms to which it is attached may together form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring, and the carbocyclic or heterocyclic ring may be saturated or partially unsaturated.

[0037] R 2 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched chain alkyl, substituted or unsubstituted C2~C 10 Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amino group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 2 The group and the atoms to which it is attached may together form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring, and the carbocyclic or heterocyclic ring may be saturated or partially unsaturated.

[0038] In another preferred embodiment, the A ring is a substituted or unsubstituted group selected from the following group:

[0039]

[0040] In another preferred embodiment, the A ring is a substituted or unsubstituted group selected from the following group:

[0041] Wherein, the substitution refers to that the corresponding group is replaced by 1 to 3 substituents selected from the following group: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, phenyl, 5-7 membered saturated or partially unsaturated heterocyclic group, and 5-7 membered heteroaryl.

[0042] In the third aspect of the present invention, a pharmaceutical composition is provided, characterized in that it comprises (1) the compound as described in the first aspect of the present invention, its racemate, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.

[0043] In the fourth aspect of the present invention, there is provided a compound as described in the first aspect of the present invention, its racemate, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition as described in the third aspect of the present invention, characterized in that it is used to prevent and / or treat indications related to abnormally increased TRPM7 activity or abnormally increased expression, such as tumors, nervous system diseases, immunity and inflammation, cardiovascular diseases, etc. Tumors include but are not limited to breast cancer, pancreatic cancer, gastric cancer, lung cancer, ovarian cancer, bladder cancer, neuroblastoma, glioblastoma, etc. Nervous system diseases include but are not limited to Alzheimer's disease, epilepsy, etc. Cardiovascular and cerebrovascular diseases include but are not limited to stroke, myocardial fibrosis, etc.

[0044] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0045] After extensive and in-depth research, the inventor unexpectedly discovered a series of compounds of general formula (I), and conducted a series of biological activity tests on them, and found that they have good TRPM7 inhibitory activity. On this basis, the present invention was completed.

[0046] definition

[0047] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0048] In this document, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, halogen, hydroxyl, carboxyl, cyano, C1-C 10 Aldehyde, C2~C6 acyl, C2~C 10 Ester group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group having 1-3 substituents, the substituents are selected from: halogen, C1~C 10 Alkyl, cyano, hydroxy, nitro, C3-C8 cycloalkyl, C1-C8 alkoxy, amino.

[0049] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom may be optionally in R configuration or S configuration, or a mixture of R configuration and S configuration.

[0050] As used herein, the term "alkyl" includes straight-chain or branched alkyl groups. For example, C1-C6 alkyl refers to a straight-chain or branched alkyl group having 1 to 6, such as 1, 2, 3, 4, 5, 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. The term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6, such as 1, 2, 3, 4, 5, 6 carbon atoms. 10 The term "straight-chain or branched-chain alkyl" has a similar definition and refers to a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0051] As used herein, the term "alkoxy" refers to a group having an alkyl-oxy structure. For example, "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc. The term "C2-C 10 The term "straight-chain or branched alkoxy" has a similar definition and refers to a straight-chain or branched alkoxy group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0052] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specific number of ring atoms (e.g., 3-12 ring atoms, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring atoms), and wherein 1-3 atoms are heteroatoms selected from N, S and O. It can be a monocyclic ring, or a bicyclic or polycyclic form, such as a bridged ring or a spirocyclic form. Specific examples can be oxetane, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, etc. In particular, when defining the heteroatom, the heteroatom can also have 1-2 H atoms (not shown here) for balancing the valence state.

[0053] As used herein, the term "aryl" refers to a cyclic aromatic group having a specific number of carbon atoms. 10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, such as phenyl, naphthyl, or the like.

[0054] As used herein, the term "heteroaryl" refers to a cyclic aromatic group having a specific number of ring atoms, wherein 1-3 atoms are heteroatoms selected from N, S and O. It can be a single ring or a condensed ring. For example, "5-12 membered aryl" refers to an aryl group having 5-12 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12 ring atoms), such as pyrrolyl, pyridyl, thienyl, furanyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolyl or the like.

[0055] As used herein, the term "acyl" refers to a -C(=O)R group having a specified number of carbon atoms. 2-6 Acyl refers to a -C(=O)R (wherein R is C 1-5 alkyl) groups, such as -C(=O)CH3, -C(=O)C2H5, -C(=O)C3H7, -C(=O)C4H9, or the like.

[0056] As used herein, the term "ester group" refers to a ROC(=O)- group having a specific number of carbon atoms. 2-6 Acyl refers to a ROC(=O)- (wherein R is C 1-5 alkyl) groups, such as -C(=O)OCH3, -C(=O)OC2H5, -C(=O)OC3H7, -C(=O)OC4H9, or the like.

[0057] As used herein, the term "alkenyl" refers to an alkenyl group having a specific number of carbon atoms, including straight or branched alkenyl groups. For example, C2-C6 alkenyl refers to a straight or branched alkenyl group having 2-6 carbon atoms (e.g., 2, 3, 4, 5, 6), such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0058] As used herein, the term "alkynyl" refers to an alkynyl group having a specific number of carbon atoms, including straight or branched alkynyl groups. For example, C2-C6 alkynyl refers to a straight or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0059] As used herein, the term "amine group" refers to an -NR 1 R 2 The group (i.e., R 1 and R2 Each independently is H or C 1-9 alkyl), such as -NH2, -NHCH3, -NHC(=O)CH3, -NHCH2CH3, -N(CH3)2, or the like. As used herein, the amine group is intended to include an amino group, i.e., -NH2.

[0060] As used herein, the term "amide" refers to a -C(=O)NR group having a specified number of carbon atoms. 1 R 2 Groups such as -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, or the like.

[0061] As used herein, the term "sulfonamide" refers to a -S(=O)2NR group having a specified number of carbon atoms. 1 R2 group: For example, C1-C6 sulfonamide refers to a sulfonamide group having 1 to 6 carbon atoms, such as -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, or the like.

[0062] As used herein, the term "sulfonyl" refers to a -S(=O)2- group.

[0063] As used herein, the term "sulfinyl" refers to a -S(=O)- group.

[0064] As used herein, the term "halogen" refers to F, Cl, Br and I.

[0065] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0066] The term "tautomer" means that structural isomers of different energies can interconvert over a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole, and valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0067] Herein, the form "C1-C6" means that the group can have 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6.

[0068] Compounds of formula I and their preparation

[0069] The present invention provides a compound of formula I and a method for preparing the same:

[0070]

[0071] In a preferred embodiment of the present invention, the compound has a structure selected from the following group:

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] The compounds can be prepared by the following exemplary methods, but it should be understood that those skilled in the art can also prepare the compounds by other methods based on the disclosure of the present invention:

[0084] The present invention also provides a method for preparing a compound represented by general formula (I), comprising the steps of:

[0085] (1) In a mixed solvent of nitromethane and an organic acid, formula II a The compound reacts with nitromethane to produce α,β-unsaturated nitro compound II by Henry reaction. b , Formula II b The compound is then subjected to a reduction reaction to obtain formula II c Compounds;

[0086]

[0087] (2) In an inert solvent, formula I a Compounds and formula I b The compound undergoes Friedel-Crafts acylation to obtain the compound of formula Ic Compound, Formula I b The compound is then reduced with a reducing agent to obtain formula I d Compound, Formula I d The compound is then subjected to ester hydrolysis to obtain the compound of formula I e Compounds;

[0088]

[0089] (3) in an inert solvent, in the presence of a condensing agent, using formula II c or III a Compounds and Formula I e Compound reaction to obtain formula I f or I g Compounds;

[0090]

[0091] (4) in an inert solvent, using formula I f or I g The compound is subjected to Bischler–Napieralski ring closure reaction to obtain formula I h Compounds;

[0092]

[0093] (5) In an inert solvent, using formula I h The compound is subjected to a reduction reaction to obtain a compound of formula I;

[0094]

[0095] Among them, R 1 , R 2 , R 3 , R 4 , R 5 The definitions of , X, Y, m, and n are as described above.

[0096] In some embodiments, the organic acid in step (1) is acetic acid or formic acid, and the reducing agent is LiAlH4, sodium borohydride or zinc powder.

[0097] In another preferred embodiment, the reducing agent in step (2) is a borane solution.

[0098] In another preferred embodiment, the condensation agent in step (3) is a combination of HATU or EDCI and HOBt.

[0099] In another preferred embodiment, the ring-closure reaction in step (4) uses POCl3 phosphorus oxychloride as Lewis acid.

[0100] In another preferred embodiment, the reduction reaction in step (5) uses borohydride as a reducing agent, or uses Noyori's catalyst as an asymmetric reduction catalyst.

[0101] Pharmaceutical compositions and methods of administration

[0102] Since the compounds of the present invention have excellent TRPM7 inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for a variety of TRPM7 diseases, such as tumors, stroke, neurodegenerative diseases, autoimmune diseases, etc.

[0103] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-3000 (active dose range 3-30 mg / kg) mg of the compound of the present invention / dose, more preferably, 10-2000 mg of the compound of the present invention / dose. Preferably, the "one dose" is a capsule or tablet.

[0104] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0105] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0106] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0107] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0108] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0109] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0110] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0111] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0112] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0113] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0114] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 6 to 600 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0115] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0116] Example 1 N-(2-(Benzo[d][1,3]-5-dioxolane)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A1)

[0117]

[0118] 1.1 Synthesis of intermediate 1-3: The starting material 1-2 (3-indolebutyric acid, 1 g, 4.9 mmol) was dissolved in 100 mL of dichloromethane, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 2.79 g, 7.35 mmol), N,N-diisopropylethylamine (DIPEA, 2.47 mL, 14.7 mmol) and 1-1 (pepperethylamine, 1.18 g, 5.88 mmol) in dichloromethane were added in sequence, and stirred at room temperature for 4 h. After the reaction was completed by TLC (thin layer chromatography), dichloromethane was added to the reaction solution for dilution, and the reaction solution was washed with 1N dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by petroleum ether / ethyl acetate = 1:1 column chromatography to obtain 930 mg of yellow-white solid product 1-3, with a yield of 54%. ESI-MS m / z 351.1 [M+H] + .

[0119] 1.2 Synthesis of intermediate 1-4: Dissolve intermediate 1-3 (930 mg, 2.7 mmol) in 20 mL of anhydrous acetonitrile, add phosphorus oxychloride (0.74 mL, 8.1 mmol), and reflux at 85 ° C for 1 h under argon protection. After the reaction is complete, monitor the reaction by TLC, evaporate to dryness under reduced pressure, add anhydrous ethanol, reflux at 80 ° C for 10 min, and move to room temperature and stir for 1 h. Solid precipitates in the reaction solution, filter, wash with anhydrous ethanol 3 times, and dry to obtain 600 mg of white solid product 1-4, yield: 60%. ESI-MS m / z 333.1 [M+H] + .

[0120] 1.3 Synthesis of Compound A1: Dissolve intermediate 1-4 (600 mg, 1.8 mmol) in 20 mL of a methanol / dichloromethane (v / v=2:1) ​​mixed solvent, add sodium borohydride (14 mg, 3.6 mmol) in batches under an ice bath, and stir at room temperature for 4 hours. After the reaction is complete as monitored by TLC, quench the reaction with a saturated ammonium chloride solution, evaporate the organic solvent under reduced pressure, and then add dichloromethane for extraction, wash with saturated sodium bicarbonate and saturated sodium chloride solutions in turn, dry the organic layer with anhydrous sodium sulfate, concentrate, and purify by column chromatography (developing solvent: dichloromethane / methanol=20 / 1, volume ratio) to obtain 310 mg of a yellow oily product A1, with a yield of 50%. 1H NMR (600MHz, DMSO-d6) δ11.27(s,1H),7.48(d,J=7.8Hz,1H),7.38(d,J=8.1Hz, 1H),7.15(s,1H),7.03(d,J=7.5Hz,1H),6.94–6.83(m,2H),6.76(d,J=7.9Hz,1 H),5.99(s,2H),4.59(t,J=5.0Hz,1H),3.29–3.23(m,2H),2.99(t,J=8.3Hz,2H ),2.77–2.59(m,2H),2.19–2.11(m,2H),2.10–2.00(m,1H),1.86–1.77(m,1H). 13 C NMR(151MHz,DMSO-d6)δ147.9,146.5,136.5,131.4,128.2,126.5,122.9,122.2,119.4,119.1,1 13.9,111.9,109.6,108.9,101.3,51.4,46.7,31.9,26.2,20.7,19.7.HRMS(ESI)m / z:calculated for C 21 H 21 N2O2[M-HCl-H] - :333.1609,found:333.1605.

[0121] Example 2: (R)-N-(2-(Benzo[d][1,3]-5-dioxolane)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine ((R)-A1)

[0122]

[0123] The synthesis of intermediate 1-4 is as described in Example 1. 1-4 (300 mg, 0.9 mmol) was dissolved in 10 mL of anhydrous DMF, and the catalyst RuCl[(R,R)-TsDPEN(p-cymene)] (17 mg, 0.027 mmol) was added at room temperature under argon protection, followed by a formic acid / triethylamine mixed solution (v / v=5 / 2, 1.1 mL), and stirred at room temperature overnight. After TLC monitoring, the reaction solution was neutralized with a saturated NaHCO3 solution until the pH was weakly alkaline, followed by addition of 5 volumes of ice water and extraction with ethyl acetate 3 times. The organic layers were combined, washed once with a NaHCO3 solution and a NaCl solution, and dried with Na2SO4. After the organic solvent was evaporated to dryness, it was purified by column chromatography (developing solvent: dichloromethane / methanol=15 / 1, volume ratio) to obtain 100 mg of a yellow solid product (R)-A1, with a yield of 34%. The optical purity was 93:7er (chromatographic conditions: chiral IA (4.6 mm×250 mml), n-hexane / isopropanol=80 / 20, 1 mL / min, 254 nm UV, room temperature). 1 H NMR (500MHz, DMSO-d6) δ11.19(s,1H),7.46(d,J=7.8Hz,1H),7.36(d,J=8.1Hz,1H),7.1 4–7.11(m,1H),7.02–6.98(m,1H),6.89(d,J=1.7Hz,1H),6.85(d,J=7.9Hz,1H),6.74(d d,J=8.0,1.7Hz,1H),5.97(s,2H),4.56(t,J=5.2Hz,1H),3.28–3.17(m,2H),2.96(t,J= 8.2Hz,2H),2.78–2.56(m,2H),2.20–2.08(m,2H),2.07–1.99(m,1H),1.82–1.80(m,1H). 13 C NMR (126MHz, DMSO-d6) δ147.9,146.5,136.5,131.4,126.5,122.9,122.2,119.4,119.0,113. 9,111.9,109.6,108.8,101.3,51.5,46.8,32.0,26.4,20.7,19.7.HRMS(ESI)m / z:calculated for C 21 H 21 N2O2[MH] - :333.1604,found:333.1609.

[0124] Example 3: (S)-N-(2-(Benzo[d][1,3]-5-dioxolane)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine ((S)-A1)

[0125]

[0126] The synthesis of intermediate 1-4 is as described in Example 1. 1-4 (300 mg, 0.9 mmol) was dissolved in 10 mL of anhydrous DMF, and the catalyst RuCl[(R,R)-TsDPEN(p-cymene)] (17 mg, 0.027 mmol) was added at room temperature under argon protection, followed by a formic acid / triethylamine mixed solution (v / v=5 / 2, 1.1 mL), and stirred at room temperature overnight. After TLC monitoring, the reaction solution was neutralized with a saturated NaHCO3 solution until the pH was weakly alkaline, followed by addition of 5 times the volume of ice water and extraction with ethyl acetate 3 times. The organic layers were combined, washed once with a NaHCO3 solution and a NaCl solution, and dried with Na2SO4. After the organic solvent was evaporated to dryness, it was purified by column chromatography (developing solvent: dichloromethane / methanol=15 / 1, volume ratio) to obtain 96 mg of a yellow solid product (S)-A1, with a yield of 33%. The optical purity was 89:11er (chromatographic conditions: chiral IA (4.6 mm×250 mml), n-hexane / isopropanol=80 / 20, 1 mL / min, 254 nm UV, room temperature). 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.36(d,J=7.9Hz,1H),7.26(d,J=8.1Hz,1H),7.0 4–7.00(m,1H),6.92–6.88(m,1H),6.79(d,J=1.7Hz,1H),6.75(d,J=7.9Hz,1H),6.64(d d,J=8.0,1.7Hz,1H),5.87(s,2H),4.42(t,J=5.4Hz,1H),3.16–3.05(m,2H),2.86(t,J= 8.2Hz,2H),2.63–2.51(m,2H),2.03–2.00(m,2H),1.96–1.90(m,1H),1.73–1.66(m,1H). 13 C NMR (126MHz, DMSO-d6) δ147.9,146.4,136.5,131.7,126.5,122.7,122.2,119.3,119.0,113. 6,111.9,109.6,108.8,101.3,51.5,46.8,32.3,26.5,20.8,19.8.HRMS(ESI)m / z:calculated for C21 H 21 N2O2[MH] - :333.1609,found:333.1611.

[0127] Example 4: N-(2-(2,2-Benzo[d][1,3]-5-dioxolane)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A2)

[0128]

[0129] Synthesis of intermediate 2-3: The starting material 2-1 (3.72 g, 20.0 mmol) was dissolved in nitromethane (21.5 mL, 400 mmol), and ammonium acetate (3.08 g, 40.0 mmol) and glacial acetic acid (11.4 mL, 200 mmol) were added in sequence. The mixture was heated and stirred at 80°C for 2 h. After the reaction was completed as monitored by TLC, the organic solvent was evaporated and saturated sodium bicarbonate was slowly added and stirred at room temperature to adjust the pH to neutral. The precipitated solid was filtered, washed once with saturated sodium bicarbonate and water in sequence, and dried to obtain 3.71 g of bright yellow intermediate 2-2 with a yield of 81%, which was directly used in the next step. Dissolve 2-2 (3.71 g, 16.0 mmol) in ultra-dry tetrahydrofuran solution for later use. In a -5°C ice bath, add 50 mL of ultra-dry tetrahydrofuran to a 250 mL two-necked round-bottom flask, add lithium aluminum tetrahydride (1.82 g, 48.0 mmol) in three batches, add 2-2 solution dropwise into the reaction flask using a dropping funnel under ice bath and argon protection. After the addition is complete, remove the dropping funnel, install a condenser and protect with argon, move to an oil bath and heat under reflux for 2 h. After the reaction was complete as monitored by TLC, the reaction flask was moved to a -5°C ice bath and stirred, and ice water was added dropwise to quench until there were no bubbles. Then the insoluble solid was filtered off and washed with ethyl acetate. The filtrate was collected, the organic solvent was dried by spin drying, extracted with water and ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with dichloromethane / methanol / ammonia water = 10:1:0.1 to obtain 2.25 g of brown liquid product 2-3, with a yield of 70%. ESI-MS m / z 202.1 [M+H] + .

[0130] Synthesis of intermediate 3-1: Referring to the synthetic route of A1, 2-3 was used to replace the raw material 1-1 in Example 1 and reacted with the raw material 1-2 to obtain a white solid product 3-1. ESI-MS m / z 387.1 [M+H] + .

[0131] Synthesis of intermediate 3-2: Intermediate 3-1 (3.08 g, 8.0 mmol) was dissolved in 50 mL of anhydrous acetonitrile, phosphorus oxychloride (4.46 mL, 48.0 mmol) was added, and refluxed and stirred for 1.5 h under argon protection. After TLC monitoring, the reaction was completed and evaporated to dryness under reduced pressure, saturated sodium bicarbonate with ice was added to adjust to weak alkalinity, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with dichloromethane / methanol = 20:1 to obtain 2.71 g of yellow solid product 3-2, with a yield of 77%. ESI-MS m / z 369.2 [M+H] + .

[0132] Synthesis of compound A2: Intermediate 3-2 (2.42 g, 6.0 mmol) was dissolved in 50 mL of a methanol / dichloromethane (v / v=2:1) ​​mixed solvent, sodium borohydride (1.37 g, 36.0 mmol) was added in batches under an ice bath, and stirred at room temperature for 4 hours. After TLC monitoring, the reaction was quenched with a saturated ammonium chloride solution, the organic solvent was evaporated under reduced pressure, and then dichloromethane was added for extraction, and then washed with saturated sodium bicarbonate and saturated sodium chloride solutions, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with dichloromethane / methanol=15:1 to obtain 1.87 g of a white solid product A2, with a yield of 84%. ESI-MS m / z 371.3[M+H] + .

[0133] Example 5: N-(3,4-dimethoxyphenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A3)

[0134] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 3,4-dimethoxyphenethylamine (CAS: 120-20-7) to obtain compound A3. 1 H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.34(d,J=7.8Hz,1H),7.29(d,J=8.0Hz, 1H),7.02–6.98(m,1H),6.93–6.90(m,1H),6.84(d,J=8.0Hz,2H),6.73(dd,J=8. 1,2.0Hz,1H),3.89(t,J=6.2Hz,1H),3.73(s,3H),3.70(s,3H),2.92–2.79(m,2 H),2.72–2.67(m,2H),2.60–2.57(m,2H),1.98–1.94(m,2H),1.72–1.69(m,2H). 13C NMR (126MHz, DMSO-d6) δ148.6,147.1,135.8,132.9,126.8,120.5,120.4,118.0,117.7,112.5, 111.9,111.0,109.2,55.6,55.4,51.3,48.4,36.2,29.5,20.8,20.5.HRMS(ESI)m / z:calculated for C 22 H 25 N2O2[MH] - :349.1922,found:349.1920.

[0135] Example 6: 2-methoxy-4-(2-((2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino)ethyl)phenol (A4)

[0136] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-(2-aminoethyl)-2-methoxyphenol (CAS: 554-52-9) to obtain compound A4. 1 H NMR (500MHz, DMSO-d6) δ10.61(s,1H),8.66(s,1H),7.32(d,J=7.7Hz,1H),7.27(d,J=8 .0Hz,1H),6.98(t,J=8.0Hz,1H),6.90(t,J=7.4Hz,1H),6.77(d,J=1.7Hz,1H),6.66(d, J=7.9Hz,1H),6.59(dd,J=8.0,1.7Hz,1H),3.87(t,J=4.6Hz,1H),3.72(s,3H),2.89–2. 77(m,2H),2.70–2.58(m,2H),2.61–2.53(m,2H),1.98–1.90(m,2H),1.71–1.66(m,2H). 13 C NMR(126MHz,DMSO-d6)δ147.9,145.1,137.3,136.3,131.7,127.3,121.1,120.9,118.5,118.1,1 15.8,113.3,111.5,109.6,56.0,51.8,49.0,36.7,29.9,21.3,21.0.HRMS(ESI)m / z:calculated for C 21 H 23 N2O2[MH] - :335.1765,found:335.1768.

[0137] Example 7: N-(4-(Benzyloxy)-3-methoxyphenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A5)

[0138] Referring to the synthetic route of A2, 4-benzyloxy-3-methoxybenzaldehyde (CAS: 2426-87-1) was used to replace the raw material 2-1 in Example 4 to obtain compound A5. 1 H NMR(600MHz,Chloroform-d)δ8.24(s,1H),7.45–7.43(m,3H),7.36–7.34(m,2H),7.30–7.27(m,1H) ,7.25(s,1H),7.14–7.10(m,1H),7.07–7.03(m,1H),6.81(d,J=8.1Hz,1H),6.75(d,J=1.8Hz,1H),6. 68(dd,J=8.1,1.8Hz,1H),5.13(s,2H),4.00(s,1H),3.85(s,3H),3.02–2.90(m,2H),2.84–2.80(m, 1H),2.75–2.61(m,3H),2.21–2.14(m,1H),2.02–1.96(m,1H),1.80–1.72(m,1H),1.66–1.60(m,1H). 13 C NMR(101MHz,DMSO-d6)δ149.5,146.5,137.9,136.3,133.7,128.8,128.2,128.2,127.2,121.1,120.8,118.6, 118.2,114.3,113.2,111.5,110.0,70.5,56.0,51.8,48.7,36.3,29.7,21.3,20.9.HRMS(ESI)m / z:calculated for C 28 H 29 N2O2[MH] - :425.2235,found:425.2237.

[0139] Example 8: N-(2-(2,3-dihydrobenzo[b][1,4]-6-dioxinyl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A6)

[0140] Referring to the synthetic route of A2, 1,4-benzodioxane-6-carboxaldehyde (CAS: 29668-44-8) was used to replace the raw material 2-1 in Example 4 to obtain compound A6. 1H NMR(600MHz,Chloroform-d)δ8.32(s,1H),7.44(d,J=7.8Hz,1H),7.27(dt,J=8.1,0.9Hz,1H),7.1 3–7.11(m,1H),7.06–7.04(m,1H),6.80(d,J=8.2Hz,1H),6.73(d,J=2.1Hz,1H),6.68(dd,J=8.2,2. 1Hz,1H),4.23(s,4H),3.99(t,J=6.8Hz,1H),3.02–2.95(m,1H),2.93–2.88(m,1H),2.80–2.75(m,1 H),2.72–2.63(m,3H),2.21–2.16(m,1H),2.03–1.98(m,1H),1.79–1.73(m,1H),1.65–1.60(m,1H). 13 C NMR(126MHz,DMSO-d6)δ143.1,141.6,135.8,133.5,126.8,121.2,120.5,118.0,117.7,117.0,116 .7,111.0,109.2,64.0,64.0,54.9,51.3,48.4,35.8,29.5,20.8,20.5.HRMS(ESI)m / z:calculated for C 22 H 23 N2O2[MH] - :347.1765,found:347.1762.

[0141] Example 9: N-(3,4-difluorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A7)

[0142] Referring to the synthetic route of A2, 3,4-difluorobenzaldehyde (CAS: 34036-07-2) was used to replace the raw material 2-1 in Example 4 to obtain compound A7. 1H NMR(500MHz,Chloroform-d)δ8.23(s,1H),7.47(d,J=7.8Hz,1H),7.29(d,J=8.1Hz,1H),7.18–7.11(m,1H),7.13–7.00(m,3H),6.95–6.89(m,1H),3.0 6–2.97(m,1H),2.97–2.88(m,1H),2.87–2.78(m,1H),2.78–2.65(m,3H),2 .25–2.16(m,1H),2.06–1.98(m,1H),1.83–1.74(m,1H),1.68–1.58(m,1H). 13 C NMR(126MHz,Chloroform-d)δ149.8(dd,J=248.0,12.7Hz),148.6(dd,J=246.2,12.5Hz),136.75–136.43(m),135.3,135.0,127.0,124.14(dd,J=5.7,3 .7Hz),121.2,118.7,117.9,117.0(d,J=16.7Hz),116.7(d,J=17.0Hz),111.1,110.4,51.9,46.5,35.7,29.6,21.3,20.5.HRMS(ESI)m / z:calculatedfor C 20 H 19 F2N2[MH] - :325.1522,found:325.1520.

[0143] Example 10: N-(3,4-dichlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A8)

[0144] Referring to the synthetic route of A1, 3,4-dichlorophenylethylamine (CAS: 21581-45-3) was used to replace the raw material 1-1 in Example 1 to obtain compound A8. ESI-MS m / z 360.2 [M+H] + .

[0145] Example 11: N-(4-chloro-3-(trifluoromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A9)

[0146] Referring to the synthetic route of A2, 4-chloro-3-trifluoromethylbenzaldehyde (CAS: 34328-46-6) was used to replace the raw material 2-1 in Example 4 to obtain compound A9. ESI-MS m / z 394.1 [M+H] + .

[0147] Example 12: N-(3,4,5-trichlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A10)

[0148] Referring to the synthetic route of A2, 3,4,5-trichlorobenzaldehyde (CAS: 56961-76-3) was used to replace the raw material 2-1 in Example 4 to obtain compound A10. ESI-MS m / z 394.2 [M+H] + .

[0149] Example 13: N-(2-(Benzo[d][1,3]dioxolan-5-yl)ethyl)-N-methyl-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A11)

[0150]

[0151] The product A1 in Example 1 was used as the raw material for this step of the reaction. A1 (1.67 g, 5.0 mmol) and iodomethane (CAS: 74-88-4) (1.07 g, 7.5 mmol) were dissolved in 50 mL of a mixed solvent of acetonitrile and tetrahydrofuran (MeCN:THF=3:1), potassium carbonate (3.45 g, 25.0 mmol) was added, and the mixture was stirred and refluxed for 24 h under Ar protection. After the reaction was completed as monitored by TLC, the solvent was evaporated, and the mixture was purified by column chromatography with dichloromethane / methanol=20:1 to obtain 1.13 g of a yellow solid A11, with a yield of 65%. 1 H NMR(500MHz,DMSO-d6)δ10.19(s,1H),7.29(dd,J=14.8,7.9Hz,2H),7.00–6.9 5(m,1H),6.91–6.87(m,1H),6.77(d,J=7.8Hz,1H),6.73(d,J=1.7Hz,1H),6.6 1(dd,J=7.8,1.7Hz,1H),5.94–5.91(m,2H),4.06(t,J=7.0Hz,1H),2.73–2.68 (m,2H),2.63–2.49(m,4H),2.26(s,3H),2.03–1.88(m,2H),1.68–1.58(m,2H). 13 C NMR(126MHz,DMSO-d6)δ147.1,145.3,136.1,135.6,134.4,121.4,120.4,118.0,117.5,111.1,1 10.7,109.1,108.1,100.6,58.6,55.2,37.6,34.5,22.3,21.4,20.7.HRMS(ESI)m / z:calculated for C 22H 24 N2O2[MH] - :347.1702,found:347.1708.

[0152] Example 14: N-(4-methoxyphenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A12)

[0153] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 2-(4-methoxyphenyl)ethylamine (CAS: 55-81-2) to obtain compound A12. 1 H NMR (500MHz, DMSO-d6) δ11.24(s,1H),7.46(d,J=7.8Hz,1H),7.36(d,J=8.1Hz ,1H),7.22–7.18(m,2H),7.14–7.11(m,1H),7.02–6.98(m,1H),6.91–6.86(m, 2H),4.55(t,J=5.4Hz,1H),3.72(s,3H),3.26–3.16(m,2H),3.05–2.92(m,2H) ,2.73–2.61(m,2H),2.17–2.11(m,2H),2.09–1.97(m,1H),1.83–1.76(m,1H). 13 C NMR (126MHz, DMSO-d6) δ158.1,136.0,129.7,129.2,126.0,122.3,118.9,118.5,114. 0,113.2,111.4,55.1,50.9,46.3,31.1,25.9,20.2,19.3.HRMS(ESI)m / z:calculated for C 21 H 23 N2O[MH] - :319.1816,found:319.1819.

[0154] Example 15: 4-(2-((2,3,4,9-tetrahydro-1H-carbazole-1-yl)amino)ethyl)phenol (A13)

[0155] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-hydroxyphenylethylamine (CAS: 51-67-2) to obtain compound A13. 1H NMR(500MHz,DMSO-d6)δ10.56(s,1H),9.10(s,1H),7.32(d,J=7.8Hz,1H),7.27(d,J=8.0Hz,1H),7.02–6.96(m,3H),6.91–6.88 (m,1H),6.67–6.63(m,2H),3.87(t,J=5.0Hz,1H),2.86–2.75(m,2H),2.70–2.53(m,4H),1.97–1.89(m,2H),1.72–1.64(m,2H). 3 C NMR (126MHz, DMSO-d6) δ155.9,137.2,136.3,130.9,129.9,127.3,120.9,118.5,118. 1,115.5,111.5,109.6,51.8,49.1,36.2,29.9,21.3,21.0.HRMS(ESI)m / z:calculated forC 20 H 21 N2O[MH] - :305.1659,found:305.1661.

[0156] Example 16: N-(4-fluorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A14)

[0157] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-fluorophenethylamine (CAS: 1583-88-6) to obtain compound A14. 1 H NMR(500MHz,Chloroform-d)δ8.18(s,1H),7.47(d,J=7.8Hz,1H),7.29–7.26(m,1H),7.20–7.13(m,3H),7.10–7.06(m,1H),7.04–6.98(m,2H),4.02 –3.96(m,1H),3.02–2.92(m,2H),2.88–2.83(m,1H),2.78–2.66(m,3H),2. 22–2.17(m,1H),2.06–1.98(m,1H),1.83–1.74(m,1H),1.66–1.59(m,1H). 13C NMR(126MHz,Chloroform-d)δ161.1(d,J=244.0Hz),135.4,135.3(d,J=3.1Hz),135.3,129.8,129.7,127.1,121 .1,118.7,117.9,114.9,114.7,110.9,110.4,51.9,47.0,35.8,29.7,21.4,20.5.HRMS(ESI)m / z:calculatedfor C 20 H 20 FN2[MH] - :307.1616,found:307.1620.

[0158] Example 17: N-(4-chlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A15)

[0159] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-chlorophenethylamine (CAS: 156-41-2) to obtain compound A15. 1 H NMR(500MHz,Chloroform-d)δ8.07(s,1H),7.44(d,J=7.7Hz,1H),7.29–7.24(m,3H),7.16–7.10(m,3H),7.07–7.03(m,1H),4.01 –3.93(m,1H),3.03–2.90(m,2H),2.85–2.62(m,4H),2.21–2.15(m,1H),2.04–1.96(m,1H),1.80–1.71(m,1H),1.63–1.57(m,1H). 13 C NMR(126MHz,Chloroform-d)δ138.7,135.8,135.7,132.0,130.2,128.6,127.5,121.5,11 9.1,118.3,111.3,110.8,52.4,47.0,36.4,30.2,21.8,20.9.HRMS(ESI)m / z:calculated for C 20 H 20 ClN2[MH] - :323.1320,found:323.1318.

[0160] Example 18: N-(4-bromophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A16)

[0161] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-bromophenethylamine (CAS: 73918-56-6) to obtain compound A16. 1 H NMR(500MHz,Chloroform-d)δ8.08(s,1H),7.44(d,J=7.8Hz,1H),7.42–7.38(m,2H),7.24(d,J=8.0Hz,1H),7.15–7.09(m,1H),7.09–7.02(m ,3H),3.98–3.91(m,1H),2.99–2.86(m,2H),2.82–2.60(m,4H),2.18– 2.12(m,1H),2.02–1.96(m,1H),1.79–1.70(m,1H),1.63–1.54(m,1H). 13 C NMR(126MHz,Chloroform-d)δ139.3,135.9,135.8,131.5,130.6,127.6,121.6,120.0,11 9.1,118.3,111.3,110.9,52.4,47.0,36.5,30.3,21.9,21.0.HRMS(ESI)m / z:calculated for C 20 H 20 BrN2[MH] - :367.0815,found:367.0814.

[0162] Example 19: N-(4-(Trifluoromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A17)

[0163] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 2-(4-trifluoromethylphenyl)ethylamine (CAS: 775-00-8) to obtain compound A17. 1 H NMR(500MHz,DMSO-d6)δ11.23(s,1H),7.70(d,J=8.0Hz,2H),7.54(d,J=8.0H z,2H),7.47(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.15–7.11(m,1H),7.03– 6.98(m,1H),4.60(t,J=5.2Hz,1H),3.40–3.31(m,2H),3.17(t,J=8.2Hz,2H) ,2.76–2.59(m,2H),2.17–2.13(m,2H),2.06–2.03(m,1H),1.85–1.77(m,1H). 13C NMR(126MHz, DMSO-d6)δ142.7,136.5,130.1,128.0(q,J=31.45Hz),126.5,125.9(q,J=272.4Hz),125.9(q,J =3.98Hz),122.9,119.4,119.1,113.9,111.9,51.5,46.1,32.0,26.3,20.7,19.7.HRMS(ESI)m / z:calculated for C 21 H 20 F3N2[MH] - :357.1584,found:357.1585.

[0164] Example 20: (R)-N-(4-(trifluoromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine ((R)-A17)

[0165] Referring to the synthetic route of (R)-A1, 2-(4-trifluoromethylphenyl)ethylamine (CAS: 775-00-8) was used to replace the raw material 1-1 in Example 2 to obtain compound (R)-A17. The optical purity was 90:10er (chromatographic conditions: chiral IA (4.6 mm×250 mml), n-hexane / isopropanol=80 / 20, 1 mL / min, 254 nm UV, room temperature). 1 H NMR (500MHz, DMSO-d6) δ10.56(s,1H),7.61(d,J=7.9Hz,2H),7.46(d,J=7.9Hz,2H),7.33(d,J=7.8Hz,1H),7.27(d,J=8.0Hz,1H),6.99 (t,J=7.5Hz,1H),6.90(t,J=7.4Hz,1H),3.89(s,1H),2.98–2.79(m,4H),2.57(d,J=5.5Hz,2H),2.00–1.90(m,2H),1.74–1.62(m,2H). 13 C NMR (126MHz, DMSO-d6) δ146.0,136.3,129.9,127.3,127.2(q,J=35.1Hz),125.5(q,J=3.8Hz),125.3(q,J=2 72.4Hz),121.0,118.5,118.1,111.5,109.8,51.7,48.1,36.7,29.9,21.3,20.9.HRMS(ESI)m / z:calculated for C 21 H 20 F3N2[MH]- :357.1584,found:357.1580.

[0166] Example 21: (S)-N-(4-(trifluoromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine ((S)-A17)

[0167] Referring to the synthetic route of (S)-A1, 2-(4-trifluoromethylphenyl)ethylamine (CAS: 775-00-8) was used to replace the raw material 1-1 in Example 3 to obtain compound (S)-A17. The optical purity was 89:11er (chromatographic conditions: chiral IA (4.6 mm×250 mml), n-hexane / isopropanol=80 / 20, 1 mL / min, 254 nm UV, room temperature). 1 H NMR (500MHz, DMSO-d6) δ10.56(s,1H),7.61(d,J=7.9Hz,2H),7.46(d,J=8.0Hz,2H),7.32(d,J=7.8Hz,1H),7.27(d,J=8.0Hz,1H),6.99(t,J =7.3Hz,1H),6.90(t,J=7.4Hz,1H),3.89(t,J=5.1Hz,1H),2.97–2.78(m,4H),2.56(d,J=5.3Hz,2H),1.98–1.90(m,2H),1.73–1.63(m,2H). 13 C NMR (126MHz, DMSO-d6) δ146.1,137.0,136.3,129.9,127.3,127.1(q,J=32.1Hz),125.5(q,J=3.7Hz),125.1(q, J=272.3Hz),121.0,118.5,118.1,111.5,109.7,51.7,48.1,36.8,29.9,21.3,20.9.HRMS(ESI)m / z:calculated for C 21 H 20 F3N2[MH] - :357.1584,found:357.1587.

[0168] Example 22: 4-(2-((2,3,4,9-tetrahydro-1H-carbazole-1-yl)amino)ethyl)benzene cyanohydride (A18)

[0169] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced with p-cyanophenylethylamine (CAS: 132224-93-2) to obtain compound A18. ESI-MS m / z 316.2 [M+H]+ .

[0170] Example 23: N-(4-phenylvinyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A19)

[0171] Referring to the synthetic route of A2, 4-vinylbenzaldehyde (CAS: 1791-26-0) was used to replace the raw material 2-1 in Example 4 to obtain compound A19. ESI-MS m / z 317.2 [M+H] + .

[0172] Example 24: N-(4-phenylethynyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A20)

[0173] Referring to the synthetic route of A2, 4-ethynylbenzaldehyde (CAS: 63697-96-1) was used to replace the raw material 2-1 in Example 4 to obtain compound A20. ESI-MS m / z 315.1 [M+H] + .

[0174] Example 25: N-(4-ethylphenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A21)

[0175] Referring to the synthetic route of A2, 4-ethylbenzaldehyde (CAS: 4748-78-1) was used to replace the raw material 2-1 in Example 4 to obtain compound A21. ESI-MS m / z 319.2 [M+H] + .

[0176] Example 26: 4-(2-((2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino)ethyl)benzyl alcohol (A22)

[0177] Referring to the synthetic route of A2, the raw material 2-1 in Example 4 was replaced with p-hydroxymethylbenzaldehyde (CAS: 52010-97-6) to obtain compound A22. ESI-MS m / z 321.2 [M+H] + .

[0178] Example 27: N-(4-(Fluoromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A23)

[0179] Referring to the synthetic route of A2, 4-(fluoromethyl)-benzaldehyde (CAS: 64747-66-6) was used to replace the raw material 2-1 in Example 4 to obtain compound A23. ESI-MS m / z 323.1 [M+H] + .

[0180] Example 28: N-(4-(Chloromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A24)

[0181] Referring to the synthetic route of A2, 4-(chloromethyl)benzaldehyde (CAS: 73291-09-5) was used to replace the raw material 2-1 in Example 4 to obtain compound A24. ESI-MS m / z 340.1 [M+H] + .

[0182] Example 29: N-(4-cyclopropylphenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A25)

[0183] Referring to the synthetic route of A2, 4-cyclopropylbenzaldehyde (CAS: 20034-50-8) was used to replace the raw material 2-1 in Example 4 to obtain compound A25. ESI-MS m / z 331.2 [M+H] + .

[0184] Example 30: N-(4-isopropylphenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A26)

[0185] Referring to the synthetic route of A2, 4-isopropylbenzaldehyde (CAS: 122-03-2) was used to replace the raw material 2-1 in Example 4 to obtain compound A26. ESI-MS m / z 333.2 [M+H] + .

[0186] Example 31: N-(4-(Difluoromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A27)

[0187] Referring to the synthetic route of A2, 4-(difluoromethyl)benzaldehyde (CAS: 55805-29-3) was used to replace the raw material 2-1 in Example 4 to obtain compound A27. ESI-MS m / z 341.2 [M+H] + .

[0188] Example 32: N-(4-(Methoxymethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A28)

[0189] Referring to the synthetic route of A2, 4-(methoxymethyl)benzaldehyde (CAS: 93943-06-7) was used to replace the raw material 2-1 in Example 4 to obtain compound A28. ESI-MS m / z 335.2 [M+H] + .

[0190] Example 33: N-(4-Butoxyphenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A29)

[0191] Referring to the synthetic route of A2, 4-butoxybenzaldehyde (CAS: 5736-88-9) was used to replace the raw material 2-1 in Example 4 to obtain compound A29. ESI-MS m / z 363.7 [M+H] + .

[0192] Example 34: N-(4-(2-aminoethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A30)

[0193] Referring to the synthetic route of A2, 4-(2-aminoethyl)benzaldehyde hydrochloride (CAS: 64353-37-3) was used to replace the raw material 2-1 in Example 4 to obtain compound A30. ESI-MS m / z 334.5 [M+H] + .

[0194] Example 35: 4-(2-((2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino)ethyl)benzamide (A31)

[0195] Referring to the synthetic route of A2, 4-p-acetylaminobenzaldehyde (CAS: 6051-41-8) was used to replace the raw material 2-1 in Example 4 to obtain compound A31. ESI-MS m / z 334.2 [M+H] + .

[0196] Example 36: 4-(2-((2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino)ethyl)phenylacetate (A32)

[0197] Referring to the synthetic route of A2, 4-acetoxybenzaldehyde (CAS: 878-00-2) was used to replace the raw material 2-1 in Example 4 to obtain compound A32. ESI-MS m / z 349.2 [M+H] + .

[0198] Example 37: 2-(4-(2-((2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino)ethyl)phenyl)acetic acid (A33)

[0199] Referring to the synthetic route of A2, 2-(4-formylphenyl)acetic acid (CAS: 34841-47-9) was used to replace the raw material 2-1 in Example 4 to obtain compound A33. ESI-MS m / z 349.2 [M+H] + .

[0200] Example 38: N-(4-(Methylsulfonyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A34)

[0201] Referring to the synthetic route of A2, the raw material 2-1 in Example 4 was replaced with p-methylsulfonylbenzaldehyde (CAS: 5398-77-6) to obtain compound A34. ESI-MS m / z 369.5 [M+H] + .

[0202] Example 39: N-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A35)

[0203] Referring to the synthetic route of A2, the raw material 2-1 in Example 4 was replaced by p-phenylbenzaldehyde (CAS: 3218-36-8) to obtain compound A35. ESI-MS m / z 367.5 [M+H] + .

[0204] Example 40: N-(4-(Piperidin-4-yl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A36)

[0205] Referring to the synthetic route of A2, 1-boc-4-(4-formylphenyl)piperidine (CAS: 732275-93-3) was used to replace the raw material 2-1 in Example 4 to obtain compound A36. ESI-MS m / z 374.5 [M+H] + .

[0206] Example 41: N-(3-fluorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A37)

[0207] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 3-fluorophenethylamine (CAS: 404-70-6) to obtain compound A37. 1H NMR(500MHz,Chloroform-d)δ8.23(s,1H),7.47(dd,J=7.9,1.2Hz,1H),7.31–7.24(m,2H) ,7.13–7.10(m,1H),7.06–7.03(m,1H),6.98–7.02(m,1H),6.92–6.90(m,2H),4.03–3.96( m,1H),3.09–3.02(m,1H),2.99–2.92(m,1H),2.91–2.84(m,1H),2.81–2.77(m,1H),2.75– 2.67(m,2H),2.24–2.17(m,1H),2.05–1.99(m,1H),1.80–1.73(m,1H),1.66–1.60(m,1H). 13 C NMR (126MHz, Chloroform-d) δ 162.5 (d, J = 245.7Hz), 142.2 (d, J = 7.2Hz), 135.3, 129.4 (d, J = 8.2Hz), 127.0, 124.0 (d, J = 2.9Hz), 121.1, 118.6,117.8,115.2(d,J=20.8Hz),112.7(d,J=21.1Hz),110.9,110.4,52.0,46.4,36.3,29.7,21.4,20.5.HRMS(ESI)m / z:calculated for C 20 H 20 FN2[MH] - :307.1616,found:307.1615.

[0208] Example 42: N-(3-(Trifluoromethyl)phenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A38)

[0209] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 3-(trifluoromethyl)-phenethylamine (CAS: 52516-30-0) to obtain compound A38. 1 H NMR (500MHz, DMSO-d6) δ10.57(s,1H),7.61–7.46(m,4H),7.33(d,J=7.8Hz,1H),7.27(d,J=8.0Hz,1H),7.02–6.95(m,1H ),6.93–6.87(m,1H),3.88(t,J=4.9Hz,1H),2.96–2.81(m,4H),2.61–2.53(m,2H),1.98–1.90(m,2H),1.73–1.62(m,2H).13 C NMR (126MHz, DMSO-d6) δ142.1, 136.6, 135.8, 132.9, 129.2, 129.0 (q, J = 31.3Hz), 126.8, 125.1 (d, J = 3.7Hz), 124.4 (q, J=272.2Hz),122.6(d,J=3.7Hz),120.5,118.0,117.7,51.2,47.9,36.1,29.5,20.8,20.4.HRMS(ESI)m / z:calculated for C 21 H 20 F3N2[MH] - :357.1584,found:357.1587.

[0210] Example 43: N-(2-chlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A39)

[0211] Referring to the synthetic route of A1, 2-chlorophenylethylamine (CAS: 13078-80-3) was used to replace the raw material 1-1 in Example 1 to obtain compound A39. ESI-MS m / z 326.1 [M+H] + .

[0212] Example 44: N-(2-(4-pyridyl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A40)

[0213] Referring to the synthetic route of A1, 4-(2-aminoethyl)pyridine (CAS: 13258-63-4) was used to replace the raw material 1-1 in Example 1 to obtain compound A40. ESI-MS m / z 292.1 [M+H] + .

[0214] Example 45: N-(2-(4-pyrimidinyl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A41)

[0215] Referring to the synthetic route of A2, pyrimidine-4-carboxaldehyde (CAS: 2435-50-9) was used to replace the raw material 2-1 in Example 4 to obtain compound A41. ESI-MS m / z 293.1 [M+H] + .

[0216] Example 46: N-(2-(3-pyrrolyl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A42)

[0217] Referring to the synthetic route of A2, pyrrole-3-carboxaldehyde (CAS: 7126-39-8) was used to replace the raw material 2-1 in Example 4 to obtain compound A42. ESI-MS m / z 280.1 [M+H] + .

[0218] Example 47: N-(2-(3-thienyl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A43)

[0219] Referring to the synthetic route of A2, 3-thiophenecarboxaldehyde (CAS: 498-62-4) was used to replace the raw material 2-1 in Example 4 to obtain compound A43. ESI-MS m / z 297.2 [M+H] + .

[0220] Example 48: N-(2-(1H-indol-6-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A44)

[0221] Referring to the synthetic route of A1, indole-6-carboxaldehyde (CAS: 1196-70-9) was used to replace the raw material 2-1 in Example 4 to obtain compound A44. ESI-MS m / z 330.5 [M+H] + .

[0222] Example 49: N-(2-(1H-benzo[d]imidazol-6-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A45)

[0223] Referring to the synthetic route of A1, 1H-benzimidazole-5-carboxaldehyde (CAS: 58442-17-4) was used to replace the raw material 1-1 in Example 1 to obtain compound A45. ESI-MS m / z 331.5 [M+H] + .

[0224] Example 50: N-(2-(1H-indazol-6-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A46)

[0225] Referring to the synthetic route of A2, 1H-indazole-6-carboxaldehyde (CAS: 669050-69-5) was used to replace the raw material 2-1 in Example 4 to obtain compound A46. ESI-MS m / z 331.5 [M+H] + .

[0226] Example 51: N-(2-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A47)

[0227] Referring to the synthetic route of A2, 1,2,3,4-tetrahydroquinoline-7-carboxaldehyde was used to replace the raw material 2-1 in Example 4 to obtain compound A47. ESI-MS m / z 346.5[M+H] + .

[0228] Example 52: N-(2-(Quinolin-7-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A48)

[0229] Referring to the synthetic route of A2, 7-quinolinecarboxaldehyde (CAS: 49573-30-0) was used to replace the raw material 2-1 in Example 4 to obtain compound A48. ESI-MS m / z 342.5 [M+H] + .

[0230] Example 53: N-(2-(9-methyl-9H-carbazol-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine (A49)

[0231] Referring to the synthetic route of A2, 9-methyl-9H-carbazole-2-carboxaldehyde (CAS: 108793-90-4) was used to replace the raw material 2-1 in Example 4 to obtain compound A49. ESI-MS m / z 394.5 [M+H] + .

[0232] Example 54: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A50)

[0233]

[0234] Synthesis of intermediate 4-4: The starting material 4-1 (3 g, 22.2 mmol) was dissolved in tetrahydrofuran (21.5 mL, 400 mmol), protected with Ar, placed in an ice bath at 0°C, and diethylaluminum chloride (4 g, 33.30 mmol) was added. After stirring for 30 min, succinic acid monomethyl chloride (5.01 g, 33.30 mmol) was added. After 15 min, the mixture was transferred to room temperature for reaction for 4 h. After TLC monitoring, the reaction was completed, and the reaction bottle was moved to an ice bath at -5°C and stirred. Ice water was added dropwise to quench until there were no bubbles. A white solid precipitated in the solution. The precipitated solid was filtered, washed once with saturated sodium bicarbonate and water in turn, and dried to obtain 5.5 g of white intermediate 4-2 with a yield of 95%. After drying, the mixture was used for the next step. 4-2 (5.5 g, 22.07 mmol) was dissolved in ultra-dry tetrahydrofuran solution for use. 2M borane dimethyl sulfide (44.13 ml, 88.27 mmol) was slowly added in an ice bath at -5 °C, stirred for 15 min, and then moved to room temperature for 2 h. After TLC monitoring of the reaction was complete, the reaction bottle was moved to an ice bath at -5 °C and stirred, and ice water was added dropwise to quench until there were no bubbles. Then the insoluble solid was filtered off and washed with ethyl acetate, the filtrate was collected, the organic solvent was spin-dried and extracted with water and ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with ethyl acetate: petroleum ether = 3:1 to obtain 2.88 g of white solid product 4-3, with a yield of 56%. Product 4-3 was directly used for the next step. 4-3 (2.88 g, 12.24 mmol) was dissolved in 30 ml of a mixed solvent (methanol: water = 2:1), potassium hydroxide (2.06 g, 36.73 mmol) was added, and the mixture was heated under reflux for 4 h. After the reaction was complete as monitored by TLC, methanol was removed, and the reaction solution was adjusted to Ph = 6 with 2M aqueous hydrochloric acid solution. A white solid was precipitated, and the precipitated solid was filtered to obtain 1.6 g of the intermediate product 4-4, with a yield of 60%. ESI-MS m / z 222.1 [M+H] + .

[0235] Synthesis of intermediate 5-1: Referring to the synthetic route of A1, 4-4 was used to replace the raw material 1-2 in Example 1 and reacted with the raw material 1-1 to obtain a white solid product 5-1. ESI-MS m / z 369.2 [M+H] + .

[0236] Synthesis of intermediate 5-2: Intermediate 5-1 (3.4 g, 8.0 mmol) was dissolved in 50 mL of anhydrous acetonitrile, phosphorus oxychloride (4.46 mL, 48.0 mmol) was added, and refluxed and stirred for 1.5 h under argon protection. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure by TLC monitoring, and saturated sodium bicarbonate with ice was added to adjust to weak alkalinity, extracted with dichloromethane, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate for organic layer, concentrated, and purified by column chromatography with dichloromethane / methanol = 20:1 to obtain 2.71 g of yellow solid product 5-2, with a yield of 77%. ESI-MS m / z 351.2 [M+H] + .

[0237] Synthesis of compound A50: Intermediate 5-2 (2.12 g, 6.0 mmol) was dissolved in 50 mL of a methanol / dichloromethane (v / v=2:1) ​​mixed solvent, sodium borohydride (1.37 g, 36.0 mmol) was added in batches under an ice bath, and stirred at room temperature for 4 hours. After TLC monitoring, the reaction was quenched with a saturated ammonium chloride solution, the organic solvent was evaporated under reduced pressure, and then dichloromethane was added for extraction, and then washed with saturated sodium bicarbonate and saturated sodium chloride solutions, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with dichloromethane / methanol=15:1 to obtain 1 g of a white solid product A50, with a yield of 84%. 1 H NMR(500MHz, DMSO-d6)δ10.68(s,1H),7.25(dd,J=8.7,4.6Hz,1H),7.06(dd,J=9.9,2.6Hz,1H),6.83–6.76(m,3H),6.66(dd,J=7.9,1.7Hz,1H),5 .93(d,J=1.4Hz,2H),3.85(q,J=5.4,4.0Hz,1H),2.88–2.74(m,2H),2.7 2–2.61(m,2H),2.55–2.49(m,2H),1.99–1.90(m,2H),1.71–1.61(m,2H). 13 C NMR (126MHz, DMSO-d6) δ 156.6 (d, J = 230.4Hz), 147.2, 145.3, 139.1, 134.3, 132.4, 127.0 (d, J = 9.7Hz), 121.4, 111.8 (d, J = 9.8Hz), 109. 5(d,J=4.6Hz),109.0,108.2(d,J=25.8Hz),108.1,102.4(d,J=22.7Hz),51.3,48.5,36.3,29.4,20.7,20.4.HRMS(ESI)m / z:calculated for C 21 H 20 FN2O2[MH]- :351.1514,found:351.1516.

[0238] Example 55: N-(4-fluorophenethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A51)

[0239] Referring to the synthetic route of A50, 4-fluorophenethylamine (CAS: 1583-88-6) was used to replace the raw material 1-1 in Example 54 to obtain compound A51. 1 H NMR(600MHz,Chloroform-d)δ8.16(s,1H),7.23–7.15(m,3H),7.11(dd,J=9.5,2.5Hz,1H),7.03(t,J=8.6Hz,2H),6.93–6.86(m,1H),4.02–3.95(m,1H), 3.06–2.94(m,2H),2.90–2.83(m,1H),2.80–2.73(m,1H),2.72–2.61(m,2H), 2.26–2.19(m,1H),2.07–2.00(m,1H),1.82–1.74(m,1H),1.65–1.58(m,1H). 13 C NMR(151MHz,Chloroform-d)δ161.5(d,J=244.0Hz),157.7(d,J=233.8Hz),138 .0,135.8(d,J=3.3Hz),132.2,130.2(d,J=7.8Hz),127.9(d,J=9.6Hz),115.3(d ,J=21.1Hz),111.5(d,J=4.6Hz),111.2(d,J=9.7Hz),109.5(d,J=26.2Hz),103. 3(d,J=23.1Hz),52.5,47.3,36.2,30.1,21.8,20.9.HRMS(ESI)m / z:calculated for C 20 H 19 F2N2[MH] - :325.1522,found:325.1526.

[0240] Example 56: N-(4-chlorophenethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A52)

[0241] Referring to the synthetic route of A50, 4-chlorophenethylamine (CAS: 156-41-2) was used to replace the raw material 1-1 in Example 54 to obtain compound A52. 1H NMR(600MHz,Chloroform-d)δ8.14(s,1H),7.31(d,J=8.1Hz,2H),7.21–7.15( m,3H),7.12(dd,J=9.6,2.5Hz,1H),6.91(td,J=9.1,2.5Hz,1H),4.02–3.95(m, 1H),3.06–2.92(m,2H),2.91–2.81(m,1H),2.80–2.71(m,1H),2.73–2.62(m,2H ),2.26–2.18(m,1H),2.08–2.01(m,1H),1.85–1.73(m,1H),1.65–1.58(m,1H). 13 C NMR(151MHz,Chloroform-d)δ157.7(d,J=233.7Hz),138.7,138.0,132.2,132.0,130.2,128.6,127.9(d,J=9.7Hz),111.5(d,J=4.5 Hz),111.3(d,J=9.6Hz),109.5(d,J=26.1Hz),103.3(d,J=23.1Hz),52.5,47.0,36.4,30.1,21.8,20.9.HRMS(ESI)m / z:calculated for C 20 H 19 ClFN2[MH] - :341.1226,found:341.1225.

[0242] Example 57: N-(4-bromophenethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A53)

[0243] Referring to the synthetic route of A50, 4-bromophenethylamine (CAS: 73918-56-6) was used to replace the raw material 1-1 in Example 54 to obtain compound A53. 1 H NMR(600MHz,Chloroform-d)δ8.14(s,1H),7.46(d,J=7.9Hz,2H),7.18(dd,J=8.8,4.3Hz,1H),7.12(d,J=8.3Hz,3H),6.91(t,J=8.5Hz,1H),3.98(t, J=6.8Hz,1H),3.06–2.93(m,2H),2.89–2.80(m,1H),2.78–2.62(m,3H),2. 25–2.18(m,1H),2.10–2.00(m,1H),1.84–1.74(m,1H),1.65–1.58(m,1H).13 C NMR(151MHz,Chloroform-d)δ157.7(d,J=233.8Hz),139.2,138.0,132.2,131.5,130.6,127.9(d,J=9.6Hz),120.1,111.5(d,J=4.6 Hz),111.3(d,J=9.6Hz),109.5(d,J=26.2Hz),103.3(d,J=23.1Hz),52.5,47.0,36.5,30.1,21.8,20.9.HRMS(ESI)m / z:calculated for C 20 H 19 BrFN2[MH] - :385.0721,found:385.0725.

[0244] Example 58: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A54)

[0245] Referring to the synthetic route of A50, 5-chloroindole (CAS: 17422-32-1) was used to replace the raw material 4-1 in Example 54 to obtain compound A54. 1 H NMR(400MHz,Chloroform-d)δ8.26(s,1H),7.43(d,J=2.0Hz,1H),7.19(d,J=8.5Hz,1H),7.09(dd,J=8.6,2.0Hz,1H),6.80–6.67(m,3H),5.96(s,2H),4 .01–3.92(m,1H),3.05–2.89(m,2H),2.86–2.76(m,1H),2.76–2.60(m,3H), 2.27–2.17(m,1H),2.09–1.97(m,1H),1.85–1.72(m,1H),1.63–1.55(m,1H). 13 C NMR(101MHz,Chloroform-d)δ147.7,146.0,137.7,134.1,133.9,128.7,124.7,121.6,121.5,117.8 ,111.7,111.0,109.2,108.3,100.9,52.4,47.4,36.7,30.1,21.8,20.8.HRMS(ESI)m / z:calculated forC 21 H 20 ClN2O2[MH] -:367.1219,found:367.1220.

[0246] Example 59: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-6-bromo-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A55)

[0247] Referring to the synthetic route of A50, 5-bromoindole (CAS: 10075-50-0) was used to replace the raw material 4-1 in Example 54 to obtain compound A55. 1 H NMR(500MHz,Chloroform-d)δ8.31(s,1H),7.56(d,J=1.9Hz,1H),7.20(dd,J=8.6,1.9Hz ,1H),7.12(d,J=8.5Hz,1H),6.76(d,J=7.8Hz,1H),6.71(d,J=1.7Hz,1H),6.66(dd,J=7.9 ,1.7Hz,1H),5.94(s,2H),4.01–3.93(m,1H),3.00–2.88(m,2H),2.84–2.75(m,1H),2.72– 2.58(m,3H),2.24–2.15(m,1H),2.04–1.97(m,1H),1.77–1.72(m,1H),1.63–1.56(m,1H). 13 C NMR(126MHz,Chloroform-d)δ147.3,145.56,136.8,133.9,133.3,128.8,123.7,121.2,120.5,111. 8,111.7,110.6,108.7,107.8,100.5,51.9,46.9,36.1,29.5,21.3,20.3.HRMS(ESI)m / z:calculated for C 21 H 20 BrN2O2[MH] - :411.0714,found:411.0718.

[0248] Example 60: N-(4-chlorophenethyl)-6-bromo-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A56)

[0249] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5-bromoindole (CAS: 10075-50-0), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenethylamine (CAS: 156-41-2) to obtain compound A56. 1H NMR(500MHz,Chloroform-d)δ8.11(s,1H),7.55(d,J=1.9Hz,1H),7.45–7.41(m,2H),7.20(dd,J=8.5,1.9Hz,1H),7.13–7.07(m,3H),3.99–3.93(m,1H), 3.00–2.91(m,2H),2.84–2.78(m,1H),2.74–2.67(m,1H),2.65–2.55(m,2H), 2.22–2.14(m,1H),2.04–1.98(m,1H),1.76–1.70(m,1H),1.64–1.51(m,1H). 3 C NMR (126MHz, Chloroform-d) δ138.7,136.7,133.8,131.1,130.2,128.8,123.7,120.5,119.6,111.8,111.7,110.6,51.9,46.4,36.0,29.6 21.4,20.3.HRMS(ESI)m / z:calculated for C 20 H 19 BrClN2[MH] - :401.0426,found:401.0426.

[0250] Example 61: N-(4-bromophenethyl)-6-bromo-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A57)

[0251] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5-bromoindole (CAS: 10075-50-0), and the raw material 1-1 in Example 54 was replaced by 4-bromophenethylamine (CAS: 73918-56-6) to obtain compound A57. 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.55(d,J=1.9Hz,1H),7.28–7.25(m,2 H),7.19(dd,J=8.5,1.9Hz,1H),7.15–7.11(m,2H),7.10(d,J=8.5Hz,1H),3.98–3. 91(m,1H),3.00–2.90(m,2H),2.86–2.77(m,1H),2.75–2.66(m,1H),2.65–2.53(m ,2H),2.20–2.15(m,1H),2.02–1.96(m,1H),1.77–1.69(m,1H),1.60–1.55(m,1H). 13C NMR(151MHz,Chloroform-d)δ138.6,137.3,134.3,132.0,130.2,129.3,128.6,124.2,12 0.9,112.3,112.2,111.1,52.4,47.0,36.4,30.1,21.8,20.7.HRMS(ESI)m / z:calculated for C 20 H 19 Br2N2[MH] - :444.9920,found:444.9926.

[0252] Example 62: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A58)

[0253] Referring to the synthetic route of A50, 5-methylindole (CAS: 614-96-0) was used to replace the raw material 4-1 in Example 54 to obtain compound A58. ESI-MS m / z 349.2 [M+H] + .

[0254] Example 63: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A59)

[0255] Referring to the synthetic route of A50, 5-methoxyindole (CAS: 1006-94-6) was used to replace the raw material 4-1 in Example 54 to obtain compound A59. 1 H NMR(500MHz,Chloroform-d)δ8.18(s,1H),7.17(d,J=8.7Hz,1H),6.91(d,J=2.5Hz,1H),6.83–6.64(m,4H),5.93(s,2H),3.98(t,J=6.4Hz,1H),3 .85(s,3H),3.02–2.87(m,2H),2.85–2.76(m,1H),2.75–2.63(m,3H),2.2 2–2.16(m,1H),2.06–1.97(m,1H),1.81–1.72(m,1H),1.67–1.57(m,1H). 13C NMR(126MHz,Chloroform-d)δ153.4,147.3,145.6,133.2,130.5,127.3,121.2,111.1,111.0,110. 8,108.7,107.8,100.4,100.1,55.5,52.0,46.8,36.0,29.5,21.3,20.5.HRMS(ESI)m / z:calculated for C 22 H 23 N2O3[MH] - :363.1714,found:363.1713.

[0256] Example 64: 6-Butoxy-N-(4-chlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A60)

[0257] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5-butoxy-1H-indole, and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A60. ESI-MS m / z 398.0 [M+H] + .

[0258] Example 65: N-(4-chlorophenethyl)-6-pentyl-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A61)

[0259] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced with 5-pentyl-1H-indole, and the raw material 1-1 in Example 54 was replaced with 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A61. ESI-MS m / z 396.0 [M+H] + .

[0260] Example 66: 6-(2-aminoethyl)-N-(4-chlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A62)

[0261] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 1H-indole-5-ethylamine (CAS: 21005-60-7), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A61. ESI-MS m / z 396.0 [M+H] + .ESI-MS m / z 369.1[M+H] + .

[0262] Example 67: 6-allyl-N-(4-chlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A63)

[0263] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5-allyl-1H-indole, and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A63. ESI-MS m / z 366.1 [M+H] + .

[0264] Example 68: N-(4-chlorophenethyl)-6-ethynyl-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A64)

[0265] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5-ethynyl-1H-indole, and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A64. ESI-MS m / z 349.8 [M+H] + .

[0266] Example 69: N-(4-chlorophenethyl)-6-(cyclopropylmethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A65)

[0267] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced with 5-cyclopropylmethyl-1H-indole, and the raw material 1-1 in Example 54 was replaced with 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A65. ESI-MS m / z 380.2 [M+H] + .

[0268] Example 70: 1-((4-chlorophenethyl)amino)-N-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide (A66)

[0269] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by N-methyl-1H-indole-5-carboxamide (CAS: 121206-74-4), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A66. ESI-MS m / z 382.9 [M+H] + .

[0270] Example 71: 1-((4-chlorophenethyl)amino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid ethyl ester (A67)

[0271] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by ethyl indole-5-carboxylate (CAS: 32996-16-0), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A67. ESI-MSm / z 397.9[M+H] + .

[0272] Example 72: 1-((4-chlorophenethyl)amino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid (A68)

[0273] Referring to the synthetic route of A50, indole-5-carboxylic acid (CAS: 1670-81-1) was used to replace the raw material 4-1 in Example 54, and 4-chlorophenylethylamine (CAS: 156-41-2) was used to replace the raw material 1-1 in Example 54 to obtain compound A68. ESI-MS m / z 369.4 [M+H] + .

[0274] Example 73: N-(4-chlorophenethyl)-2,3,4,6,7,8,9,10-octahydro-1H-pyrido[2,3-b]carbazole-9-amine (A69)

[0275] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinoline, and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A69. ESI-MS m / z 380.1 [M+H] + .

[0276] Example 74: N-(4-chlorophenethyl)-2,3,4,5-tetrahydro-1H-benzo[b]carbazole-4-amine (A70)

[0277] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 2,3-benzocarbazole (CAS: 243-28-7), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A70. ESI-MS m / z 370.2 [M+H] + .

[0278] Example 75: N-(4-chlorophenethyl)-1,5,6,7,8,9-hexahydropyrrolo[2,3-b]carbazole-8-amine (A71)

[0279] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 1,7-dihydropyrroloindole, and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A71. ESI-MS m / z 364.8 [M+H] + .

[0280] Example 76: N-(4-chlorophenethyl)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A72)

[0281] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 6-phenyl-1H-indole, and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A72. ESI-MS m / z 402.2 [M+H] + .

[0282] Example 77: N-(4-chlorophenethyl)-6-(3-thienyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A73)

[0283] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 6-thiophen-3-yl-1H-indole, and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A73. ESI-MS m / z 408.5 [M+H] + .

[0284] Example 78: N-(4-chlorophenethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-8-amine (A74)

[0285] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 7-azaindole (CAS: 271-63-6), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A74. ESI-MS m / z 327.2 [M+H] + .

[0286] Example 79: N-(4-chlorophenethyl)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-8-amine (A75)

[0287] Referring to the synthetic route of A50, 5-fluoro-1H-pyrrolo[2,3-B]pyridine (CAS: 866319-00-8) was used to replace the raw material 4-1 in Example 54, and 4-chlorophenylethylamine (CAS: 156-41-2) was used to replace the raw material 1-1 in Example 54 to obtain compound A75. ESI-MS m / z 345.3 [M+H] + .

[0288] Example 80: N-(4-chlorophenethyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-amine (A76)

[0289] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 4-azaindole (CAS: 272-49-1), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A76. ESI-MS m / z 327.2 [M+H] + .

[0290] Example 81: N-(4-chlorophenethyl)-6,7,8,9-tetrahydro-5H-pyrido[4,3-b]indol-6-amine (A77)

[0291] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5-azaindole (CAS: 271-34-1), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A77. ESI-MS m / z 327.3 [M+H] + .

[0292] Example 82: N-(4-chlorophenethyl)-4-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,4-b]indol-6-amine (A78)

[0293] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 4-fluoro-6-azaindole (CAS: 1363380-64-6), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A78. ESI-MS m / z 345.2 [M+H] + .

[0294] Example 83: N-(4-chlorophenethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-8-amine (A79)

[0295] Referring to the synthetic route of A50, 7H-pyrrolo[2,3-D]pyrimidine (CAS: 271-70-5) was used to replace the raw material 4-1 in Example 54, and 4-chlorophenylethylamine (CAS: 156-41-2) was used to replace the raw material 1-1 in Example 54 to obtain compound A79. ESI-MS m / z 328.3 [M+H] + .

[0296] Example 84: 2-Bromo-N-(4-chlorophenethyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]indol-6-amine (A80)

[0297] Referring to the synthetic route of A50, 5-bromo-4,7-diazaindole (CAS: 875781-43-4) was used to replace the raw material 4-1 in Example 54, and 4-chlorophenylethylamine (CAS: 156-41-2) was used to replace the raw material 1-1 in Example 54 to obtain compound A80. ESI-MS m / z 406.4 [M+H] + .

[0298] Example 85: N-(4-fluorophenethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A81)

[0299] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 1-1 in Example 54 was replaced by 4-fluorophenethylamine (CAS: 1583-88-6) to obtain compound A81. 1 H NMR(600MHz,Chloroform-d)δ8.14(s,1H),7.27–7.10(m,3H),7.10–6.89(m,3H),3.96(t,J=6.9Hz,1H),3.13–2.91(m,2H),2.93 –2.83(m,1H),2.81–2.71(m,1H),2.68–2.50(m,2H),2.26–2.17(m,1H),2.07–1.98(m,1H),1.83–1.72(m,1H),1.64–1.55(m,1H). 13C NMR (151MHz, Chloroform-d) δ 161.5 (d, J = 244.2Hz), 147.6 (dd, J = 239.4, 15.7Hz), 146. 1(dd,J=236.9,14.7Hz),137.6,135.7(d,J=3.2Hz),130.6(d,J=10.2Hz),130.2(d,J=7 .8Hz),122.8(d,J=7.7Hz),115.3(d,J=21.1Hz),111.4(d,J=4.1Hz),104.8(d,J=18.8H z),98.8(d,J=21.7Hz),52.4,47.3,36.2,30.0,21.8,20.8.HRMS(ESI)m / z:calculated for C 20 H 18 F3N2[MH] - :343.1428,found:343.1426.

[0300] Example 86: N-(4-chlorophenethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A82)

[0301] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 1-1 in Example 54 was replaced by 4-chlorophenethylamine (CAS: 156-41-2) to obtain compound A82. 1 H NMR(600MHz,Chloroform-d)δ8.26(s,1H),7.28–7.25(m,2H),7.17–7.09(m,3H),7.01(dd,J=10.7,6.7Hz,1H),3.99–3.92(m,1H),3.00–2.88 (m,2H),2.86–2.79(m,1H),2.78–2.65(m,1H),2.62–2.51(m,2H),2.19 –2.14(m,1H),2.02–1.97(m,1H),1.78–1.70(m,1H),1.62–1.55(m,1H). 13C NMR(151MHz,Chloroform-d)δ147.6(dd,J=244.4,16.2Hz),146.1(dd,J=237.4,14.4Hz),138.3,136.7,132.1,130.7(d,J=10.2Hz),130.2, 128.6,122.7(d,J=7.6Hz),111.7,104.9(d,J=18.8Hz),98.8(d,J=21.7Hz),52.3,46.8,36.1,29.7,21.7,20.8.HRMS(ESI)m / z:calculated for C 20 H 18 ClF2N2[MH] - :359.1132,found:359.1136.

[0302] Example 87: N-(4-bromophenethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A83)

[0303] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 1-1 in Example 54 was replaced by 4-bromophenethylamine (CAS: 73918-56-6) to obtain compound A83. 1 H NMR (600MHz, Chloroform-d) δ8.10 (s, 1H), 7.44–7.40 (m, 2H), 7.13 (dd, J = 10. 8,7.8Hz,1H),7.10–7.06(m,2H),7.01(dd,J=10.7,6.7Hz,1H),3.97–3.90(m,1 H),2.98–2.88(m,2H),2.84–2.76(m,1H),2.74–2.66(m,1H),2.63–2.52(m,2H ),2.21–2.12(m,1H),2.03–1.95(m,1H),1.74–1.70(m,1H),1.62–1.55(m,1H). 13C NMR(151MHz,Chloroform-d)δ147.6(dd,J=239.7,15.7Hz),146.1(dd,J=237.0,14.7Hz),139.1,137.2,131.5,130.6,122.7(d,J=7.4H z),120.1,111.5(d,J=3.1Hz),104.8(d,J=18.8Hz),98.8(d,J=21.7Hz),52.4,46.8,36.4,29.9,21.8,20.8.HRMS(ESI)m / z:calculated for C 20 H 18 BrF2N2[MH] - :403.0627,found:403.0625.

[0304] Example 88: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A84)

[0305] Referring to the synthetic route of A50, 5,6-difluoroindole (CAS: 169674-01-5) was used to replace the raw material 4-1 in Example 54 to obtain compound A84. 1 H NMR(500MHz,Chloroform-d)δ8.21(s,1H),7.14(dd,J=10.8,7.8Hz,1H),7.02(dd,J=10 .7,6.6Hz,1H),6.76(d,J=7.8Hz,1H),6.71(d,J=1.7Hz,1H),6.67(dd,J=7.8,1.7Hz,1H) ,5.94(q,J=1.4Hz,2H),3.98–3.90(m,1H),3.00–2.86(m,2H),2.83–2.75(m,1H),2.71–2 .56(m,3H),2.22–2.15(m,1H),2.03–1.97(m,1H),1.80–1.71(m,1H),1.60–1.54(m,1H). 13C NMR(126MHz,Chloroform-d)δ147.3,147.1(dd,J=239.5,15.7Hz),145.7(dd,J=2 36.8,14.6Hz),145.6,137.2(d,J=3.5Hz),133.4,130.2(d,J=10.1Hz),122.3(d,J =7.3Hz),121.2,110.9(d,J=3.8Hz),108.7,107.8,104.4(d,J=18.8Hz),100.5,9 8.3(d,J=21.6Hz),52.0,46.9,36.2,29.5,21.3,20.3.HRMS(ESI)m / z:calculated for C 21 H 19 F2N2O2[MH] - :369.1420,found:369.1416.

[0306] Example 89: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A85)

[0307] Referring to the synthetic route of A50, 5,6-dichloroindole (CAS: 121859-57-2) was used to replace the raw material 4-1 in Example 54 to obtain compound A85. 1 H NMR(500MHz,Chloroform-d)δ8.18(s,1H),7.48(s,1H),7.31(s,1H),6.79–6.64(m,3H),5.95(d,J=7.0Hz,2H),2.97–2.85 (m,2H),2.82–2.73(m,1H),2.71–2.52(m,3H),2.22–2.14(m,1H),2.05–1.95(m,1H),1.79–1.68(m,1H),1.61–1.52(m,1H). 13 CNMR(126MHz,Chloroform-d)δ147.3,145.6,137.9,134.0,133.4,127.0,124.3,122.4,121.2,118. 8,111.7,110.5,108.7,107.8,100.5,51.9,46.8,36.3,29.5,21.3,20.2.HRMS(ESI)m / z:calculated for C 21 H 19 Cl2N2O2[MH] -:401.0829,found:401.0831.

[0308] Example 90: N-(Benzo[d][1,3]-5-dioxolanealkylmethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A86) Referring to the synthetic route of A1, 3,4-methylenedioxybenzylamine (CAS: 2620-50-0) was used to replace the raw material 1-1 in Example 1 to obtain compound A86. 1 H NMR (600MHz, DMSO-d6) δ10.61(s,1H),7.30(dd,J=20.5,7.9Hz,2H),7.06(d,J=1.6H z,1H),6.99–6.96(m,J=8.1,7.0,1.2Hz,1H),6.90–6.87(m,1H),6.85(dd,J=7.9,1. 6Hz,1H),6.80(d,J=7.9Hz,1H),5.94(s,2H),3.84(t,J=5.7Hz,1H),3.78–3.65(m,2 H),2.56(t,J=5.4Hz,2H),2.05–1.98(m,1H),1.99–1.95(m,1H),1.70–1.60(m,2H). 13 C NMR(151MHz,DMSO-d6)δ147.7,146.3,137.3,136.3,135.7,127.3,121.3,120.9,118.5,118.1 ,111.5,109.8,109.0,108.2,101.1,51.4,50.0,29.8,21.4,21.3.HRMS(ESI)m / z:calculated for C 20 H 19 N2O2[MH] - :319.1452,found:319.1450.

[0309] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-methoxybenzylamine (CAS: 2393-23-9) to obtain compound A87. 1H NMR(400MHz,Chloroform-d)δ8.35(s,1H),7.52(d,J=7.5Hz,1H),7.39–7.30(m,3H),7.22–7.13(m,1H),7.15–7.07(m,1H),6.96–6.91(m, 2H),4.07–4.01(m,1H),4.00–3.81(m,5H),2.80–2.72(m,2H),2.41–2 .31(m,1H),2.15–2.04(m,1H),1.86–1.80(m,1H),1.78–1.68(m,1H). 13 C NMR(101MHz,Chloroform-d)δ158.78,136.04,135.80,132.57,129.34,127.54,121.51,1 19.06,118.30,113.93,111.31,110.82,55.34,51.73,49.71,30.37,21.84,21.00.ESI-MS m / z 307.1[M+H] + .

[0310] Example 92: N-(4-methylbenzyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A88)

[0311] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-methylbenzylamine (CAS: 104-84-7) to obtain compound A88. 1 H NMR(500MHz,DMSO-d6)δ10.66(s,1H),7.37–7.30(m,4H),7.13(d,J=7.8Hz,2H),7.01–6.99(m,1H),6.94–6.90(m,1H),3.8 8(t,J=5.8Hz,1H),3.8(dd,J=41.2,28.3Hz,2H),2.60(t,J=5.6Hz,2H),2.28(s,3H),2.09–1.96(m,2H),1.76–1.60(m,2H). 13 CNMR(126MHz,DMSO-d6)δ138.1,136.8,135.8,135.4,128.6,127.9,126.8,120.5,1 18.0,117.6,111.0,109.3,51.0,49.6,29.3,20.9,20.7.HRMS(ESI)m / z:calculated for C 20 H 21 N2[MH] -:289.1710,found:289.1708.

[0312] Example 93: 4-(2-((2,3,4,9-tetrahydro-1H-carbazole-1-yl)amino)methyl)benzene cyanohydride (A89)

[0313] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by p-cyanobenzylamine (CAS: 10406-25-4) to obtain compound A76. 1 H NMR (500MHz, Chloroform-d) δ8.26 (s, 1H), 7.64 (d, J = 8.3Hz, 2H), 7.55 (d, J = 8. 3Hz,2H),7.49(d,J=7.8Hz,1H),7.33(d,J=8.1Hz,1H),7.18–7.14(m,1H),7.11– 7.08(m,1H),4.06(dd,J=54.5,14.2Hz,2H),4.04–4.00(m,1H),2.78–2.67(m,2 H),2.33–2.31(m,1H),2.12–2.04(m,1H),1.83–1.75(m,1H),1.74–1.66(m,1H). 13 C NMR(126MHz,Chloroform-d)δ135.8,135.2,132.3,128.7,127.5,121.8,119.3,118.9 ,118.4,111.8,110.9,110.8,52.1,49.6,30.2,21.7,20.9.HRMS(ESI)m / z:calculated for C 20 H 18 N3[MH] - :300.1506,found:300.1504.

[0314] Example 94: N-(4-bromobenzyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A90)

[0315] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by p-bromobenzylamine (CAS: 3959-07-7) to obtain compound A77. 1H NMR(500MHz,Chloroform-d)δ8.27(s,1H),7.54–7.44(m,3H),7.35–7.27(m,3H),7.18–7.14(m,1H),7.11–7.08(m,1H),4.02–3 .97(m,1H),3.97–3.81(m,2H),2.77–2.67(m,2H),2.37–2.27(m,1H),2.12–2.04(m,1H),1.86–1.75(m,1H),1.72–1.66(m,1H). 13 C NMR(126MHz,Chloroform-d)δ139.1,135.3,131.1,129.4,127.1,121.2,120.4 118.7,117.9,111.0,110.4,51.4,49.1,29.9,21.3,20.5.HRMS(ESI)m / z:calculated for C 19 H 18 BrN2[MH] - :353.0659,found:353.0658.

[0316] Example 95: N-(4-chlorobenzyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A91)

[0317] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by p-chlorobenzylamine (CAS: 104-86-9) to obtain compound A78. 1 H NMR(500MHz,Chloroform-d)δ8.26(s,1H),7.49(d,J=7.8Hz,1H),7.38–7.30(m,5H),7.18–7.14(m,1H),7.11–7.08(m,1H),4.01(t,J=7 .5Hz,1H),3.91(dd,J=63.2,13.3Hz,2H),2.79–2.69(m,2H),2.35–2.30(m,1H),2.11–2.06(m,1H),1.86–1.76(m,1H),1.71–1.65m,1H). 13 C NMR(126MHz,Chloroform-d)δ138.6,135.3,132.3,129.0,128.1,127.1,121.2,11 8.7,117.9,111.0,110.4,51.4,49.1,29.9,21.4,20.5.HRMS(ESI)m / z:calculated for C19 H 18 ClN2[MH] - :309.1164,found:309.1168.

[0318] Example 96: (R)-N-(4-chlorobenzyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine ((R)-A91)

[0319] Referring to the synthetic route of (R)-A1, the raw material 1-1 in Example 2 was replaced by p-chlorobenzylamine (CAS: 104-86-9) to obtain compound (R)-A78. The optical purity was 82:18er (chromatographic conditions: chiral IA (4.6 mm×250 mml), n-hexane / isopropanol=80 / 20, 1 mL / min, 254 nm UV, room temperature). 1 H NMR(500MHz,DMSO-d6)δ11.31(s,1H),7.72–7.65(m,2H),7.54–7.46(m,3H),7.39(d,J=8.1Hz,1H),7.18–7.11(m,1H),7.03 (d,J=7.5Hz,1H),4.67(s,1H),4.29(s,2H),2.77–2.65(m,2H),2.22(q,J=6.0Hz,2H),2.15–2.05(m,1H),1.87–1.77(m,1H). 13 C NMR(126MHz,DMSO-d6)δ136.5,134.1,132.7,131.5,129.0,128.1,126.5,122.9,11 9.4,119.1,114.3,111.9,51.6,47.6,26.0,20.7,20.1.HRMS(ESI)m / z:calculated for C 19 H 18 ClN2[MH] - :309.1164,found:309.1161.

[0320] Example 97: (S)-N-(4-chlorobenzyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine ((S)-A91)

[0321] Referring to the synthetic route of (S)-A1, the raw material 1-1 in Example 3 was replaced by p-chlorobenzylamine (CAS: 104-86-9) to obtain compound (S)-A78. The optical purity was 84:16er (chromatographic conditions: chiral IA (4.6 mm×250 mml), n-hexane / isopropanol=80 / 20, 1 mL / min, 254 nm UV, room temperature).1 H NMR (500MHz, DMSO-d6) δ11.26 (s, 1H), 7.72–7.65 (m, 2H), 7.54–7.47 (m, 3H), 7.40 (d, J = 8.2Hz, 1H), 7.19–7.12 (m, 1H), 7.06–7. 00(m,1H),4.67(s,1H),4.30(d,J=10.9Hz,2H),2.75–2.63(m,2H),2.22(q,J=5.8Hz,2H),2.12–2.05(m,1H),1.86–1.80(m,1H). 13 C NMR(126MHz,DMSO-d6)δ136.5,134.2,132.7,131.5,129.0,128.0,126.5,122.9,11 9.4,119.1,114.3,112.0,51.7,47.7,26.1,20.7,20.0.HRMS(ESI)m / z:calculated for C 19 H 18 ClN2[MH] - :309.1164,found:309.1163.

[0322] Example 98: N-(4-chlorobenzyl)-N-methyl-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A92)

[0323] Referring to the synthetic route of A17, the raw material A1 in Example 19 was replaced by A78 to obtain compound A79. 1 H NMR(500MHz,DMSO-d6)δ10.63(s,1H),7.55–7.51(m,2H),7.40–7.32(m,4H),7.04–6.98(m,1H),6.95–6.88(m,1H),4.1 5–4.09(m,1H),3.58(s,2H),2.66–2.54(m,2H),2.09(s,3H),2.05–1.95(m,2H),1.85–1.74(m,1H),1.69–1.59(m,1H). 13 C NMR (126MHz, DMSO-d6) δ139.0,136.1,135.2,131.2,130.3,128.0,126.9,120.5,118. 0,117.6,111.1,111.0,57.8,56.2,36.9,22.3,21.0,20.7.HRMS(ESI)m / z:calculated for C 20 H 20ClN2[MH] - :323.1320,found:323.1322.

[0324] Example 99: N-(3-(4-chlorophenyl)propyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A93)

[0325] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 3-(4-chlorophenyl)-propylamine (CAS: 18655-50-0) to obtain compound A80. 1 H NMR(400MHz,Chloroform-d)δ8.38(s,1H),7.53(d,J=7.7Hz,1H),7.35(d,J=8.0Hz,1H),7.32–7.27(m,2H),7.22–7.11(m,4H),4.0 0–3.93(m,1H),2.95–2.86(m,1H),2.78–2.62(m,5H),2.31–2.21(m,1H),2.11–2.02(m,1H),1.91–1.79(m,3H),1.69–1.60(m,1H). 13 C NMR(101MHz,Chloroform-d)δ140.6,136.2,135.8,131.6,129.8,128.5,127.6,121.6,119. 1,118.3,111.2,110.9,52.4,45.6,33.0,32.2,30.4,21.7,21.0.HRMS(ESI)m / z:calculated for C 21 H 22 ClN2[MH] - :337.1477,found:337.1479.

[0326] Example 100: N-(3-(4-methoxyphenyl)propyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A94)

[0327] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 3-(4-methoxyphenyl)-propylamine (CAS: 36397-23-6) to obtain compound A81. 1H NMR(500MHz,Chloroform-d)δ8.35(s,1H),7.48(d,J=7.8Hz,1H),7.34–7.28(m,1H),7.18–7.10(m,3H),7.12–7.05(m,1H),6.88–6.83(m,2H),3.9 5(t,J=6.5Hz,1H),3.80(s,3H),2.90–2.81(m,1H),2.75–2.63(m,5H),2. 27–2.18(m,1H),2.07–1.99(m,1H),1.87–1.77(m,3H),1.66–1.60(m,1H). 13 C NMR(126MHz,Chloroform-d)δ157.4,135.6,135.3,133.7,128.9,127.0,121.1,118.6,117.8,1 13.4,110.8,110.4,54.8,51.9,45.2,32.3,31.9,29.8,21.3,20.5.HRMS(ESI)m / z:calculated for C 22 H 25 N2O[MH] - :333.1972,found:333.1975.

[0328] Example 101: N-(4-(3,4-dichlorophenyl)propyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A95)

[0329] Referring to the synthetic route of A1, 3,4-dichlorophenylpropylamine (CAS: 76706-60-0) was used to replace the raw material 1-1 in Example 1 to obtain compound A95. ESI-MS m / z 374.3 [M+H] + .

[0330] Example 102: N-(4-(3,4-dichlorophenyl)butyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A96)

[0331] Referring to the synthetic route of A1, 3,4-dichlorophenylbutylamine was used to replace the raw material 1-1 in Example 1 to obtain compound A96. ESI-MS m / z 388.4 [M+H] + .

[0332] Example 103: N-(4-(3,4-dichlorophenyl)pentyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A97)

[0333] Referring to the synthetic route of A1, 3,4-dichlorophenylpentylamine was used to replace the raw material 1-1 in Example 1 to obtain compound A97. ESI-MS m / z 402.1[M+H] + .

[0334] Example 104: (E)-N-(2-(Benzo[d][1,3]-5-dioxolane)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A98)

[0335] Referring to the synthetic route of A102, the raw material 4-4 in Example 108 was replaced by indole-3-butyric acid (IBA)-BBI (CAS: 133-32-4), and the raw material 6-1 in Example 108 was replaced by piperidine (CAS: 1484-85-1) to obtain compound A98. 1 H NMR(500MHz, CDCl3)δ13.30(s,1H),12.60(s,1H),7.53(ddd,J=7.5,5.9,1.0Hz,2H),7.41(ddd,J=8.4,6.9,1.0Hz,1H),7.12–7.07(m,1H),6 .77–6.66(m,3H),5.90(s,2H),3.88(d,J=6.6Hz,2H),3.18(t,J=6.9Hz,2H),2.91(t,J=6.2Hz,2H),2.51(t,J=6.2Hz,2H),2.04–1.92(m,2H). 13 C NMR (126MHz, CDCl3) δ166.37,148.00,146.68,141.02,134.83,130.79,129.97,124.96,124.81,12 2.34,121.31,121.19,113.77,109.26,108.66,101.07,47.63,34.65,27.09,23.34,21.14.ESI-MS m / z 370.1[M+H] + .

[0336] Example 105: (E)-N-(2-(2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A99)

[0337] Referring to the synthetic route of A2, the raw material 1-2 in Example 4 was replaced by indole-3-butyric acid (IBA)-BBI (CAS: 656-42-8), and the raw material 2-1 in Example 4 was replaced by 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde (CAS: 1484-85-1) to obtain compound A99. ESI-MS m / z 369.1 [M+H] + .

[0338] Example 106: (E)-N-(4-chlorophenethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A100)

[0339] Referring to the synthetic route of A102, the raw material 4-4 in Example 108 was replaced by indole-3-butyric acid (IBA)-BBI (CAS: 133-32-4), and the raw material 6-1 in Example 108 was replaced by 4-chlorophenethylamine (CAS: 156-41-2) to obtain compound A100. 1 H NMR(500MHz,Chloroform-d)δ13.29(s,1H),12.58(s,1H),7.54–7.47(m,2H),7.44–7.38(m,1H),7.24–7.20(m,4H),7.13– 7.06(m,1H),3.91(q,J=6.7Hz,2H),3.25(t,J=6.9Hz,2H),2.88(t,J=6.2Hz,2H),2.48(t,J=6.3Hz,2H),2.01–1.92(m,2H). 13 C NMR(126MHz,Chloroform-d)δ166.0,140.6,135.2,134.7,132.6,130.1,129.7,128.6,12 4.5,124.7,120.9,120.8,113.2,46.8,33.6,26.6,22.8,20.6.HRMS(ESI)m / z:calculated forC 20 H 19 Cl2N2[MH] - :357.0931,found:357.0933.

[0340] Example 107: (E)-N-(2-(Benzo[d][1,3]-5-dioxolane)ethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A101)

[0341] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by piperidine (CAS: 1484-85-1) to obtain compound A101. 1 H NMR(500MHz,Chloroform-d)δ13.36(s,1H),12.91(s,1H),7.31–7.25(m,2H),6.75–6.69(m,3H),5.91(s,2H), 3.90(q,J=6.6Hz,2H),3.18(t,J=6.8Hz,2H),2.89(t,J=6.1Hz,2H),2.53(t,J=6.2Hz,2H),2.07–1.98(m,2H). 13 C NMR (126MHz, Chloroform-d) δ 166.2, 153.1 (dd, J = 253.6, 16.7Hz), 148.1, 147. 6(dd,J=244.9,15.9Hz),146.8,136.7(d,J=11.2Hz),134.3,130.6,126.0(d,J =3.1Hz),122.3,120.3(d,J=8.1Hz),109.2,108.7,107.7(d,J=18.9Hz),101.1 (d,J=22.1Hz),101.1,47.8,34.6,27.0,23.2,21.1.HRMS(ESI)m / z:calculated for C 21 H 17 F2N2O2[M-HCl-H] - :367.1264,found:367.1262.

[0342] Example 108: (E)-N-(4-fluorophenethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A102)

[0343]

[0344] Synthesis of intermediate 4-4: refer to Example 54.

[0345] Synthesis of intermediate 6-2: Referring to the synthetic route of A1, 4-4 was used to replace the raw material 1-2 in Example 1 and reacted with the raw material 6-1 to obtain a white solid product 6-2. ESI-MS m / z 343.1 [M+H] + .

[0346] Synthesis of compound A102: Intermediate 6-2 (2.744 g, 8.0 mmol) was dissolved in 50 mL of anhydrous acetonitrile, phosphorus oxychloride (4.46 mL, 48.0 mmol) was added, and the mixture was refluxed and stirred at 85°C for 1.5 h under argon protection. After the reaction was completed as monitored by TLC, the mixture was evaporated to dryness under reduced pressure, 5 ml of anhydrous ethanol was added, and the mixture was refluxed and stirred at 80°C for 10 min, then transferred to room temperature and stirred for 30 min. Solid precipitated, the solid was filtered out, washed twice with anhydrous ethanol, and dried to obtain 1.1 g of yellow solid product A87, with a yield of 50%. 1 H NMR(500MHz,Chloroform-d)δ13.44(s,1H),12.73(s,1H),7.48(dd,J=9.1,4.2Hz,1H),7.28–7.23(m,2H),7.19(td,J=9.1,2.5Hz,1H),7.12(dd,J =8.6,2.5Hz,1H),6.99–6.93(m,2H),3.93(q,J=6.7Hz,2H),3.27(t,J=6. 9Hz,2H),2.86(t,J=6.2Hz,2H),2.48(t,J=6.3Hz,2H),2.02–1.94(m,2H). 13 C NMR(126MHz,Chloroform-d)δ166.8,162.0(d,J=246.4Hz),158.0(d,J=240.2Hz ),137.6,134.1(d,J=6.4Hz),132.8(d,J=3.2Hz),130.7(d,J=8.0Hz),125.9,12 4.8(d,J=10.0Hz),119.6(d,J=27.5Hz),115.9(d,J=21.4Hz),115.0(d,J=9.3Hz ),105.1(d,J=23.2Hz),47.7,33.9,27.1,23.2,21.1.HRMS(ESI)m / z:calculated for C 21 H 17 F2N2O2[M-HCl-H] - :367.1264,found:367.1262.

[0347] Example 109: (E)-N-(4-chlorophenethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A103)

[0348] Referring to the synthetic route of A102, 4-chlorophenethylamine (CAS: 156-41-2) was used to replace the raw material 6-1 in Example 108 to obtain compound A103. 1H NMR(500MHz,Chloroform-d)δ13.51(s,1H),12.75(s,1H),7.51(dd,J=9.1,4.2Hz,1H),7.27–7.24(m,4H),7.23–7.18(m,1H),7.16( dd,J=8.6,2.5Hz,1H),3.94(q,J=6.6Hz,2H),3.29(t,J=6.7Hz,2H),2.89(t,J=6.1Hz,2H),2.48(t,J=6.2Hz,2H),2.02–1.96(m,2H). 13 C NMR(126MHz,Chloroform-d)δ166.3,157.6(d,J=240.5Hz),137.3,135.1,133.8(d,J=6.3Hz),132.8,130.1,128.7,1 25.5,124.4(d,J=10.0Hz),119.3(d,J=27.5Hz),114.7(d,J=9.2Hz),104.7(d,J=23.2Hz).HRMS(ESI)m / z:calculated for C 20 H 18 Cl2FN2[MH] - :375.0837,found:375.0838.

[0349] Example 110: (E)-N-(4-bromophenethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A104)

[0350] Referring to the synthetic route of A102, 4-bromophenethylamine (CAS: 73918-56-6) was used to replace the raw material 6-1 in Example 108 to obtain compound A104. 1 H NMR(500MHz,Chloroform-d)δ13.46(s,1H),12.72(s,1H),7.48(dd,J=9.1,4.2Hz,1H),7.42–7.38(m,2H),7.22–7.12 (m,4H),3.93(q,J=6.7Hz,2H),3.26(t,J=6.9Hz,2H),2.87(t,J=6.2Hz,2H),2.50(t,J=6.3Hz,2H),2.03–1.95(m,2H). 13CNMR(126MHz,Chloroform-d)δ166.4,157.6(d,J=240.2Hz),137.2,135.6,133.8(d,J=6.3Hz),131.6,130.4,125.5,124.4(d,J=9.9H z),120.8,119.3(d,J=27.6Hz),114.6(d,J=9.1Hz),104.7(d,J=23.1Hz),46.9,33.6,26.7,22.8,20.6.HRMS(ESI)m / z:calculatedfor C 20 H 17 BrFN2[M-HCl-H] - :383.0565,found:383.0568.

[0351] Example 111: (E)-N-(4-fluorophenethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A105)

[0352] Referring to the synthetic route of A102, 5,6-difluoroindole (CAS: 169674-01-5) was used to replace the raw material 4-1 in Example 108 to obtain compound A105. 1 H NMR(500MHz,Chloroform-d)δ13.39(s,1H),12.90(s,1H),7.31–7.21(m,4H),6.97(t,J=8.6Hz,2H),3.93 (q,J=6.7Hz,2H),3.27(t,J=6.8Hz,2H),2.87(t,J=6.2Hz,2H),2.48(t,J=6.3Hz,2H),2.04–1.94(m,2H). 13 C NMR(126MHz,Chloroform-d)δ165.7,161.5(d,J=246.2Hz),152.7(dd,J=253.9,16.8Hz ),147.2(dd,J=245.1,16.4Hz),136.3(d,J=11.3Hz),134.1,132.3(d,J=3.4Hz),130.2( d,J=8.0Hz),125.5(d,J=3.1Hz),119.8(d,J=8.4Hz),115.4(d,J=21.2Hz),106.7(d,J= 19.0Hz),100.7(d,J=22.5Hz),47.2,33.4,26.5,22.7,20.6.HRMS(ESI)m / z:calculated forC 20 H17 ClF3N2[MH] - :377.1038,found:377.1039.

[0353] Example 112: (E)-N-(4-chlorophenethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A106)

[0354] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 4-chlorophenethylamine (CAS: 156-41-2) to obtain compound A106. 1 HNMR(500MHz,Chloroform-d)δ13.38(s,1H),12.88(s,1H),7.30–7.22(m,6H),3.93(q,J=6.7H z,2H),3.27(t,J=6.9Hz,2H),2.88(t,J=6.2Hz,2H),2.50(t,J=6.3Hz,2H),2.04–1.96(m,2H). 13 C NMR(126MHz,Chloroform-d)δ166.2,153.2(dd,J=253.9,16.9Hz),147.7(dd,J=245.3,15.8Hz),136.8(d,J=10.9Hz),135.5,134.6, 133.2,130.5,129.1,125.9(d,J=3.1Hz),120.3(d,J=8.1Hz),107.2(d,J=19.1Hz),101.1(d,J=22.1Hz).HRMS(ESI)m / z:calculated for C 20 H 17 Cl2F2N2[MH] - :393.0742,found:393.0749.

[0355] Example 113: (E)-N-(4-bromophenethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A107)

[0356] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 4-bromophenethylamine (CAS: 73918-56-6) to obtain compound A107. 1HNMR(500MHz,Chloroform-d)δ13.37(s,1H),12.88(s,1H),7.42–7.36(m,2H),7.29–7.23(m,2H),7.19–7.14(m,2 H),3.93(q,J=6.7Hz,2H),3.25(t,J=6.9Hz,2H),2.88(t,J=6.2Hz,2H),2.51(t,J=6.3Hz,2H),2.04–1.97(m,2H). 13 C NMR(126MHz,Chloroform-d)δ165.7,152.7(dd,J=253.7,16.8Hz),147.2(dd,J=245.3,16.0Hz),136.3(d,J=11.1Hz),135.5,134.2(d,J=5.8Hz),131.6,1 30.4,125.5(d,J=3.2Hz),120.8,119.8(d,J=8.0Hz),106.8(d,J=19.1Hz),100.6(d,J=22.1Hz),46.9,33.6,26.5,22.7,20.6.HRMS(ESI)m / z:calculated for C 20 H 17 BrClF2N2[MH] - :437.0237,found:437.0234.

[0357] Example 114: (E)-N-(4-chlorophenethyl)-5,7,8,9-tetrahydro-6-pyrimido[5,4-b]indole-6-imine (A108)

[0358] Referring to the synthetic route of A102, 5H-pyrrolo[3,2-D]pyrimidine (CAS: 272-50-4) was used to replace the raw material 4-1 in Example 108, and 4-chlorophenylethylamine (CAS: 156-41-2) was used to replace the raw material 6-1 in Example 108 to obtain compound A108. ESI-MS m / z 325.8 [M+H] + .

[0359] Example 115: (E)-(1-((4-chlorophenethyl)imino)-2,3,4,9-tetrahydro-1H-carbazol-7-yl)methanamine (A109)

[0360] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 1H-indole-6-methylamine (CAS: 3468-17-5), and the raw material 6-1 in Example 108 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2) to obtain compound A109. ESI-MS m / z 352.8 [M+H] + .

[0361] Example 116: (E)-N-(2-(5-chloropyridin-2-yl)ethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A110)

[0362] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-(5-chloropyridin-2-yl)ethylamine (CAS: 1060802-15-4) to obtain compound A110. ESI-MS m / z 360.8 [M+H] + .

[0363] Example 117: (E)-N-(2-(1H-indol-5-yl)ethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A111) ESI-MS m / z 364.4 [M+H] + .

[0364] Example 118: (E)-6,7-difluoro-N-(2-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A112)

[0365] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-(1,2,3,4-tetrahydroquinolin-7-yl)ethane-1-amine to obtain compound A112. ESI-MS m / z 380.4 [M+H] + .

[0366] Example 119: 1-(4-chlorophenethyl)thio)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole (A113)

[0367] Referring to the synthetic route of A50, 5,6-difluoroindole (CAS: 169674-01-5) was used to replace the raw material 4-1 in Example 54, and 4-bromophenethylamine (CAS: 73918-56-6) was used to replace the raw material 6-1 in Example 108 to obtain compound A113. ESI-MS m / z 378.8 [M+H] + .

[0368] Example 120: 6,7-difluoro-1-(4-chlorophenethoxy)-2,3,4,9-tetrahydro-1H-carbazole (A114)

[0369] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 1-1 in Example 54 was replaced by p-chlorophenylethanol (CAS: 1875-88-3) to obtain compound A114. ESI-MSm / z 362.4[M+H] + .

[0370] Example 121: 6,7-difluoro-1-(3-(4-chlorophenyl)propyl)-2,3,4,9-tetrahydro-1H-carbazole (A115)

[0371] Referring to the synthetic route of A50, the raw material 4-1 in Example 54 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 1-1 in Example 54 was replaced by 1-chloro-4-propylbenzene (CAS: 52944-34-0) to obtain compound A115. ESI-MS m / z 360.2 [M+H] + .

[0372] Example 122: 3-(4-chlorophenyl)-1-(6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetone (A116)

[0373] ESI-MS m / z 374.8[M+H] + .

[0374] Example 123: 1-((3-(4-chlorophenyl)propyl)sulfonyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole (A117)

[0375] ESI-MS m / z 424.9[M+H] + .

[0376] Example 124: 8-Fluoro-N-(4-chlorophenethyl)-1,2,3,4-tetrahydrodibenzo[b,d]furan-4-amine (A118)

[0377] Referring to the synthetic route of A50, the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2), and the raw material 4-1 in Example 54 was replaced by 5-fluorobenzofuran (CAS: 24410-59-1) to obtain compound A118. ESI-MS m / z 344.4 [M+H] + .

[0378] Example 125: N-(4-chlorophenethyl)-8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]thiophene-4-amine (A119)

[0379] Referring to the synthetic route of A50, the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2), and the raw material 4-1 in Example 54 was replaced by 5-fluorobenzo[b]thiophene (CAS: 70060-12-7) to obtain compound A119. ESI-MS m / z 360.8 [M+H] + .

[0380] Example 126: N-(4-chlorophenethyl)-6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-carbazole-1-amine (A120)

[0381] Referring to the synthetic route of A50, the raw material 1-1 in Example 54 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2), and the raw material 4-1 in Example 54 was replaced by 5-fluoro-1-methyl-1H-indole (CAS: 116176-92-2) to obtain compound A120. ESI-MS m / z 390.1 [M+H] + .

[0382] Example 127: N-(2-(Benzo[d][1,3]-5-dioxolanyl)ethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-amine (A121)

[0383] Referring to the synthetic route of A2, the raw material 2-1 in Example 4 was replaced by piperidine (CAS: 1484-85-1), and the raw material 1-2 in Example 4 was replaced by 3-indolepropionic acid (CAS: 830-96-6) to obtain compound A121. ESI-MS m / z 321.1 [M+H] + .

[0384] Example 128: N-(2-(2,2-Benzo[d][1,3]-5-dioxolanyl)ethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-amine (A122)

[0385] Referring to the synthetic route of A2, 3-indolepropionic acid (CAS: 830-96-6) was used to replace the raw material 1-2 in Example 4 to obtain compound A122. ESI-MS m / z 357.1 [M+H] +

[0386] Example 129: N-(4-chlorophenethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-amine (A123)

[0387] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2), and the raw material 1-2 in Example 1 was replaced by 3-indolepropionic acid (CAS: 830-96-6) to obtain compound A123. ESI-MS m / z 312.1 [M+H] + .

[0388] Example 130: N-(4-chlorophenethyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-6-amine (A124)

[0389] Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 4-chlorophenylethylamine (CAS: 156-41-2), and the raw material 1-2 in Example 1 was replaced by 3-indole valeric acid to obtain compound A124. ESI-MS m / z 312.1 [M+H] + .

[0390] Example 131: (E)-7-Chloro-6-fluoro-N-(2-(naphthalen-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A125)

[0391] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 6-chloro-5-fluoroindole (CAS: 122509-72-2), and the raw material 6-1 in Example 108 was replaced by 2-naphthalene-2-ethylamine (CAS: 2017-68-7) to obtain compound A125. ESI-MS m / z 389.8 [MH] - .

[0392] Example 132: (E)-6,7-difluoro-N-(2-(naphthalen-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A126)

[0393] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-naphthalene-2-ethylamine (CAS: 2017-68-7) to obtain compound A125. ESI-MS m / z 373.4 [MH] - .

[0394] Example 133: (E)-6,7-difluoro-N-(2-(3,4,4a,8a-tetrahydroisoquinolin-2(1H)-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A127)

[0395] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-(3,4-dihydroisoquinolin-2(1H)-yl)ethylamine (CAS: 53356-51-7) to obtain compound A127. ESI-MS m / z 380.5 [MH] - .

[0396] Example 134: (E)-6,7-difluoro-N-(2-(1,3,3a,7a-tetrahydro-2H-isoindol-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A128)

[0397] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-(2,3-dihydro-1H-isoindol-2-yl)ethane-1-amine (CAS: 61695-06-5) to obtain compound A128. ESI-MS m / z 365.4 [MH] - .

[0398] Example 135: (E)-N-(2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A129)

[0399] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethylamine (CAS: 658066-44-5) to obtain compound A129. ESI-MS m / z 426.8 [MH] - .

[0400] Example 136: (E)-6,7-difluoro-N-(2-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-8-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A130) ESI-MS m / z 405.5 [MH] - .

[0401] Example 137: (E)-6,7-difluoro-N-(2-(pyridin-4-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A131)

[0402] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 4-(2-aminoethyl)pyridine (CAS: 13258-63-4) to obtain compound A131. ESI-MS m / z 324.4 [MH] - .

[0403] Example 138: (E)-6,7-difluoro-N-(2-(thiophen-4-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A132)

[0404] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-thiopheneethylamine (CAS: 30433-91-1) to obtain compound A132. ESI-MS m / z 329.2 [MH] - .

[0405] Example 139: (E)-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A133)

[0406] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 4,4-difluoroaminoethylpiperidine (CAS: 605659-03-8) to obtain compound A133. ESI-MS m / z 366.4 [MH] - .

[0407] Example 140: (E)-N-(2-cyclohexylethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A134)

[0408] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-cyclohexylethylamine (CAS: 4442-85-7) to obtain compound A134. ESI-MS m / z 329.4 [MH] - .

[0409] Example 141: (E)-N-(2-cyclopentylethyl)-6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A135)

[0410] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-cyclopentylethylamine (CAS: 5763-55-3) to obtain compound A135. ESI-MS m / z 315.4 [MH] - .

[0411] Example 142: (E)-6,7-difluoro-N-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A136)

[0412] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-methyl-1,3-dioxolane-2-ethylamine (CAS: 62240-37-3) to obtain compound A136. ESI-MS m / z 334.4 [MH] - .

[0413] Example 143: (E)-6,7-difluoro-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A137)

[0414] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 4-(2-aminoethyl)tetrahydropyran (CAS: 65412-03-5) to obtain compound A137. ESI-MS m / z 331.4 [MH] - .

[0415] Example 144: (E)-6,7-difluoro-N-(2-morpholinoethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A138)

[0416] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by N-(2-aminoethyl)morpholine (CAS: 2038-03-1) to obtain compound A138. ESI-MS m / z 332.4 [MH] - .

[0417] Example 145: (E)-6,7-difluoro-N-(2-(2-methylpiperidin-1-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-imine (A139)

[0418] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 2-(2-methyl-1-piperidinyl)ethylamine (CAS: 768-08-1) to obtain compound A139. ESI-MS m / z 344.4 [MH] - .

[0419] Example 146: (E)-tert-butyl 3-(2-((6,7-difluoro-2,3,4,9-tetrahydro-1H-carbazole-1-ylidene)amino)ethyl)piperidine-1-carboxylate (A140)

[0420] Referring to the synthetic route of A102, the raw material 4-1 in Example 108 was replaced by 5,6-difluoroindole (CAS: 169674-01-5), and the raw material 6-1 in Example 108 was replaced by 1-Boc-3-(2-aminoethyl)piperidine (CAS: 259180-77-3) to obtain compound A140. ESI-MS m / z 430.5 [MH] - .

[0421] Pharmacological Activity Test Example

[0422] Pharmacological Example 1. Activity detection of derivatives on TRPM7 channel

[0423] Experimental principle: TRPM7 is a non-selective cation channel. After being opened by voltage stimulation, the pore area of ​​the channel can allow Ca 2+ Mg 2+ , K + 、Na +Divalent and monovalent cations flow across the membrane along the electrochemical potential gradient to form an electric current. After binding to effective small molecule compounds, the protein conformation changes and the current level (amplitude) of the TRPM7 channel changes.

[0424] Experimental steps:

[0425] 1. TRPM7 Stable Cell Culture

[0426] TRPM7-HEK293 stable transfected cells (Center for Neuropsychiatric Diseases, Shanghai Institute of Materia Medica)

[0427] Culture medium formula: 90% DMEM basal medium (Gibco), 10% fetal bovine serum (Fetal bovine Fetalbovine serum), 1% antibiotics (penicillin-streptomycin), hygromycin B (Hygromycin B, 100 μg / mL) and blasticidin S HCl (Blasticidin S HCl, 5 μg / mL). Cell culture was carried out in a sterile environment with saturated humidity at 37°C, 5% CO2, and 0.25% trypsin was used for digestion, passage and plating. TRPM7 stable transfected cells were induced to express TRPM7 using doxycycline hyclate (Doxycycline hyclate, 0.3 μg / mL), and manual electrophysiological recording was performed 24 hours later.

[0428] 2. TRPM7 channel current recording and compound activity detection

[0429] Electrophysiological recordings were performed using an Axopatch 700B patch clamp amplifier (Molecular Devices). Electrodes were drawn from borosilicate glass capillaries (World Precision Instruments), and the electrode resistance was 1.5 to 3 MΩ after intracellular solution was perfused. Recordings were performed at room temperature, and compound solutions were perfused using a perfusion drug delivery system (ALA, USA) until the current stabilized.

[0430] Extracellular fluid formula: 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 20 mM HEPES, 10 mM glucose (NaOH adjusted to pH = 7.4).

[0431] Intracellular solution formula: 145 mM CsCl, 8 mM NaCl, 10 mM HEPES, 10 mM EGTA (CsOH adjusted to pH = 7.2).

[0432] Use DMSO to prepare a 20mM compound stock solution, refrigerate at -20℃, and dilute it with extracellular fluid to the test concentration in the experiment (the volume percentage of DMSO in the test concentration is 0.1%). In the electrophysiological recording, the cells are clamped at 0mV, and a ramp voltage (-100mV~+100mV 300ms) is given to stimulate. After the current stabilizes, the compound solution is given through the perfusion drug delivery system, and the changes in the TRPM7 channel current amplitude at +100mV before and after the drug administration are recorded.

[0433] 3. Experimental results analysis

[0434] Electrophysiological data were analyzed using Clampfit 10.2 (Molecular Devices) and GraphPad Prim 5 (GraphPad Sofware), and the dose-effect curves were fitted using the Hill equation. Drug / I Control is the inhibitory strength of the compound, I Control is the current value before drug administration, I Drug is the current value after drug administration, inhibition rate % = (1-I Drug / I Control )×100%. All experimental data are expressed as mean±SEM.

[0435] Table 1: Activity data of some compounds a

[0436]

[0437]

[0438] a “ / ” means not tested.

[0439] Experimental conclusion: From the above experimental results, it can be seen that this series of compounds has a good inhibitory effect on TRPM7. Among them, 34 compounds have an inhibition rate of more than 80% at a concentration of 10μM. Compounds A15, A51, A52, A53, A81, A82, A83, A101, A102, A103, A104, A106, and A107 still showed strong TRPM7 inhibitory activity at a concentration of 500nM, with an inhibition rate of more than 50%. Further dose-effect curve test results showed that compounds A15, A82, and A83 have a strong inhibitory effect on TRPM7 channels, and their IC 50 The values ​​were 0.22μM, 0.26μM and 0.27μM respectively. Compound A106 showed the strongest TRPM7 channel inhibitory activity, IC 50The above results show that this type of tetrahydrocarbazole derivatives has good prospects in the prevention, treatment or auxiliary treatment of various diseases related to TRPM7, such as tumors, nervous system diseases, immunity and inflammation, and cardiovascular diseases.

[0440] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of the structure represented by general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof: in, X is selected from the group consisting of O, S or NR 3 ; Y is selected from the following group: O, S, C=O, SO2, N, CR 4 or NR 4 ; m and n are each independently selected from the group consisting of 0, 1, 2, 3 or 4; R 1 For 1, 2, 3 or 4 substituents on the ring, and the R 1 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10 Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amine group, NH2, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group, or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 1 The group can form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring with the atoms to which it is connected, and the carbocyclic or heterocyclic ring can be saturated or partially unsaturated; R 2 For 1, 2, 3 or 4 substituents on the ring, and the R 2 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched chain alkyl, substituted or unsubstituted C2~C 10 Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amine group, NH2, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group, or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 2 The group can form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring with the atoms to which it is connected, and the carbocyclic or heterocyclic ring can be saturated or partially unsaturated; The ring is selected from the following groups: substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl; and when the A ring is phenyl, the R 1 At least one of the groups is not H; preferably, the A ring is selected from a substituted or unsubstituted fragment selected from the following group: The ring is selected from the following groups: substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl; preferably, the B ring is selected from substituted or unsubstituted fragments selected from the following group: Among them, each of the above X 2 and X 3 Each independently selected from the following group: O, S, C=O, CHR 5 or NR 5 ; X 4 Selected from the following group: N, CR 5 ; R 3 , R 4 and R 5 Each of them is independently selected from the following group: hydrogen, C1-C6 alkylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with aryl or heteroaromatic ring, C1-C6 alkyl substituted with cycloalkane or heterocyclic group, C3-C8 saturated or partially unsaturated carbocyclic group, C3-C8 halogenated saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered heterocyclic group; The bond is a single bond or a double bond; wherein the heteroaryl or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; Unless otherwise specified, the substitution means that the corresponding group is substituted by 1 to 3 substituents selected from the following groups: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group and 5- to 12-membered heteroaryl; The halogen is F, Cl, Br or I; the cycloalkane, heterocyclic group, aryl or heteroaryl is a monocyclic ring, a condensed ring, a spirocyclic ring or a bridged ring; the aryl or heteroaryl is a monocyclic ring or a condensed ring; the heterocyclic group or heteroaryl has one or more heteroatoms selected from the following group: N, S or O.

2. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The compound has a structure shown in the following formula Ia or Ib: 。 3. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The compound has a structure shown in the following formula Ic or Id: Wherein, Y1, Y2, Y3, and Y4 are each independently selected from the following group: N or CH, and the H on the CH can be replaced by R 2 Replacement (in which case the CH is C).

4. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: R 1 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10 Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-10 membered heterocyclic group, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, NH2, substituted or unsubstituted C1-C6 alkyl-NH-, substituted or unsubstituted C1-C6 alkyl)2-N-, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 1 The group can form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring with the atoms to which it is connected, and the carbocyclic or heterocyclic ring can be saturated or partially unsaturated; R 2 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, thiol, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched chain alkyl, substituted or unsubstituted C2~C 10 Straight-chain or branched alkoxy, C2-C6 straight-chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amino group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein two adjacent R 2 The group and the atoms to which it is attached may together form a 5-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring, and the carbocyclic or heterocyclic ring may be saturated or partially unsaturated.

5. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The A ring is a substituted or unsubstituted group selected from the following group:

6. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The A ring is a substituted or unsubstituted group selected from the following group: in, The substitution refers to that the corresponding group is replaced by 1 to 3 substituents selected from the following groups: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, phenyl, 5-7 membered saturated or partially unsaturated heterocyclic group, and 5-7 membered heteroaryl.

7. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The compound is selected from the following group:

8. A pharmaceutical composition, characterized in that The invention comprises (1) the compound according to the first aspect of the present invention, its racemate, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.

9. Use of the compound according to claim 1, its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, characterized in that: Used for preparing the prevention and / or treatment of indications related to abnormally increased TRPM7 activity or abnormally increased expression.

10. The use according to claim 9, characterized in that The indications are selected from the following groups: tumors, nervous system diseases, immunity and inflammation, cardiovascular diseases; preferably, the tumors are selected from the following groups: breast cancer, pancreatic cancer, gastric cancer, lung cancer, ovarian cancer, bladder cancer, neuroblastoma, glioblastoma; and the nervous system diseases are selected from the following groups: Alzheimer's disease, epilepsy; the cardiovascular and cerebrovascular diseases are selected from the following groups: stroke, myocardial fibrosis.

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