Pyrrolizine [2, 3-c] quinoline derivative as well as synthesis method and application thereof

Abstract

The invention provides a plurality of pyrrolizine [2, 3-c] quinoline derivatives, and a preparation method and an application of the pyrrolizine [2, 3-c] quinoline derivatives. The pyrrolizino [2, 3-c] quinoline derivative, and the pharmaceutically acceptable salt, solvate, hydrate or crystal form thereof provided by the invention have a remarkable inhibition effect on various cancer cells, and have an application prospect in preparation of antitumor drugs.

Description

Technical Field

[0001] The present invention relates to various pyrrolizino[2,3-c]quinoline derivatives, their preparation methods, and the field of pharmaceutical compositions for treating various tumors. Background Art

[0002] The tetrahydropyrrolizino[2,3-c]quinoline alkaloid compound (Bungeanoline G) is a novel natural product isolated from the plant Corydalis bungeana Turcz. of the genus Corydalis in the Papaveraceae family, and has a unique 6 / 6 / 5 / 5 tetracyclic fused tetrahydropyrrolizino[2,3-c]quinoline skeleton. Research has found that Bungeanoline G has significant dual inhibitory activities against acetylcholinesterase and butyrylcholinesterase, and may be used to treat or improve diseases such as Alzheimer's disease, vascular dementia, and myasthenia gravis. Due to the extremely low natural content of Bungeanoline G and few known natural analogs thereof, in-depth chemical and biological studies on such compounds have rarely been reported.

[0003] Structural modification of natural products is a very useful method for preparing new bioactive compounds in current drug discovery. In view of the novel 6 / 6 / 5 / 5 tetracyclic fused tetrahydropyrrolizino[2,3-c]quinoline skeleton structure of Bungeanoline G, the present invention has carried out diverse structural derivatizations on it. Pharmacological activity tests show that among these derivatives, many have good bioactivities against the proliferation of various tumor cells and can be used in the preparation of drugs for treating or improving various malignant tumor diseases. Summary of the Invention

[0004] One of the objectives of the present invention is to provide various pyrrolizino[2,3-c]quinoline derivatives and their preparation methods, which are suitable for the preparation of various anti-tumor pharmaceutical compositions.

[0005] One of the advantages of the present invention is that the pyrrolizino[2,3-c]quinoline derivatives proposed by the present invention have obvious anti-tumor proliferation activities. In particular, pyrrolizino[2,3-c]quinoline derivatives with various amino groups generally exhibit better anti-tumor proliferation activities and selectivity for tumor cells, and they have the potential to be used as drug active ingredients for the treatment of various cancer diseases.

[0006] Another advantage of the present invention is that the preparation method of the pyrrolizino[2,3-c]quinoline derivatives proposed by the present invention is simple and fast, and the yields of some compounds are very high, which is conducive to process scale-up production.

[0007] As shown in the experimental part of the present invention, on a variety of tumor cell models, most of the compounds of the present invention have anti-tumor proliferation activity, and the activity IC of some compounds 50 even reaches the level of ten nanomolar value, and has a certain selectivity for tumor cells. Therefore, in some aspects, the compounds of the present invention exhibit broad-spectrum anti-tumor proliferation activity and can be used for the treatment of a variety of cancers, such as ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, colorectal cancer, liver cancer, leukemia, skin cancer, epithelial cell cancer, prostate cancer, bladder cancer, kidney cancer, nasopharyngeal cancer, thyroid cancer, malignant glioma, pancreatic cancer, lymphoma or melanoma and other diseases.

[0008] The pyrrolizino[2,3-c]quinoline derivatives proposed by the present invention include one or two or more of the compounds shown in the following general structural formulas I and II and their pharmaceutically acceptable salts, solvates, hydrates or crystalline compounds:

[0009]

[0010] Among them,

[0011] R1 is one or two or more of -NH2, R1'-NH- or R1'R1”N- substituted at any position on the phenyl group (at 4 positions where substituents can be carried); among them, R1' refers to substituted or unsubstituted C 1-5 alkyl, and R1” refers to substituted or unsubstituted C 1-3 alkyl; or R1', R1” and N in R1'R1”N- form a 4-, 5- or 6-membered ring structure;

[0012] R2 is one or two or more of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, R2'R2”N-; among them, R2' and R2” each independently refer to one or two or more of H, substituted or unsubstituted C 1-5 alkyl, or substituted or unsubstituted aryl; or, R2' and R2” form a 4-, 5- or 6-membered ring structure;

[0013] R3 is H, F, Cl, Br, I, amino group, aldehyde group, acetyl group, substituted or unsubstituted C 1-3 alkyl;

[0014] n is 1 or 2; preferably n is 1.

[0015] In some embodiments, R1 of Compound I is one or more of -NH2, R1'-NH-, or R1'R1''N- substituted at any position on the phenyl group; wherein, R1' refers to a substituted or unsubstituted C 1-5 alkyl group, and R1'' refers to a substituted or unsubstituted C 1-3 alkyl group. Here, the substituent refers to -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C≡CH, -CH=CH2 substituted at any position on the C 1-5 alkyl group or C 1-3 alkyl group; or in some cases, R1', R1'', and N form one or more of 4-, 5-, or 6-membered ring structures; further, R1 of Compound I is one or more of -NH2, R1'-NH-, R1'-NCH3-, or R1'-NCH2CH3- substituted at any position on the phenyl group, wherein, R1' refers to a substituted or unsubstituted C 1-5 alkyl group. Here, the substituent refers to -OH, -NHCH3, -N(CH3)2, -C≡CH substituted at any position on the C 1-5 alkyl group; or, R1', R1'' and N form Preferably, R1 of Compound I is one or more of CH3NH-, CH3CH2NH-, CH3CH2CH2NH-, CH3CH2CH2CH2NH-, HOCH2CH2NH-, HC≡CCH2NH-, (CH3)2NCH2CH2NH-, (CH3)2N- among others.

[0016] In some embodiments, R2 of Compound II is one or more of H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy R2'R2''N- among others, wherein, R2' and R2'' each independently refer to one or more of H, a substituted or unsubstituted C 1-5 alkyl group, a substituted or unsubstituted aryl group, or in some cases, R2', R2'', and N form one or more of 4-, 5-, or 6-membered ring structures; here, the aryl group refers to phenyl, thienyl, furyl, pyridyl, and the substituent refers to on the C 1-5-OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH3), -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2, -N(CH3)(CH2CH2NHCH3), -N(CH3)(CH2CH2N(CH3)2), Ar, which are substituted at any position of an alkyl or aryl group wherein Ar refers to one or two or more of phenyl, thienyl, furyl, pyridyl, pyrrolyl which are optionally connected, X refers to one or two or more of -CH2-, -CHCH3-, -NCH3-, -NCH2CH3-, -O-, Y is one or two or more of H, -CH3 or -CH2CH3, n' is 0, 1 or 2, and when n' is 0, X can only be one or two of -CH2- or -CHCH3-; further, R2 of compound II is H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH2, R2'-NH-, R2'-NCH3- or R2'-NCH2CH3- which are one or two or more of them; wherein R2' refers to one or two or more of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, substituted C 1-5 alkyl, substituted phenyl; herein, the substituent refers to -OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3) which are substituted at any position of an alkyl or phenyl group 1-5 or one or two or more of them; in some cases, R2', R2” and N form

[0017] one or two or more of them; further still, R2 of compound II is H, Br, methyl, methoxy which are substituted at any position of a phenyl group

[0018] R2'-NH- or R2'R2”N- which are one or two or more of them, wherein R2' refers to one or two or more of methyl, ethyl, propyl, butyl, or substituted C alkyl; herein, the substituent refers to -OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3) which are substituted at any position of an alkyl or phenyl group 1-5 alkyl; herein, the substituent refers to -OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3) which are substituted at any position of an alkyl or phenyl group 1-5-OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3), etc. which are substituted at the terminal position far away from -NH- or -R2”N- of the alkyl group

[0019] one or two or more of the above; preferably, R2 of compound II is H, Br, methyl, methoxy, etc. which are substituted at any position on the phenyl group one or two or more of R2'-NH-, where R2' refers to one or two or more of methyl, ethyl, propyl, butyl, or substituted C 1-4 alkyl group, herein, the substituent refers to -OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3), etc. which are substituted at the terminal position far away from -NH- of the C 1-4 alkyl group one or two or more of the above; in some cases, R2', R2” and N form one or two or more of the above.

[0020] In some embodiments, R3 of compound II is one or two or more of H, F, Cl, Br, I, -NH3, -CHO, -COCH3, substituted or unsubstituted C 1-3 alkyl group, herein, the substituent refers to -OH, -NH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2, etc. which are substituted at any position of the C 1-3 alkyl group; further, R3 of compound II is one or two or more of H, Br, -CHO, -COCH3, -CH2OH, -CHOHCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)2, -CH2NHCH2CH2NHCH3, -CH2NHCH2CH2N(CH3)2; preferably, R3 of compound II is one or two or more of H, Br, -CHO, -CH2OH, -CHOHCH3, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2NHCH2CH2N(CH3)2.

[0021] In some preferred embodiments, Compound I and II have one or two or more of the following structures:

[0022]

[0023]

[0024]

[0025] In some embodiments, Compound I or II described above may form salts with pharmaceutically acceptable acids, and these acids refer to one or more of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, acetic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, citric acid, camphorsulfonic acid, malic acid, benzoic acid, gluconic acid.

[0026] In the general formula compounds I and II, the appropriate groups R1, R2, R3 and n, if applicable, are independently selected. The embodiments described in the present invention can be combined, and such combinations are still within the protection scope of the present invention.

[0027] In the compounds according to the present invention, the term "C 1-3 alkyl", "C 1-4 alkyl", "C 1-5 alkyl", "alkyl" itself or as part of other groups refers to straight-chain, branched-chain or cyclic aliphatic hydrocarbons. For example: methyl, propyl, isopropyl, tert-butyl, pentyl, cyclohexyl, etc.

[0028] The term "C 1-3 alkoxy" represents a straight-chain or branched-chain alkyl C 1-3 having 1 to 3 carbon atoms and bonded through an oxygen atom. The following are examples that can be mentioned: methoxy, ethoxy, propoxy, isopropoxy.

[0029] Unless specifically mentioned as having conflicts, in the present invention, the combination of substituents and / or variables refers to chemically allowed situations that can produce stable compounds. A "stable" compound is one that can be prepared, isolated, and whose structure and properties remain unchanged for a period of time sufficient to be used for some of the purposes described in the present invention (for example, administering to a subject in need of treatment).

[0030] The compounds of the present invention may contain carbon or nitrogen atoms with asymmetric R or S configurations. The compounds of the present invention are not limited to specific stereoisomers. For example, in some embodiments, the compounds described in the present invention include mixtures of diastereoisomers in any ratio, diastereoisomer monomers, mixtures of enantiomers in any ratio, enantiomer monomers, and one or more of their pharmaceutically acceptable salts, solvates, hydrates or various crystal forms.

[0031] The pyrrolizino[2,3-c]quinoline derivatives of the present invention have excellent tumor inhibitory activity and can be used as active pharmaceutical ingredients for preparing therapeutic drugs for various cancers or for use in inhibiting the proliferation process or substances of tumor cells. The cancers described in the present invention are generally one or more of ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, colorectal cancer, liver cancer, leukemia, skin cancer, epithelial cell cancer, prostate cancer, bladder cancer, kidney cancer, nasopharyngeal cancer, thyroid cancer, malignant glioma, pancreatic cancer, lymphoma or melanoma.

[0032] The present invention also relates to a pharmaceutical composition comprising one or more of the above-mentioned pyrrolizino[2,3-c]quinoline derivatives. In other words, one or more of the compounds of formula I, compounds of formula II or their pharmaceutically acceptable salts, solvates, hydrates or crystal form compounds according to the present invention can be used as pharmaceutically active substances, especially as anti-tumor drugs, for preparing pharmaceutical preparations containing at least one of the said compounds.

[0033] The compounds according to the present invention or salts formed with pharmaceutically acceptable acids can be made into appropriate galenical dosage forms according to acceptable pharmaceutical procedures, such as oral, injection, spray administration compositions, etc. The pharmaceutical composition according to the present invention contains an effective amount of the compound of the present invention, as well as suitable pharmaceutically acceptable carriers or diluents, which are well known in the art. The carrier can be any inert raw material, organic or inorganic, suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum arabic, lactose, microcrystalline cellulose starch, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silica, etc. The composition may also contain other pharmaceutically active agents and conventional additives, such as stabilizers, wetting agents, emulsifying agents, flavoring agents, buffering agents, etc.

[0034] The composition according to the present invention can be made into solid or liquid dosage forms for oral administration, such as tablets, capsules, powders, syrups; made into sterile solutions, suspensions or emulsion dosage forms for parenteral administration; made into dry powder preparations, sterile solutions, suspensions or emulsion dosage forms for spray administration.

[0035] As described above, the compounds or compositions can be used for the treatment of various cancers. The dosage of a specific compound will vary depending on its potency, the mode of administration, the age and weight of the patient, and the severity of the condition being treated.

[0036] Schedule description: Table 1, inhibitory activities of some Compound I against HepG2 cells; Table 2, half-inhibitory concentration IC 50 value. Description of the Drawings

[0037] Figure 1 Inhibitory activities of Compound I against HepG2 cells at 1.0 and 10.0 μM, with 5-FU (50 μM) as the positive compound.

[0038] Figure 2 Inhibitory activities of Compound II against HepG2 cells at 1.0 and 10.0 μM, with 5-FU (50 μM) as the positive compound.

[0039] Figure 3 Inhibitory activities of some highly active compounds against human normal liver cells L02 cells, with 5-FU (50 μM) as the positive compound.

[0040] Figure 4 In vivo antitumor activities of Compound II-23, II-29, II-30 in a human breast cancer MCF-7 xenograft nude mouse model, with 5-FU as the positive compound. Detailed Description of the Invention

[0041] Experimental Section

[0042] General Methods

[0043] Referring to similar literature reports or the specific examples shown below, experienced researchers can easily select the appropriate reaction conditions for the described chemical reactions. The starting materials necessary for such reactions can be purchased or prepared by oneself according to conventional methods. The 1 H, 13 C-NMR spectra were acquired on a Brucker AVANCE III 400 MHz instrument, and the resulting spectra were referenced to tetramethylsilane (TMS) as an internal standard. Liquid chromatography-mass spectrometry (LC-MS) analysis was performed on a Waters Alliance e2695-ZQ2000 system, reporting m / z values and relative abundances. Unless otherwise noted, all solvents were used directly. The ratios of all mixed solvents refer to volume ratios (v / v). All temperatures are in degrees Celsius (°C).

[0044] The following non-limiting examples and pharmacological experiments will further illustrate the present invention.

[0045] The present invention further relates to a method for preparing the above compounds. The preparation method is as follows:

[0046] Under the conditions disclosed in the present invention, an experienced researcher can easily prepare the compounds represented by general formulas I and II. In particular, according to the present invention, the following methods are provided:

[0047] Synthesis method 1

[0048]

[0049] Reaction A

[0050] Dissolve compound SM1 (1.0 mmol, 1.0 molar equivalent) in acetic acid (5 ml), add NBS (1.0 molar equivalent relative to SM1) at 0 °C, stir at room temperature for 1.0 h, add saturated sodium sulfite solution to the reaction solution until the color of the reaction solution changes from reddish-brown to yellow. Rotate the reaction solution to dryness, add saturated sodium carbonate solution until pH = 7.5, extract with dichloromethane three times (5 - 10 ml each time), collect the organic phase and concentrate to remove the solvent, and purify the crude product by column chromatography to obtain the target product SM2.

[0051] Reaction B

[0052] Dissolve SM2 (1.0 mmol, 1.0 molar equivalent) and substrate amine (3.0 molar equivalents relative to SM2) in dioxane (10 ml), add Pd2(dba)3 (0.1 molar equivalent relative to SM2), BINAP (0.2 molar equivalent relative to SM2), and sodium tert-butoxide (3.0 molar equivalents relative to SM2), protect with nitrogen, and stir at 90 °C for 16 h. After TLC detection is complete, cool the reaction solution to room temperature, filter, concentrate the filtrate, and purify by column chromatography to obtain the target product I.

[0053] Synthesis method 2

[0054]

[0055] Here, R4 refers to one or more of H, methyl, ethyl, methoxy, ethoxy, F, Cl, Br, and hydroxyl groups substituted at any position of the phenyl group; in reaction F, -NHR3’ is part of R3 defined in claim 4.

[0056] Reaction C

[0057] Dissolve SM3 (1.0 mmol, 1.0 molar equivalent) in toluene (10 ml), add MnO2 (5.0 molar equivalents relative to SM3), and reflux and stir at 110 °C for 16 h. After TLC detection shows that the reaction is complete, cool the reaction solution to room temperature, filter, concentrate the filtrate, and purify by column chromatography to obtain the target product II-a.

[0058] Reaction D

[0059] Dissolve II-a (1.0 mmol, 1.0 molar equivalent) in acetic acid (10 ml), add hexamethylenetetramine (1.2 molar equivalents relative to II-a), and heat to 100 °C with stirring for 36 h. After detecting the completion of the reaction by LCMS, concentrate the reaction solution to remove acetic acid, adjust to pH = 7.5 with saturated sodium carbonate solution, extract three times with dichloromethane (10 ml each time), combine the organic phases, dry and concentrate, and purify by column chromatography to obtain the target product II-b.

[0060] Reaction E

[0061] Dissolve II-b (1.0 mmol, 1.0 molar equivalent) in methanol (10 ml), add sodium borohydride (1.0 molar equivalent relative to II-d) under ice bath, and stir at room temperature for 0.5 h. After detecting the completion of the reaction of the starting materials by TLC, add 1.0 N hydrochloric acid (2.0 ml) to the reaction solution, adjust to pH = 7.5 with saturated sodium carbonate solution, extract three times with dichloromethane (10 ml each time), combine the organic phases, dry and concentrate, and purify the organic phase by column chromatography to obtain the product II-c.

[0062] Reaction F

[0063] Dissolve II-b (1.0 mmol, 1.0 molar equivalent) in methanol, add the substrate amine R3’NH2 (3.0 molar equivalents relative to II-b), stir at room temperature for 0.5 h, add sodium cyanoborohydride (3.0 molar equivalents relative to II-b), and stir at room temperature for 18 h. After detecting the completion of the reaction by TLC, adjust the reaction solution to pH = 7.0 - 8.0 with saturated sodium carbonate solution, extract three times with dichloromethane (10 ml each time), combine the organic phases, dry and concentrate, and purify by column chromatography to obtain the target product II-d.

[0064] Reaction G

[0065] Dissolve II-b (1.0 mmol, 1.0 molar equivalent) in tetrahydrofuran (10 ml), add methylmagnesium bromide (3.0 molar equivalents relative to II-b) under ice bath, and stir at room temperature for 18 h. After detecting the completion of the reaction of the starting materials by TLC, adjust the reaction solution to pH = 7.5 with saturated sodium carbonate solution, extract three times with dichloromethane (10 ml each time), combine the organic phases, dry and concentrate, and purify by column chromatography to obtain the target product II-e.

[0066] Synthesis Method 3

[0067]

[0068] Reaction H

[0069] Dissolve SM2 (1.0 mmol, 1.0 molar equivalent) in toluene (10 ml), add MnO2 (5.0 molar equivalents relative to SM2), and stir under reflux at 110 °C for 16 h. After the reaction is detected to be complete by TLC, the reaction solution is cooled to room temperature, filtered, and the filtrate is concentrated to obtain the target product II-f.

[0070] Reaction I

[0071] Dissolve II-f (1.0 mmol, 1.0 molar equivalent) and the substrate amine (3.0 molar equivalents relative to II-f) in dioxane (10 ml), add Pd2(dba)3 (0.1 molar equivalent relative to II-f), BINAP (0.2 molar equivalent relative to II-f), and sodium tert-butoxide (3.0 molar equivalents relative to II-f), protect with nitrogen, and stir at 90 °C for 16 h. After the reaction is detected to be complete by TLC, the reaction solution is cooled to room temperature, filtered, and the filtrate is concentrated and purified by column chromatography to obtain the target product II-g.

[0072] Synthesis method 4

[0073]

[0074] Here, R4 refers to one or more of H, methyl, ethyl, methoxy, ethoxy, F, Cl, Br substituted at any position of the benzene ring;

[0075] Reaction J

[0076] Dissolve SM3 (1.0 mmol, 1.0 molar equivalent) in acetic acid (10 ml), dropwise add a solution of liquid bromine (3.0 molar equivalents relative to SM3) in acetic acid at 0 °C, heat to 65 °C and stir for 12 h, and detect the completion of the reaction by LCMS. Add saturated sodium bisulfite solution (8 ml) to the reaction solution to quench the reaction, then adjust to pH = 7.5 with saturated sodium carbonate solution, extract with ethyl acetate three times (10 ml each time), combine the organic phases, dry and concentrate, and purify by column chromatography to obtain the target product II-h.

[0077] Synthesis method 5

[0078] When compound I or II forms a salt with a pharmaceutically acceptable acid (HX) (these acids refer to various pharmaceutically acceptable acids, such as: hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, acetic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, citric acid, camphorsulfonic acid, malic acid, benzoic acid, gluconic acid, one or more of them), the synthesis method is as follows:

[0079] Dissolve substrate I or II (1.0 mmol, 1.0 molar equivalent) in dry tetrahydrofuran and / or dichloromethane and / or ethyl acetate and / or dioxane (1.0 mmol of substrate is dissolved in 10 ml), add various pharmaceutically acceptable acids (1.0 mmol), stir for 1.0 h, and then concentrate by rotary evaporation to remove the solvent to obtain the corresponding acid salt.

[0080] Alternatively, the product resolution method in the above synthesis methods 1-5

[0081] When compound I or II is a chiral monomer, the racemate can be resolved by chiral chromatography:

[0082] Dissolve the racemic compound I or II in methanol, and separate and purify it by supercritical fluid chromatography through a BH (chiral) chromatographic column. The mobile phase A is CO2, B is triethylamine-methanol (volume concentration 0.1% - 2%), the A / B ratio is in the range of 80 / 20, the elution time is 0 - 20 minutes, isocratic elution, and collect according to the chromatographic peaks to obtain the chiral monomer.

[0083] The following non-limiting examples and pharmacological experiments will further illustrate the present invention. Unless otherwise specified, the compounds are racemates or mixtures of diastereoisomers.

[0084] The following examples are intended to illustrate the present invention rather than further limit the present invention, and the present invention can be implemented in any manner described in the invention content.

[0085] The starting materials SM1 and SM3 used in the synthesis method of the examples of the present invention are synthesized as follows:

[0086] Synthesis method 6

[0087]

[0088] Here, R4 refers to one or more of H, methyl, ethyl, methoxy, ethoxy, F, Cl, Br substituted at any position of the benzene ring; wherein, when R4 is all H, the product is SM1, and when R4 is not all H, the product is SM3;

[0089] Reaction K

[0090] Dissolve substrate 1 (1 mmol, 1.0 molar equivalent) in THF (10 ml), and then add substrate 2 (1.5 molar equivalents relative to substrate 1), Pd(PPh3)2Cl2 (0.03 molar equivalents relative to substrate 1), CuI (0.03 molar equivalents relative to substrate 1), PPh3 (0.03 molar equivalents relative to substrate 1), and triethylamine (2 molar equivalents relative to substrate 1). Stir to dissolve at room temperature. After replacing the reaction system with a nitrogen atmosphere, heat to 60 °C and continue stirring for 12 hours. After monitoring the reaction to completion by LC-MS, cool the reaction solution to room temperature, filter, concentrate the filtrate by rotary evaporation, and purify the concentrate by silica gel column chromatography to obtain product 3 (as substrate 3).

[0091] Reaction L

[0092] Dissolve substrate 3 (1 mmol, 1.0 molar equivalent) in acetone (15 ml), and successively add water (5 ml), mercuric sulfate (1.5 molar equivalents relative to substrate 3), and concentrated sulfuric acid (98% mass concentration, 2 molar equivalents relative to substrate 3) with stirring. Stir at 30 °C for 72 hours. After monitoring the reaction to completion by LC-MS, add saturated sodium carbonate solution to the reaction solution to neutralize the sulfuric acid to pH 8, extract with ethyl acetate (10 ml of ethyl acetate each time) 3 times, dry the organic phase with anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by silica gel column chromatography to obtain the corresponding product 4 (as substrate 4).

[0093] Reaction M

[0094] Dissolve substrate 4 (1 mmol, 1.0 molar equivalent) in methanol (10 ml), add acetic acid (4 molar equivalents relative to substrate 4) and benzylamine (4 molar equivalents relative to substrate 4), stir and react at 25 °C for 8 hours, then add sodium cyanoborohydride (4 molar equivalents relative to substrate 4), and stir at 25 °C for 16 hours. Add water (10 ml) to the reaction solution and stir for 0.5 hour, wash with ethyl acetate (10 ml of ethyl acetate each time) 3 times, discard the organic phase, add concentrated hydrochloric acid (38% mass concentration) dropwise to the aqueous phase to adjust the pH to 2, add palladium on carbon (specification 10 wt%, 0.2 mass equivalents relative to substrate 4), and stir at 25 °C under normal pressure in hydrogen for 16 hours. Add saturated sodium carbonate solution to the reaction solution to pH 8, extract with ethyl acetate (10 ml of ethyl acetate each time) 3 times, dry the organic phase with anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by silica gel column chromatography to obtain the target product I.

[0095] Reaction N

[0096] Dissolve substrate 4 (1 mmol, 1.0 molar equivalent) in methanol (10 ml), add acetic acid (4 molar equivalents relative to substrate 4) and p-methoxybenzylamine (4 molar equivalents relative to substrate 4), stir at 25 °C for 2 hours, add sodium cyanoborohydride (4 molar equivalents relative to substrate 4), and stir at 25 °C for 16 hours. Remove methanol under reduced pressure from the reaction solution, add saturated sodium carbonate solution until the pH is 8, extract with ethyl acetate (10 ml each time) 3 times, dry the organic phase over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by silica column chromatography to obtain the corresponding product 5 (as substrate 5).

[0097] Reaction O

[0098] Dissolve substrate 5 (1 mmol, 1.0 molar equivalent) in acetonitrile (5 ml) and water (20 ml), add 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.5 molar equivalents relative to substrate 5), heat to 70 °C and stir for 12 hours. Remove acetonitrile under reduced pressure from the reaction solution, add 2N hydrochloric acid (5 ml) and an equal volume of ethyl acetate, separate the layers, extract the organic phase with 2N hydrochloric acid (5 ml each time) 3 times, discard the organic phase, combine the acidic aqueous phases, adjust the pH to 8 with saturated sodium carbonate solution, extract with ethyl acetate (5 ml each time) 3 times, dry the organic phase over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by silica column chromatography to obtain the target product SM1 or SM3.

[0099] The synthetic routes of compounds SM1-1, SM1-2, SM2-1, SM2-2, SM2-3, and SM3-1 are as follows:

[0100]

[0101] Synthesis of 4-chloro-3-(5-chloropent-1-yn-1-yl)quinoline (3')

[0102] According to the steps and conditions described in Reaction K of Synthetic Method 6 of the above general formula compounds, using 4-chloro-3-bromo-quinoline (1') and 5-chloropent-1-yne (2') as substrates, the target product 3' can be obtained with a yield of 85%. 1 1H-NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.22 (dd, J = 8.4, 0.9 Hz, 1H), 8.09 (dd, J = 8.4, 0.5 Hz, 1H), 7.74 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.65 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 3.80 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.15 (p, J = 6.6 Hz, 2H). MS [M+H] + m / z 264.06

[0103] Synthesis of 5-chloro-1-(4-chloroquinolin-3-yl)pentan-2-one (4')

[0104] According to the steps and conditions of Reaction L in the general formula compound synthesis method 6 above, using 3' as the substrate, the target product 4' can be obtained with a yield of 57%. 1 H-NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.78 (t, J = 7.0 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 4.11 (s, 2H), 3.60 (s, 2H), 2.82 (t, J = 6.2 Hz, 2H), 2.21–2.04 (m, 2H). MS [M+H] + m / z 282.00

[0105] Synthesis of 7a,8,9,10-tetrahydro-7H-pyrrolizino[2,3-c]quinoline (SM1-1)

[0106] According to the steps and conditions of Reaction M in the general formula compound synthesis method 6 above, using 4' as the substrate, the target product SM1-1 can be obtained with a yield of 27%. 1 H-NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.00 (t, J = 11.4 Hz, 1H), 7.93 (dd, J = 8.4, 0.9 Hz, 1H), 7.59 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.38 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 4.29–4.18 (m, 1H), 3.91 (ddd, J = 10.1, 5.7, 3.3 Hz, 1H), 3.55–3.43 (m, 1H), 3.30 (dd, J = 15.9, 10.3 Hz, 1H), 3.15 (dd, J = 15.9, 4.3 Hz, 1H), 2.12–1.93 (m, 3H), 1.47–1.37 (m, 1H). MS [M+H] + m / z 211.12

[0107] Synthesis of 2-bromo-7a,8,9,10-tetrahydro-7H-pyrrolizino[2,3-c]quinoline (SM2-1), 3-bromo-7a,8,9,10-tetrahydro-7H-pyrrolizino[2,3-c]quinoline (SM2-2), 4-bromo-7a,8,9,10-tetrahydro-7H-pyrrolizino[2,3-c]quinoline (SM2-3)

[0108] According to the steps and conditions in Reaction A of the above general formula compound synthesis method 1, using SM1-1 and an appropriate amount of NBS as substrates, the target products SM2-1, SM2-2, and SM2-3 can be obtained respectively, with yields of 58%, 11%, and 10% respectively.

[0109] SM2-1: 1 H-NMR(400MHz,CDCl3)δ8.50(s,1H),7.82(ddd,J=9.6,7.9,1.2Hz,2H),7.11(dd,J=8.3,7.5Hz,1H),4.21–4.10(m,1H),3.83–3.74(m,1H),3.34(td,J=9.5,7.9Hz,1H),3.21(dd,J=16.1,10.4Hz,1H),3.06(dd,J=16.1,4.4Hz,1H),2.00–1.88(m,3H),1.37–1.26(m,1H).MS[M+H] + m / z 289.02.

[0110] SM2-2: 1 H-NMR(400MHz,CDCl3)δ8.42(s,1H),8.03(d,J=2.1Hz,1H),7.94(d,J=9.1Hz,1H),7.66(dd,J=9.1,2.1Hz,1H),4.36–4.23(m,1H),3.96–3.85(m,1H),3.58–3.45(m,1H),3.29(dd,J=16.2,10.5Hz,1H),3.12(dd,J=16.2,4.9Hz,1H),2.18–2.09(m,3H),1.44(dt,J=11.0,7.7Hz,1H).MS[M+H] + m / z 289.03.

[0111] SM2-3: 1 H-NMR(400MHz,CDCl3)δ8.46(s,1H),8.05(d,J=2.0Hz,1H),7.88(d,J=9.1Hz,1H),7.64(dd,J=9.1,2.1Hz,1H),4.26(dt,J=10.4,5.3Hz,1H),3.95–3.85(m,1H),3.47(dd,J=16.9,9.4Hz,1H),3.30(dd,J=16.1,10.4Hz,1H),3.16–3.10(m,1H),2.13–1.99(m,3H),1.43(dt,J=10.9,3.5Hz,1H).MS[M+H] +m / z 289.03。

[0112]

[0113] Synthesis of 4-chloro-3-(6-chlorohex-1-yn-1-yl)quinoline (6’)

[0114] According to the steps and conditions of Reaction K in the general formula compound synthesis method 6 above, using 3-bromo-4-chloro-quinoline (1’) and 6-chlorohex-1-yne (5’) as substrates, the target product 6’ can be obtained with a yield of 78%. 1 H-NMR(400MHz,CDCl3)δ8.83(s,1H),8.24(dd,J=8.4,0.9Hz,1H),8.11(d,J=8.4Hz,1H),7.75(ddd,J=8.4,7.0,1.4Hz,1H),7.66(ddd,J=8.2,7.0,1.2Hz,1H),3.65(t,J=6.5Hz,2H),2.62(t,J=6.9Hz,2H),2.05(tt,J=13.1,6.7Hz,2H),1.87(dt,J=9.6,7.0Hz,2H).MS[M+H] + m / z 278.06。

[0115] Synthesis of 6-chloro-1-(4-chloro-6-methoxyquinolin-3-yl)hexan-2-one (7’)

[0116] According to the steps and conditions of Reaction L in the general formula compound synthesis method 6 above, using 6’ as the substrate, the target product 7’ can be obtained with a yield of 75%. 1 H-NMR(400MHz,CDCl3)δ8.70(s,1H),8.24(dd,J=8.4,0.7Hz,1H),8.13(d,J=8.4Hz,1H),7.76(ddd,J=8.4,7.0,1.3Hz,1H),7.72–7.61(m,1H),4.07(s,2H),3.62–3.48(m,2H),2.73–2.56(m,2H),1.87–1.73(m,4H).MS[M+H] + m / z 296.06。

[0117] Synthesis of 4-chloro-3-(((1-(4-methoxybenzyl)piperidin-2-yl)methyl)quinoline (8’)

[0118] According to the steps and conditions of Reaction N in the general formula compound synthesis method 6 above, using 7’ as the substrate, the target product 8 can be obtained with a yield of 53%. 1H-NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.22 (dd, J = 8.4, 0.9 Hz, 1H), 8.08 (dd, J = 8.4, 0.6 Hz, 1H), 7.71 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.62 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.27–7.25 (m, 2H), 6.88–6.76 (m, 2H), 4.03 (d, J = 13.4 Hz, 1H), 3.79 (s, 3H), 3.57 (d, J = 13.4 Hz, 1H), 3.47 (dd, J = 13.0, 4.0 Hz, 1H), 3.09–2.99 (m, 1H), 2.95 (d, J = 2.0 Hz, 1H), 2.85 (dt, J = 11.3, 4.4 Hz, 1H), 2.39–2.28 (m, 1H), 1.76–1.66 (m, 1H), 1.61–1.50 (m, 3H), 1.44–1.34 (m, 2H). MS [M+H] + m / z 381.30。

[0119] Synthesis of 7,7a,8,9,10,11-hexahydroindolizino[2,3-c]quinoline (SM1-2)

[0120] According to the steps and conditions of Reaction O in the above general formula compound synthesis method 6, using 8’ as the substrate, the target product SM1-2 can be obtained with a yield of 52%. 1 H-NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.11 (dd, J = 19.3, 9.3 Hz, 2H), 7.61 (t, J = 6.9 Hz, 1H), 7.34 (dd, J = 16.8, 9.6 Hz, 1H), 4.69 (d, J = 12.9 Hz, 1H), 3.87 (dt, J = 11.8, 5.8 Hz, 1H), 3.41 (td, J = 12.6, 2.8 Hz, 1H), 3.27 (dd, J = 15.4, 9.4 Hz, 1H), 2.75 (dd, J = 15.3, 9.2 Hz, 1H), 2.08–1.88 (m, 3H), 1.77–1.56 (m, 3H). MS [M+H] + m / z 225.13。

[0121]

[0122] Synthesis of 4-chloro-3-(5-chloropent-1-yn-1-yl)-6-methoxyquinoline (10’)

[0123] According to the steps and conditions of Reaction K in the synthesis method 6 of the above general formula compounds, using 3-bromo-4-chloro-6-methoxyquinoline (9') and 5-chloropent-1-yne (2') as substrates, the target product 10' can be obtained with a yield of 69%. 1 H-NMR(400MHz,CDCl3)δ8.68(s,1H),7.97(d,J=9.1Hz,1H),7.43(d,J=2.7Hz,1H),7.38(d,J=2.8Hz,1H),7.36(d,J=2.8Hz,1H),3.98(s,3H),3.80(t,J=6.3Hz,2H),2.77(t,J=6.8Hz,2H),2.20–2.10(m,2H).MS[M+H] + m / z 264.06.

[0124] Synthesis of 5-chloro-1-(4-chloro-6-methoxyquinolin-3-yl)pentan-2-one (11')

[0125] According to the steps and conditions of Reaction L in the synthesis method 6 of the above general formula compounds, using 10' as the substrate, the target product 11' can be obtained with a yield of 35%. 1 H-NMR(400MHz,CDCl3)δ8.58(s,1H),8.04(d,J=9.1Hz,1H),7.45(d,J=2.7Hz,1H),7.41(dd,J=9.1,2.8Hz,1H),4.08(s,2H),3.98(s,3H),3.60(t,J=6.2Hz,2H),2.80(t,J=6.9Hz,2H),2.16–2.06(m,2H).MS[M+H] + m / z312.09.

[0126] Synthesis of 4-chloro-6-methoxy-3-((1-(4-methoxybenzyl)pyrrolidin-2-yl)methyl)quinoline (12')

[0127] According to the steps and conditions of Reaction N in the synthesis method 6 of the above general formula compounds, using 11' as the substrate, the target product 12' can be obtained with a yield of 32%. 1H-NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 6.88–6.83 (m, 2H), 4.09 (d, J = 12.8 Hz, 1H), 3.98 (s, 3H), 3.82–3.77 (m, 3H), 3.38 (dd, J = 14.5, 6.0 Hz, 2H), 3.07–2.83 (m, 3H), 2.33–2.18 (m, 1H), 1.77–1.65 (m, 4H). MS [M+H] + m / z 397.25。

[0128] Synthesis of 2-methoxy-7a,8,9,10-tetrahydro-7H-pyrrolizino[2,3-c]quinoline (SM3-1)

[0129] According to the steps and conditions of Reaction O in the above general formula compound synthesis method 6, using 12’ as the substrate, the target product SM3-1 can be obtained with a yield of 27%. 1 H-NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 4.25–4.10 (m, 1H), 3.87–3.75 (m, 4H), 3.41 (dd, J = 17.4, 8.9 Hz, 1H), 3.22 (dd, J = 15.9, 10.3 Hz, 1H), 3.05 (dd, J = 15.9, 4.3 Hz, 1H), 2.07–1.87 (m, 3H), 1.44–1.34 (m, 1H). MS [M+H] + m / z 241.13。

[0130] Example 1

[0131]

[0132] According to the steps and conditions of Reaction B in the above general formula compound synthesis method 1, using SM2-1 and an appropriate amount of ethylamine as the substrates, the target product I-1 can be obtained with a yield of 48%. MS (m / z): 254.21 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 4.34–4.20 (m, 1H), 3.91 (s, 1H), 3.87 (s, 1H), 3.61–3.48 (m, 1H), 3.33–3.17 (m, 3H), 3.09 (dd, J = 15.8, 3.8 Hz, 1H), 2.07 (dd, J = 15.0, 7.8 Hz, 3H), 1.51–1.41 (m, 1H), 1.33 (t, J = 7.0 Hz, 3H).

[0133] Example 2

[0134]

[0135] According to the steps and conditions described in Reaction B of the above General Formula Compound Synthesis Method 1, using SM2-2 and an appropriate amount of ethylamine as substrates, the target product I-2 can be obtained, yield: 79%. MS (m / z): 254.21 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.04 (dd, J = 9.1, 2.6 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 4.28 (dq, J = 15.4, 5.2 Hz, 1H), 3.91–3.84 (m, 1H), 3.57 (dt, J = 17.1, 8.6 Hz, 1H), 3.32–3.18 (m, 3H), 3.10 (dd, J = 16.0, 4.6 Hz, 1H), 2.16–1.98 (m, 3H), 1.53–1.44 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H).

[0136] Example 3

[0137]

[0138] According to the steps and conditions described in Reaction B of the above General Formula Compound Synthesis Method 1, using SM2-3 and an appropriate amount of ethylamine as substrates, the target product I-3 can be obtained, yield: 68%. MS (m / z): 254.21 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.06 (dd, J = 8.4, 1.1 Hz, 1H), 6.50 (d, J = 7.4 Hz, 1H), 4.18–4.09 (m, 1H), 3.80–3.73 (m, 1H), 3.43 (dt, J = 9.8, 7.9 Hz, 1H), 3.24 (q, J = 7.2 Hz, 2H), 3.19 (dd, J = 13.2, 7.6 Hz, 1H), 3.03 (dd, J = 15.8, 4.2 Hz, 1H), 2.02–1.86 (m, 3H), 1.40 - 1.34 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).

[0139] Example 4

[0140]

[0141] According to the steps and conditions described in Reaction B of Synthesis Method 1 of the above general formula compounds, using SM2-1 and an appropriate amount of butylamine as substrates, the target product I-4 can be obtained, yield: 29%. MS (m / z): 282.20 [M + H] + 。 1 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 6.84 (s, 1H), 4.46 (dt, J = 10.2, 5.1 Hz, 1H), 4.02 (t, J = 9.0 Hz, 1H), 3.92–3.76 (m, 1H), 3.31–3.25 (m, 1H), 3.22–3.06 (m, 3H), 2.22 (ddd, J = 14.1, 10.1, 6.3 Hz, 3H), 1.68 (dt, J = 19.7, 7.3 Hz, 2H), 1.52 (dt, J = 15.0, 6.7 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H).

[0142] Example 5

[0143]

[0144] According to the steps and conditions described in Reaction B of Synthesis Method 1 of the above general formula compounds, using SM2-1 and an appropriate amount of propargylamine as substrates, the target product I-5 can be obtained, yield: 32%. MS (m / z): 264.24 [M + H] + 。 11H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.72 (d, J = 9.1 Hz, 1H), 6.93 (dd, J = 9.1, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 4.18–4.13 (m, 1H), 3.80 (s, 2H), 3.76 (dd, J = 6.8, 3.4 Hz, 1H), 3.41–3.36 (m, 1H), 3.33–3.29 (m, 2H), 3.21–3.14 (m, 2H), 3.09 (s, 1H), 3.04–2.99 (m, 1H), 2.05–1.94 (m, 3H).

[0145] Example 6

[0146]

[0147] According to the steps and conditions described in Reaction B of Synthesis Method 1 of the above general formula compounds, using SM2-1 and an appropriate amount of ethanolamine as substrates, the target product I-6 can be obtained, with a yield of 34%. MS (m / z): 270.25 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.72 (d, J = 9.1 Hz, 1H), 6.93 (dd, J = 9.1, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 4.18–4.13 (m, 1H), 3.85 (t, J = 5.2 Hz, 2H), 3.76 (dd, J = 6.8, 3.4 Hz, 1H), 3.41–3.36 (m, 1H), 3.33–3.29 (m, 2H), 3.21–3.14 (m, 2H), 3.04–2.99 (m, 1H), 2.05–1.94 (m, 3H).

[0148] Example 7

[0149]

[0150] According to the steps and conditions described in Reaction B of Synthesis Method 1 of the above general formula compounds, using SM2-1 and an appropriate amount of N,N-dimethylethylenediamine as substrates, the target product I-7 can be obtained, with a yield of 57%. MS (m / z): 297.32 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.07 (dd, J = 9.1, 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 4.24 (dt, J = 10.2, 5.1 Hz, 1H), 3.90–3.82 (m, 1H), 3.52 (dd, J = 17.2, 9.3 Hz, 1H), 3.31–3.19 (m, 3H), 3.10 (dd, J = 15.9, 4.4 Hz, 1H), 2.70–2.59 (m, 2H), 2.30 (s, 6H), 2.11–2.05 (m, 2H), 2.01 (dt, J = 7.0, 5.8 Hz, 2H), 1.51–1.39 (m, 1H).

[0151] Example 8

[0152]

[0153] According to the steps and conditions described in Reaction B of Synthesis Method 1 of the above general formula compounds, using SM2-1 and an appropriate amount of dimethylamine as substrates, the target product I-8 can be obtained, with a yield of 51%. MS (m / z): 254.26 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.00 (d, J = 9.4 Hz, 1H), 7.29 (dd, J = 9.4, 2.8 Hz, 1H), 6.89 (d, J = 2.7 Hz, 1H), 4.28 (dq, J = 15.4, 5.1 Hz, 1H), 3.94–3.85 (m, 1H), 3.58 (dd, J = 17.2, 9.4 Hz, 1H), 3.27 (dd, J = 15.9, 10.4 Hz, 1H), 3.10 (dd, J = 16.0, 4.7 Hz, 1H), 3.05 (s, 6H), 2.15–1.98 (m, 3H), 1.51–1.42 (m, 1H).

[0154] Example 9

[0155]

[0156] According to the steps and conditions described in Reaction B of Synthesis Method 1 of the above general formula compounds, using SM2-1 and an appropriate amount of pyrrolidine as substrates, the target product I-9 can be obtained, with a yield of 31%. MS (m / z): 280.25 [M+H] + . 11H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.38 (dd, J = 9.2, 2.3 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 4.49 (dt, J = 15.9, 5.3 Hz, 1H), 4.08 (dd, J = 13.4, 5.3 Hz, 1H), 3.97–3.84 (m, 1H), 3.46–3.35 (m, 4H), 3.35–3.31 (m, 1H), 3.15 (dd, J = 16.3, 6.0 Hz, 1H), 2.23 (tdd, J = 13.2, 9.5, 3.6 Hz, 3H), 2.15–2.01 (m, 4H), 1.63–1.48 (m, 1H).

[0157] Example 10

[0158]

[0159] According to the steps and conditions described in Reaction C of the above general formula compound synthesis method 2, using SM1-1 as the substrate, the target product II-1 can be obtained, yield: 80%. MS (m / z): 209.10 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.16–8.09 (m, 1H), 8.06 (dd, J = 8.1, 1.4 Hz, 1H), 7.56–7.38 (m, 2H), 6.32 (s, 1H), 4.42 (t, J = 7.1 Hz, 2H), 2.99 (dd, J = 11.2, 4.3 Hz, 2H), 2.66 (dt, J = 18.3, 7.4 Hz, 2H).

[0160] Example 11

[0161]

[0162] According to the steps and conditions described in Reaction C of the above general formula compound synthesis method 2, using SM3-1 as the substrate, the target product II-2 can be obtained, yield: 55%. MS (m / z): 239.12 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.05–7.99 (m, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 9.1, 2.7 Hz, 1H), 6.27 (d, J = 1.0 Hz, 1H), 4.45–4.31 (m, 2H), 3.87 (d, J = 6.4 Hz, 3H), 2.97 (t, J = 7.5 Hz, 2H), 2.69–2.58 (m, 2H).

[0163] Example 12

[0164]

[0165] According to the steps and conditions described in Reaction J of the above general formula compound synthesis method 4, using SM1-1 as the substrate, the target product II-3 can be obtained with a yield of 44%. MS (m / z): 288.26 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 8.09–7.98 (m, 1H), 7.59 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.56–7.49 (m, 1H), 4.50 (t, J = 7.1 Hz, 2H), 3.01 (t, J = 7.5 Hz, 2H), 2.76 (dd, J = 14.5, 7.5 Hz, 2H).

[0166] Example 13

[0167]

[0168] According to the steps and conditions described in Reaction J of the above general formula compound synthesis method 4, using SM3-1 as the substrate, the target product II-4 can be obtained with a yield of 19%. MS (m / z): 318.20 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.22–7.20 (m, 1H), 4.53 (t, J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.99 (t, J = 7.5 Hz, 2H), 2.79–2.67 (m, 2H).

[0169] Example 14

[0170]

[0171] According to the steps and conditions described in Reaction D of the above General Formula Compound Synthesis Method 2, using II-1 as the substrate, the target product II-5 can be obtained, with a yield of 47%. MS (m / z): 237.10 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 9.76 (d, J = 3.3 Hz, 1H), 9.43 (d, J = 3.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 4.26 (dd, J = 9.5, 4.9 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.80–2.65 (m, 2H).

[0172] Example 15

[0173]

[0174] According to the steps and conditions described in Reaction E of the above General Formula Compound Synthesis Method 2, using II-5 as the substrate, the target product II-6 can be obtained, with a yield of 76%. MS (m / z): 239.31 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 9.13–8.81 (m, 1H), 8.00 (s, 2H), 7.48 (dd, J = 4.4, 2.9 Hz, 2H), 4.77 (d, J = 3.4 Hz, 2H), 4.33 (d, J = 4.1 Hz, 2H), 2.99 (d, J = 3.9 Hz, 2H), 2.64 (d, J = 4.2 Hz, 2H).

[0175] Example 16

[0176]

[0177] According to the steps and conditions described in Reaction G of the above General Formula Compound Synthesis Method 2, using II-5 as the substrate, the target product II-7 can be obtained, with a yield of 65%. MS (m / z): 253.23 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.48–7.32 (m, 2H), 5.16 (q, J = 6.5 Hz, 1H), 4.19–4.05 (m, 2H), 2.96 (dd, J = 14.2, 7.3 Hz, 2H), 2.62–2.48 (m, 2H), 1.56 (d, J = 6.6 Hz, 3H).

[0178] Example 17

[0179]

[0180] According to the steps and conditions described in Reaction F of Synthesis Method 2 of the above general formula compounds, using II-5 and dimethylamine as substrates, the target product II-8 can be obtained, with a yield of 35%. MS (m / z): 266.21 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.09 (ddd, J = 11.9, 8.3, 1.4 Hz, 2H), 7.57–7.37 (m, 2H), 4.45 (t, J = 7.1 Hz, 2H), 3.97 (s, 2H), 3.01 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.20 (s, 6H).

[0181] Example 18

[0182]

[0183] According to the steps and conditions described in Reaction F of Synthesis Method 2 of the above general formula compounds, using II-5 and ethylamine as substrates, the target product II-9 can be obtained, with a yield of 45%. MS (m / z): 266.21 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.09 (ddd, J = 11.9, 8.3, 1.4 Hz, 2H), 7.57–7.37 (m, 2H), 4.45 (t, J = 7.1 Hz, 2H), 3.97 (s, 2H), 3.01 (t, J = 7.5 Hz, 2H), 2.69 (q, J = 7.2 Hz, 4H), 1.09 (t, J = 7.1 Hz, 3H).

[0184] Example 19

[0185]

[0186] According to the steps and conditions of Reaction F in the above-mentioned General Formula Compound Synthesis Method 2, using II-5 and N,N-dimethylethylenediamine as substrates, the target product II-10 can be obtained, yield: 40%. MS (m / z): 309.31 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.12–8.07 (m, 1H), 8.05 (dd, J = 8.1, 1.3 Hz, 1H), 7.49 (dtd, J = 14.8, 7.0, 1.5 Hz, 2H), 4.43 (t, J = 7.1 Hz, 2H), 4.07 (s, 2H), 3.09 (t, J = 7.5 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.74–2.67 (m, 2H), 2.52 (t, J = 6.0 Hz, 2H), 2.20 (s, 6H).

[0187] Example 20

[0188]

[0189] According to the steps and conditions of Reaction H in the above-mentioned General Formula Compound Synthesis Method 3, using SM2-1 as the substrate, the target product II-11 can be obtained, yield: 78%. MS (m / z): 286.99 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 6.41 (s, 1H), 4.51 (dd, J = 8.5, 5.7 Hz, 2H), 3.09 (dd, J = 11.2, 4.3 Hz, 2H), 2.82–2.70 (m, 2H).

[0190] Example 21

[0191]

[0192] According to the steps and conditions of Reaction I in the above-mentioned General Formula Compound Synthesis Method 3, using II-11 and dimethylamine as substrates, the target product II-12 can be obtained, yield: 19%. MS (m / z): 252.20 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 9.2, 2.7 Hz, 1H), 6.29 (s, 1H), 4.52 (t, J = 7.1 Hz, 2H), 3.06–2.91 (m, 8H), 2.67 (dd, J = 14.6, 7.2 Hz, 2H).

[0193] Example 22

[0194]

[0195] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and N,N'-dimethylethylenediamine as substrates, the target product II-13 can be obtained, yield: 64%. MS (m / z): 295.28 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.04 (d, J = 9.3 Hz, 1H), 6.78 (s, 1H), 6.18 (s, 1H), 4.26 (t, J = 7.2 Hz, 2H), 3.05 (s, 2H), 2.91 (s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 2.60 (d, J = 10.4 Hz, 3H), 2.56 (d, J = 7.0 Hz, 1H), 2.00 (s, 2H).

[0196] Example 23

[0197]

[0198] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and N,N-dimethyl-N'-ethylethylenediamine as substrates, the target product II-14 can be obtained, yield: 16%. MS (m / z): 323.30 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.07 (dd, J = 9.1, 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 4.24 (dt, J = 10.2, 5.1 Hz, 1H), 3.90–3.82 (m, 1H), 3.52 (dd, J = 17.2, 9.3 Hz, 1H), 3.31–3.19 (m, 6H), 3.10 (dd, J = 15.9, 4.4 Hz, 1H), 2.70–2.59 (m, 2H), 2.30 (s, 6H), 2.11–2.05 (m, 2H), 2.01 (dt, J = 7.0, 5.8 Hz, 2H), 1.51–1.39 (m, 1H), 1.33 (t, J = 7.0 Hz, 3H).

[0199] Example 24

[0200]

[0201] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N,N,N'-triethylethylenediamine as substrates, the target product II-15 can be obtained, yield: 21%. MS (m / z): 351.35 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 11.6 Hz, 1H), 6.94 (s, 1H), 6.37 (s, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 3.37 (t, J = 6.3 Hz, 2H), 3.35 - 3.25 (m, 6H), 2.99 (t, J = 7.5 Hz, 2H), 2.74–2.62 (m, 2H), 1.40 - 1.30 (m, 9H).

[0202] Example 25

[0203]

[0204] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N,N',N''-trimethyldiethylenetriamine as substrates, the target product II-16 can be obtained, yield: 19%. MS (m / z): 352.20 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.04 (d, J = 9.3 Hz, 1H), 6.78 (s, 1H), 6.18 (s, 1H), 4.26 (t, J = 7.2 Hz, 2H), 3.05 (s, 3H), 2.91 (s, 3H), 2.85 (m, 4H), 2.60 (m, 5H), 2.56 (d, J = 7.0 Hz, 1H), 2.35 (s, 3H), 2.00 (s, 2H).

[0205] Example 26

[0206]

[0207] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and n-butylamine as substrates, the target product II-17 can be obtained with a yield of 61%. MS (m / z): 280.17 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.9, 2.1 Hz, 1H), 6.24 (s, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3.15 (t, J = 7.0 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.68–2.57 (m, 2H), 1.61 (dd, J = 14.7, 7.3 Hz, 2H), 1.42 (dd, J = 14.9, 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0208] Example 27

[0209]

[0210] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and 2-methoxyethylamine as substrates, the target product II-18 can be obtained with a yield of 42%. MS (m / z): 282.25 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 9.0, 2.4 Hz, 1H), 6.35 (s, 1H), 4.54 (t, J = 7.1 Hz, 2H), 4.36 (s, 1H), 3.70 (t, J = 5.2 Hz, 2H), 3.44 (s, 5H), 3.07 (t, J = 7.5 Hz, 2H), 2.73 (dd, J = 14.6, 7.2 Hz, 2H).

[0211] Example 28

[0212]

[0213] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and 2-methylthioethylamine as substrates, the target product II-19 can be obtained, with a yield of 49%. MS (m / z): 298.23 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.15 (s, 1H), 7.01–6.93 (m, 1H), 6.33 (s, 1H), 4.51 (t, J = 7.0 Hz, 2H), 4.40 (s, 1H), 3.47 (s, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.77–2.66 (m, 2H), 2.16 (s, 3H).

[0214] Example 29

[0215]

[0216] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and trifluoroethylamine as substrates, the target product II-20 can be obtained, with a yield of 55%. MS (m / z): 306.10 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 9.0, 2.6 Hz, 1H), 6.32 (s, 1H), 4.45 (t, J = 7.1 Hz, 2H), 4.41–4.27 (m, 1H), 3.96–3.82 (m, 2H), 3.03 (t, J = 7.6 Hz, 2H), 2.71 (dt, J = 18.5, 7.4 Hz, 2H).

[0217] Example 30

[0218]

[0219] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compound, using II-11 and 2-methylsulfonylethylamine hydrochloride as substrates, the target product II-21 can be obtained, yield: 27%. MS (m / z): 330.15 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 8.9, 2.0 Hz, 1H), 6.34 (s, 1H), 4.52 (t, J = 7.1 Hz, 2H), 3.88 (t, J = 5.9 Hz, 2H), 3.36 (t, J = 6.1 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.97 (s, 3H), 2.78–2.68 (m, 2H).

[0220] Example 31

[0221]

[0222] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compound, using II-11 and N,N,-diethylethylenediamine as substrates, the target product II-22 can be obtained, yield: 53%. MS (m / z): 323.32 [M+H] + 。 11H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 11.6 Hz, 1H), 6.94 (s, 1H), 6.37 (s, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 3.37 (t, J = 6.3 Hz, 2H), 3.25 (q, J = 7.2 Hz, 4H), 2.99 (t, J = 7.5 Hz, 2H), 2.74–2.62 (m, 2H), 1.34 (t, J = 7.2 Hz, 6H).

[0223] Example 32

[0224]

[0225] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N,N-dimethylethylenediamine as substrates, the target product II-23 can be obtained, yield: 58%. MS (m / z): 295.28 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 9.0, 2.4 Hz, 1H), 6.24 (s, 1H), 4.43 (t, J = 7.1 Hz, 2H), 3.20 (t, J = 5.9 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.64 (dd, J = 14.5, 7.3 Hz, 2H), 2.57 (t, J = 5.9 Hz, 2H), 2.23 (s, 6H).

[0226] Example 33

[0227]

[0228] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N,N-dimethylbutanediamine as substrates, the target product II-24 can be obtained, yield: 77%. MS (m / z): 323.32 [M+H] + 。 11H NMR (400 MHz, DMSO) δ 8.94–8.54 (m, 1H), 7.94 (s, 1H), 6.99 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.36–6.26 (m, 1H), 4.48 (t, J = 14.3 Hz, 1H), 3.21 (s, 1H), 3.05–2.98 (m, 1H), 2.74–2.65 (m, 1H), 2.55 (d, J = 6.0 Hz, 1H), 2.39 (s, 1H), 2.05 (s, 1H), 1.74 (s, 1H).

[0229] Example 34

[0230]

[0231] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and 2-aminoethylthiophene as substrates, the target product II-25 can be obtained, yield: 35%. MS (m / z): 334.23 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 4.7, 3.0 Hz, 1H), 7.07 (s, 1H), 7.00 (s, 1H), 6.95 (d, J = 4.7 Hz, 1H), 6.85 (d, J = 6.9 Hz, 1H), 6.27 (s, 1H), 4.45 (t, J = 7.0 Hz, 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.04–2.93 (m, 4H), 2.66 (dt, J = 14.6, 7.3 Hz, 2H).

[0232] Example 35

[0233]

[0234] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N-aminoethylpyrrole as substrates, the target product II-26 can be obtained, yield: 56%. MS (m / z): 317.27 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 9.0, 2.4 Hz, 1H), 6.70 (t, J = 1.9 Hz, 2H), 6.32 (s, 1H), 6.20 (t, J = 1.9 Hz, 2H), 4.46 (t, J = 7.1 Hz, 2H), 4.17 (t, J = 5.9 Hz, 2H), 3.99 (s, 1H), 3.61 (t, J = 5.5 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.77–2.66 (m, 2H).

[0235] Example 36

[0236]

[0237] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and 3-aminoethylpyridine as substrates, the target product II-27 can be obtained with a yield of 57%. MS (m / z): 329.21 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 4.8, 1.3 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 4.9, 2.6 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.83 (dd, J = 8.9, 2.4 Hz, 1H), 6.23 (s, 1H), 4.37 (t, J = 7.1 Hz, 2H), 3.99 (s, 1H), 3.45 (t, J = 7.0 Hz, 2H), 2.94 (dt, J = 11.6, 7.3 Hz, 4H), 2.63 (dd, J = 14.5, 7.3 Hz, 2H).

[0238] Example 37

[0239]

[0240] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N-aminoethylpyrrolidine as substrates, the target product II-28 can be obtained with a yield of 89%. MS (m / z): 321.20 [M+H] + 。 11H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 9.1 Hz, 1H), 7.12 (s, 1H), 6.49 (s, 1H), 4.55 (t, J = 7.1 Hz, 2H), 3.69 (t, J = 6.1 Hz, 2H), 3.48 (t, J = 6.1 Hz, 2H), 3.41 (s, 4H), 3.06 (t, J = 7.4 Hz, 2H), 2.74 (dt, J = 14.7, 7.4 Hz, 2H), 2.10 (s, 4H). 13 13C NMR (101 MHz, MeOD) δ 147.60, 147.54, 135.72, 131.34, 127.41, 124.30, 123.77, 118.66, 118.12, 96.40, 95.20, 53.76, 52.94, 46.85, 39.84, 27.81, 24.90, 22.83.

[0241] Example 38

[0242]

[0243] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N-aminopropyl tetrahydropyrrole as substrates, the target product II-29 can be obtained with a yield of 50%. MS (m / z): 335.30 [M+H] + . 1 1H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 11.4 Hz, 1H), 6.86 (s, 1H), 6.40 (s, 1H), 4.39 (t, J = 7.2 Hz, 2H), 3.36 (d, J = 7.9 Hz, 3H), 3.34–3.30 (m, 3H), 3.01 (t, J = 7.4 Hz, 2H), 2.69 (dt, J = 14.3, 7.1 Hz, 2H), 2.23–2.14 (m, 2H), 2.09 (q, J = 6.9 Hz, 4H), 1.32 (d, J = 14.6 Hz, 2H). 13C NMR (101 MHz, MeOD) δ 147.60, 147.54, 135.72, 131.34, 127.41, 124.30, 123.77, 118.66, 118.12, 96.40, 95.20, 53.76, 52.94, 46.85, 40.22, 27.77, 25.25, 22.79, 22.71.

[0244] Example 39

[0245]

[0246] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and N-aminoethylpiperidine as substrates, the target product II-30 can be obtained, yield: 44%. MS (m / z): 335.30 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 7.78–7.71 (m, 1H), 7.06–6.97 (m, 2H), 6.29 (s, 1H), 4.39 (dd, J = 14.8, 7.5 Hz, 2H), 3.38 (d, J = 6.6 Hz, 2H), 3.02–2.92 (m, 2H), 2.80–2.72 (m, 2H), 2.64 (s, 6H), 1.74–1.65 (m, 4H), 1.53 (d, J = 4.6 Hz, 2H). 13 C NMR (101 MHz, MeOD) δ 146.73, 145.45, 139.44, 130.41, 127.51, 125.38, 119.35, 116.68, 116.66, 96.80, 93.67, 57.20, 54.22, 46.48, 39.84, 27.81, 24.90, 23.43, 22.83.

[0247] Example 40

[0248]

[0249] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and 1-methyl-4-aminoethylpiperidine as substrates, the target product II-31 can be obtained, yield: 59%. MS (m / z): 349.30 [M+H] + 。 11H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 11.5 Hz, 1H), 6.72 (s, 1H), 6.13 (s, 1H), 4.04 (t, J = 7.1 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H), 2.94 (d, J = 15.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.52–2.41 (m, 2H), 2.33 (s, 3H), 2.19–2.07 (m, 2H), 1.76 (d, J = 12.8 Hz, 2H), 1.57 (dd, J = 14.2, 6.9 Hz, 2H), 1.43 (ddd, J = 9.5, 6.8, 3.4 Hz, 1H), 1.38–1.29 (m, 2H), 1.27 (dd, J = 10.0, 4.5 Hz, 1H). 13 13C NMR (101 MHz, MeOD) δ 146.89, 144.88, 139.46, 135.01, 130.03, 127.73, 125.38, 119.38, 116.46, 96.27, 93.25, 55.12, 46.14, 44.61, 40.71, 35.14, 32.44, 31.23, 27.53, 22.62.

[0250] Example 41

[0251]

[0252] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N-aminoethylmorpholine as substrates, the target product II-32 can be obtained, with a yield of 38%. MS (m / z): 337.21 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.9, 2.2 Hz, 1H), 6.27 (s, 1H), 4.49 (t, J = 7.1 Hz, 2H), 3.75–3.62 (m, 4H), 3.25 (t, J = 5.8 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.72–2.60 (m, 4H), 2.46 (d, J = 4.1 Hz, 4H).

[0253] Example 42

[0254]

[0255] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and N-methyl-4-aminomethylpiperidine as substrates, the target product II-33 can be obtained with a yield of 77%. MS (m / z): 335.23 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.10 (s, 1H), 6.91 (d, J = 6.3 Hz, 1H), 6.32 (s, 1H), 4.52 (t, J = 7.0 Hz, 2H), 3.16 (d, J = 6.5 Hz, 2H), 3.05 (t, J = 7.5 Hz, 3H), 2.96 (d, J = 11.3 Hz, 3H), 2.74 (dd, J = 14.5, 7.2 Hz, 2H), 2.32 (s, 3H), 2.02 (dd, J = 20.6, 8.9 Hz, 3H), 1.85 (d, J = 12.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 146.00, 144.16, 141.65, 137.02, 130.42, 130.22, 125.85, 119.58, 116.21, 97.49, 93.85, 55.44, 49.85, 46.77, 46.07, 35.33, 30.25, 29.71, 23.59.

[0256] Example 43

[0257]

[0258] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and N-methyl-2-aminoethylpyrrolidine as substrates, the target product II-34 can be obtained with a yield of 44%. MS (m / z): 335.23 [M+H] + 。 1HNMR(400MHz,MeOD)δ8.49(s,1H),7.72(d,J=9.0Hz,1H),6.96(d,J=11.6Hz,1H),6.85(d,J=2.6Hz,1H),6.19(s,1H),4.16(dd,J=9.9,4.0Hz,2H),3.13(tdd,J=12.1,7.0,4.8Hz,3H),2.87(t,J=7.5Hz,2H),2.57–2.49(m,2H),2.41(s,3H),2.35(dd,J=18.6,9.1Hz,2H),2.16–2.07(m,2H),1.85–1.76(m,2H),1.66–1.55(m,2H). 13 C NMR(101MHz,MeOD)δ146.77,144.95,139.67,135.18,130.11,127.88,125.44,119.40,116.45,96.58,93.31,64.90,56.39,46.26,40.80,39.15,31.91,30.43,30.14,29.39,27.64,22.69,21.22.

[0259] Example 44

[0260]

[0261] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-11 and N-methyl-4-aminopiperidine as substrates, the target product II-35 can be obtained, with a yield of 89%. MS(m / z): 321.20 [M+H] + 。 1 H NMR(400MHz,MeOD)δ8.48(s,1H),7.70(d,J=9.1Hz,1H),7.06(d,J=11.5Hz,1H),6.94(s,1H),6.27(s,1H),4.30(t,J=7.1Hz,2H),3.63–3.59(m,1H),3.26(d,J=12.4Hz,2H),2.93(t,J=7.5Hz,2H),2.87(t,J=10.7Hz,2H),2.66(d,J=8.1Hz,3H),2.64–2.56(m,2H),2.21(d,J=11.3Hz,2H),1.77(dd,J=20.7,10.1Hz,2H). 1313C NMR(101MHz,MeOD)δ146.45,146.07,137.47,131.97,130.70,129.00,127.45,125.63,124.68,118.89,117.33,97.57,94.42,62.89,53.17,43.54,29.90,27.75,22.74.

[0262] Example 45

[0263]

[0264] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and 4-dimethylaminomethylaniline as substrates, the target product II-36 can be obtained, yield: 85%. MS (m / z): 357.30 [M+H] + 。 1 1H NMR(400MHz,MeOD)δ8.64(s,1H),7.86(d,J = 9.0Hz,1H),7.71(d,J = 2.3Hz,1H),7.41–7.31(m,3H),7.24(d,J = 8.5Hz,2H),6.34(s,1H),4.26(t,J = 7.1Hz,2H),3.90(s,2H),2.97(t,J = 7.5Hz,2H),2.66–2.61(m,2H),2.61(s,6H).

[0265] Example 46

[0266]

[0267] According to the steps and conditions described in Reaction I of the above general formula compound synthesis method 3, using II-11 and 1-methylpiperazine as substrates, the target product II-37 can be obtained, yield: 84%. MS (m / z): 307.21 [M+H] + 。 1 1H NMR(400MHz,CDCl3)δ8.79(s,1H),7.98(d,J = 9.1Hz,1H),7.33(d,J = 2.8Hz,1H),7.22(dd,J = 9.2,2.7Hz,1H),6.24(s,1H),4.40(t,J = 7.1Hz,2H),3.33–3.23(m,4H),2.94(t,J = 7.6Hz,2H),2.63(dd,J = 14.5,7.4Hz,2H),2.60–2.54(m,4H),2.32(s,3H).

[0268] Example 47

[0269]

[0270] According to the steps and conditions in Reaction A of the above general formula compound synthesis method 1, using SM1-2 and NBS as substrates, the target product SM2-4 can be obtained with a yield of 58%. MS (m / z): 303.04 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 1.3 Hz, 1H), 8.20–8.04 (m, 2H), 7.74 (d, J = 8.1 Hz, 1H), 4.63 (d, J = 13.4 Hz, 1H), 4.14 (d, J = 8.5 Hz, 1H), 3.65 - 3.56 (m, 1H), 3.40 (dd, J = 15.9, 9.9 Hz, 1H), 3.13 (d, J = 7.3 Hz, 1H), 2.83 (dd, J = 16.0, 8.6 Hz, 1H), 2.12 (d, J = 8.2 Hz, 1H), 2.02 (d, J = 9.5 Hz, 2H), 1.68 (d, J = 10.7 Hz, 2H).

[0271] According to the steps and conditions in Reaction C of the above general formula compound synthesis method 2, using SM2-4 as the substrate, the target product II-38 can be obtained with a yield of 72%. MS (m / z): 301.03 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.0 Hz, 1H), 6.47 (s, 1H), 4.61 (t, J = 6.3 Hz, 2H), 3.08 (t, J = 6.9 Hz, 2H), 2.22 (dd, J = 7.6, 4.1 Hz, 2H), 1.99 - 1.91 (m, 2H).

[0272] Example 48

[0273]

[0274] According to the steps and conditions in Reaction I of the above general formula compound synthesis method 3, using II-38 and N,N-dimethylethylenediamine as substrates, the target product II-39 can be obtained with a yield of 79%. MS (m / z): 309.20 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 9.0, 2.3 Hz, 1H), 6.37 (s, 1H), 4.64 (t, J = 6.3 Hz, 2H), 3.29 (t, J = 5.9 Hz, 2H), 3.03 (t, J = 6.3 Hz, 2H), 2.72 - 2.62 (m, 2H), 2.32 (s, 6H), 2.20 - 2.10 (m, 2H), 1.94 - 1.85 (m, 2H).

[0275] Example 49

[0276]

[0277] According to the steps and conditions described in Reaction I of Synthesis Method 3 of the above general formula compounds, using II-38 and N-aminoethylpiperidine as substrates, the target product II-40 can be obtained with a yield of 78%. MS (m / z): 349.24 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.30 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.37 (s, 1H), 4.99 (s, 1H), 4.63 (t, J = 6.1 Hz, 2H), 3.32 (t, J = 5.5 Hz, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 2.53 (s, 4H), 2.21–2.12 (m, 2H), 1.98–1.86 (m, 2H), 1.70–1.62 (m, 4H), 1.48 (s, 2H).

[0278] Example of Activity Test:

[0279] Tumor cells such as HepG2, MCF-7, Hela, HT-29, A549, HGC-27 and normal human liver cells L02 were obtained from the Cell Bank of the Chinese Academy of Sciences' Committee for Type Culture Collection (Shanghai, China). Culture media such as DMEM, RPMI 1640, and McCoy's 5A (brand: Gibco) were purchased from Invitrogen (Shanghai) Trading Co., Ltd. Fetal bovine serum (FBS) was purchased from Suzhou Qianshe Biotechnology Co., Ltd. (brand: PAN). Phosphate buffered saline (PBS) was purchased from Sangon Biotech (Shanghai) Co., Ltd. (brand: Sangon). Dimethyl sulfoxide (DMSO) and trypsin without EDTA were purchased from Shanghai Beyotime Biotechnology Co., Ltd. (brand: Beyotime). The cell apoptosis detection kit, CCK8 kit, and JC-1 mitochondrial membrane potential detection kit (brand: Beyotime) were purchased from Shanghai Beyotime Biotechnology Co., Ltd. The cell viability test and fluorescence intensity test platform was the Ensight multimode microplate reader from PE Company. The apoptosis detection platform was the SH800 flow cytometer from Sony Company.

[0280] Cell culture: HepG2, MCF-7 and Hela were respectively cultured in DMEM medium containing 10% (v / v) FBS, HT-29 was cultured in McCoy's 5A medium containing 10% (v / v) FBS, and A549 and HGC-27 were respectively cultured in RPMI 1640 medium containing 10% (v / v) FBS. They were cultured in an incubator at 37°C with 5% (v / v) CO2 in air and used for various test experiments when the cells were in the logarithmic phase.

[0281] Preparation of drug solution: The pyrrolo[2,3-c]quinoline derivatives were dissolved in DMSO to prepare a 10 mM solution and stored at -20°C.

[0282] Test Example 1: In vitro anti-tumor activity experiment

[0283] Test method:

[0284] a) Take the cell suspension in the logarithmic phase and inoculate it into a 96-well cell culture plate, 100 μL per well, 4,000 cells per well, and culture it in an incubator at 37°C with 5% (v / v) CO2 in air.

[0285] b) After culturing the cells for 24 h, the test pyrrolo[2,3-c]quinoline derivatives were added to the experimental group (the dosing concentrations for detecting single-point activity were 10 μM and 1 μM respectively when detecting IC 50When the administration concentration was at a certain value, it was diluted 2-fold to 8 concentration gradients from 10 μM: namely 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.1563 μM, 0.0781 μM). The control group was added with 50 μM of 5-fluorouracil (5-FU), and the blank group was added with DMSO with a volume concentration of 0.1%. Then it was cultured in an incubator at 37 °C with a volume concentration of 5% CO₂ air content for 72 h.

[0286] c) After removing the old culture medium in each well, 100 μL of fresh culture medium containing CCK8 detection reagent with a volume concentration of 10% was added. The cell-free group was set as the blank control and continued to be cultured in an incubator at 37 °C with a volume concentration of 5% CO₂ air content for 0.5 - 1 h (the incubation time varies with different cell lines. For MCF-7, Hela, and A549, it is about 30 min; for HepG2, HT-29, and HGC-27, it is about 40 min; for L02 cells, it is about 50 min).

[0287] d) The OD values of each well in the above groups were detected using an Ensight microplate reader at a wavelength of 450 nm. According to the formula (OD 实验 -OD 空白 ) / (OD 对照 -OD 空白 ), the survival rate after treatment with each pyrrolo[2,3-c]quinoline derivative was calculated.

[0288] First, the single-concentration inhibitory activities of pyrrolo[2,3-c]quinoline derivatives I and II were detected on hepatocellular carcinoma HepG2 cells, and the results are as Figure 1 and Figure 2 shown. Figure 1 It shows that under the condition of 10 μM concentration, some compounds I have strong inhibitory activities on cell proliferation. Table 1 gives the half-maximal inhibitory concentration IC 50 values of some compounds I. Among them, compound I-4 (IC 50 = 3.739 ± 0.989 μM) exhibits inhibitory activity comparable to that of 5-FU (IC 50 = 2.314 ± 0.285 μM). Figure 2 It shows that even under the condition of 1.0 μM concentration, some compounds II still have strong inhibitory activities on HepG2 cell proliferation. Table 2 gives the half-maximal inhibitory concentration IC 50 values of some highly active compounds II on HepG2 and other 5 types of tumor cells. The results show that the selected compounds all have good inhibitory effects on these tumor cells, and most of the IC 50The value can reach below 1 μM. In particular, for compounds II-23 and II-30 on MCF-7 and Hela, and compound II-29 on HT-29, their IC 50 values all reach below 0.1 μM, showing good development potential. As a comparison, the inhibitory activities of some highly active compounds II on normal liver cells L02 are as Figure 3 shown. At a concentration of 1.0 μM, the inhibition rates of most of the selected compounds are only about 50%, showing a certain selectivity towards tumor cells.

[0289] Table 1. Inhibitory activities of some compounds I against HepG2 cells, with 5-FU as the positive compound.

[0290]

[0291] Table 2. Half inhibitory concentration IC 50 values of some compounds II against various tumor cells.

[0292]

[0293]

[0294] Example 2: Inhibition of MCF-7 tumor growth by pyrrolizino[2,3-c]quinoline derivatives II-23, II-29, and II-30 in vivo

[0295] Test method:

[0296] a) Culture MCF-7 cells in a 10 cm cell culture dish and place it in an incubator at 37 °C with a 5% (v / v) CO2 air content.

[0297] b) When MCF-7 cells are in the logarithmic phase, digest them with trypsin, centrifuge to collect the cells, wash them twice with PBS, and then resuspend them in a certain volume of serum-free medium.

[0298] c) Select female Balb / c nude mice (6 weeks old, weighing 16 - 18 g) as the experimental subjects. After cell counting, subcutaneously inoculate 5×10 6 cells per nude mouse into the right axilla. Track and record the body weight of the nude mice and the tumor growth. After 10 days, start grouping according to the tumor volume, dividing them into 5 groups, with 6 tumor-bearing nude mice in each group.

[0299] d) Calculate the dosage according to the body weight of nude mice. The experimental group includes compounds II-23, II-29, and II-30, with a dosage of 10 mg / kg; the control group is 5-FU, with a dosage of 10 mg / kg; the blank solvent group (Normal Saline) only injects normal saline. Administer the drug intraperitoneally once a day and track and record the body weight and tumor volume of nude mice.

[0300] The test results are as Figure 4 shown. After treatment with 10 mg / kg pyrrolizino[2,3-c]quinoline derivatives II-23, II-29, and II-30, there was no significant change in body weight, and the tumor volume decreased significantly and showed a statistically significant difference compared with the solvent group. That is, pyrrolizino[2,3-c]quinoline derivatives II-23, II-29, and II-30 have biosafety and in vivo anti-MCF-7 xenograft tumor activity. These results indicate that such compounds have good potential for the development of anti-tumor drugs.

Claims

1. Pyrrolizino[2,3-c]quinoline derivatives, including one or more of the compounds represented by the following general formula I and / or II, and one or more of their pharmaceutically acceptable salts, solvates, hydrates or crystalline compounds (compounds represented by general formula I and / or II): Wherein, R1 is one or more of -NH2, R1'-NH-, or R1'R1”N- substituted at any position on the phenyl group (at 4 positions where substituents may be present); Among them, R1' refers to a substituted or unsubstituted C 1-5 alkyl group, and R1'' refers to a substituted or unsubstituted C 1-3 alkyl group; or in R1'R1''N-, R1', R1'' and N form a 4-, 5- or 6-membered ring structure; R2 is H, F, Cl, Br, I, C substituted at any position on the phenyl group (at 4 positions where substituents may be present), 1-3 alkyl, C 1-3 alkoxy, one or two or more of R2'R2”N-; wherein, R2' and R2” each independently refer to one or two or more of H, substituted or unsubstituted C 1-5 alkyl, or substituted or unsubstituted aryl; or, R2', R2” and N form a 4-, 5- or 6-membered ring structure; R3 is H, F, Cl, Br, I, amino, aldehyde, acetyl, substituted or unsubstituted C 1-3 alkyl; n is 1 or 2; preferably n is 1.

2. The derivative according to claim 1, wherein R1 of compound I is one or more of -NH2, R1'-NH-, or R1'R1”N- substituted at any position on the phenyl group; Among them, R1' refers to a substituted or unsubstituted C 1-5 alkyl group, and R1" refers to a substituted or unsubstituted C 1-3 alkyl group. Here, the substituent in the substituted C 1-5 alkyl group or the substituted C 1-3 alkyl group refers to one or two or more of -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C≡CH, -CH=CH2 substituted at any position of the C 1-5 alkyl group or the C 1-3 alkyl group; or in some cases, R1', R1" and N form one or two or more of 4-, 5- or 6-membered ring structures; Further, R1 of compound I is one or two or more of -NH2, R1'-NH-, R1'-NCH3-, or R1'-NCH2CH3- substituted at any position on the phenyl group, where R1' refers to a substituted or unsubstituted C 1-5 alkyl group, herein, the substituted C 1-5 alkyl group, the substituent in which refers to one or two or more of -OH, -NHCH3, -N(CH3)2, -C≡CH substituted at any position of the C 1-5 alkyl group; or, R1', R1” and N form one or two of them; Preferably, R1 of Compound I is CH3NH-, CH3CH2NH-, CH3CH2CH2NH-, CH3CH2CH2CH2NH-, HOCH2CH2NH-, HC≡CCH2NH-, (CH3)2NCH2CH2NH-, (CH3)2N-, one or more of the following.

3. The derivative according to claim 1, wherein R2 of Compound II is H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, one or more of R2'R2”N-, wherein R2' and R2” each independently refer to one or more of H, substituted or unsubstituted C 1-5 alkyl, one or more of substituted or unsubstituted aryl, or in some cases, R2', R2” and N form one or more of 4-, 5- or 6-membered ring structures; herein, aryl refers to one or more of phenyl, thienyl, furyl, pyridyl, 1-5 the substituent in the substituted C 1-5 alkyl or aryl is one or more of -OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH3), -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2, -N(CH3)(CH2CH2NHCH3), -N(CH3)(CH2CH2N(CH3)2), Ar, one or more of them, wherein Ar refers to one or more of phenyl, thienyl, furyl, pyridyl, pyrrolyl, X refers to -CH2-, -CHCH3-, -NCH3-, -NCH2CH3-, -O-, Y is one or more of H, -CH3 or -CH2CH3, n' is 0, 1 or 2, and when n' is 0, X can only be one or more of -CH2- or -CHCH3-; Further, R2 of Compound II is one or two or more of H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH2, R2'-NH-, R2'-NCH3-, or R2'-NCH2CH3-; wherein, R2' refers to one or two or more of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, substituted C 1-5 alkyl, substituted phenyl; herein, the substituent refers to -OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3), 1-5 substituted at any position of the C one or two or more of; in some cases, R2', R2” form one or two or more of; Further, R2 of compound II is one or more of H, Br, methyl, methoxy, R2'-NH- or R2'-NCH3- substituted at any position on the phenyl group; wherein, R2' refers to one or more of methyl, ethyl, propyl, butyl, or substituted C 1-5 alkyl; herein, the substituent refers to -OH, -OCH3, -SH, -SCH3, -CF3, methanesulfonyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3) 1-5 substituted at the terminal position of the C alkyl far from -NH- or -NCH3-; one or more of them; Preferably, R2 of Compound II is H, Br, methyl, methoxy, which are substituted at any position on the phenyl group, one or two or more of those in R2'-NH-; wherein, R2' refers to one or two or more of methyl, ethyl, propyl, butyl, or substituted C 1-4 alkyl; herein, the substituent refers to -OH, -OCH3, -SH, -SCH3, -CF3, mesyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH2NHCH3), 1-4 substituted at the terminal position far from -NH- of C one or two or more of those; in some cases, R2', R2” and N form one or two or more of those.

4. The derivative according to claim 1, characterized in that, R3 of Compound II is one or more of H, F, Cl, Br, I, -NH3, -CHO, -COCH3, substituted or unsubstituted C 1-3 alkyl, where the substituent refers to one or more of -OH, -NH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2 substituted at any position of C 1-3 alkyl; Furthermore, R3 of compound II is one or more of H, Br, -CHO, -COCH3, -CH2OH, -CHOHCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)2, -CH2NHCH2CH2NHCH3, -CH2NHCH2CH2N(CH3)2; Preferably, R3 of compound II is one or more of H, Br, -CHO, -CH2OH, -CHOHCH3, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2NHCH2CH2N(CH3)2.

5. The derivative according to any one of claims 1-4, characterized in that, Its preferred compounds include one or more of the following: One or more of the above.

8. The derivative according to any one of claims 1-5, characterized in that, The said compound includes one or more of its corresponding enantiomeric mixtures, enantiomeric monomers, diastereomeric mixtures, diastereomeric monomers, and one or more of their pharmaceutically acceptable salts, solvates, hydrates or various crystalline compounds; The pharmaceutically acceptable salts refer to salts that the compound can form with pharmaceutically acceptable acids, and these acids refer to one or more of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, acetic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, citric acid, camphorsulfonic acid, malic acid, benzoic acid, gluconic acid.

7. Use of a derivative according to any one of claims 1-6 in the preparation of a medicament for treating cancer, characterized in that, The application of one or more of compound I, compound II, or their pharmaceutically acceptable salts, solvates, hydrates or crystalline compounds as active ingredients in the preparation of drugs for treating cancer, or in the application of inhibiting the process or substances of tumor cell proliferation.

9. The application according to claim 8, wherein the cancer is one or more of ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, colorectal cancer, liver cancer, leukemia, skin cancer, epithelial cell cancer, prostate cancer, bladder cancer, kidney cancer, nasopharyngeal cancer, thyroid cancer, malignant glioma, pancreatic cancer, lymphoma or melanoma.

9. A pharmaceutical composition comprising a derivative according to any one of claims 1-6 as an active ingredient, characterized in that, A pharmaceutical composition comprising, as an active ingredient, one or more of Compound I, Compound II, or one or more of pharmaceutically acceptable salts, solvates, hydrates, or crystalline forms thereof (Compound I and Compound II).

10. A pharmaceutical composition comprising, as an active ingredient, one or more of the Compound I, Compound II, or one or more of pharmaceutically acceptable salts, solvates, hydrates, or crystalline forms thereof as described in any one of claims 1-8, and any pharmaceutically acceptable excipients and / or other active compounds; The diseases to which the pharmaceutical composition is applicable are various cancers, such as one or more of ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, colorectal cancer, liver cancer, leukemia, skin cancer, epithelial cell cancer, prostate cancer, bladder cancer, kidney cancer, nasopharyngeal cancer, thyroid cancer, malignant glioma, pancreatic cancer, lymphoma, or melanoma.

11. A method for preparing any of the derivatives according to any one of claims 1-6, characterized in that, One or more of the following synthetic methods 1-5 are used for the synthesis of some derivatives: Synthetic Method 1 Reaction A Dissolve Compound SM1 (1.0 mmol, 1.0 molar equivalent) in acetic acid (1-10 ml), add N-bromosuccinimide (NBS, 1.0-2.0 molar equivalents relative to SM1) at 0-5 °C, stir at room temperature for 0.5-2.0 h, add saturated sodium sulfite solution to the reaction solution until the color of the reaction solution changes from reddish-brown to yellow; evaporate the reaction solution to dryness, add saturated sodium carbonate solution until pH = 7.0-9.0, extract with dichloromethane three times (5-10 ml each time), collect the organic phase and concentrate to remove the solvent, and purify the crude product by column chromatography to obtain the target product SM2; Reaction B Dissolve SM2 (1.0 mmol, 1.0 molar equivalent) and the substrate amine (3.0 molar equivalents relative to SM2) in dioxane (2-20 ml), add tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 0.1 molar equivalent relative to SM2), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP, 0.2 molar equivalent relative to SM2), and sodium tert-butoxide (3.0 molar equivalents relative to SM2), protect with nitrogen, and stir at 90 °C for 8-24 h; after TLC detection is complete, cool the reaction solution to room temperature, filter, concentrate the filtrate, and purify by column chromatography to obtain the target product I; Synthetic Method 2 R4 refers to one or more of H, methyl, ethyl, methoxy, ethoxy, F, Cl, Br substituted at any position of the phenyl group; In Reaction F, -NHR3’ is part of R3 as defined in claim 4 above; Reaction C Dissolve SM3 (1.0 mmol, 1.0 molar equivalent) in toluene (2-20 ml), add MnO2 (5.0 molar equivalents relative to SM3), and reflux and stir at 110 °C for 8-24 h; after TLC detection shows that the reaction is complete, cool the reaction solution to room temperature, filter, concentrate the filtrate, and purify by column chromatography to obtain the target product II-a; Reaction D Dissolve II-a (1.0 mmol, 1.0 molar equivalent) in acetic acid (2 - 20 ml), add hexamethylenetetramine (1.0 - 2.0 molar equivalents relative to II-a), heat to 100 °C and stir for 12 - 48 h; after detecting the completion of the reaction by LCMS, concentrate the reaction solution to remove acetic acid, add saturated sodium carbonate solution to adjust the pH to 7.0 - 8.0, extract with dichloromethane 2 - 4 times (10 ml each time), combine the organic phases, dry and then concentrate, and purify by column chromatography to obtain the target product II-b; Reaction E Dissolve II-b (1.0 mmol, 1.0 molar equivalent) in methanol (2 - 20 ml), add sodium borohydride (1.0 molar equivalent relative to II-d) under ice bath, and stir at room temperature for 0.5 h; after detecting the completion of the reaction of the raw materials by TLC, add 1.0 N hydrochloric acid (1.0 - 5.0 ml) to the reaction solution, add saturated sodium carbonate solution to adjust the pH to 7.0 - 8.0, extract with dichloromethane 2 - 4 times (10 ml each time), combine the organic phases, dry and then concentrate, and purify the organic phase by column chromatography to obtain the product II-c; Reaction F Dissolve II-b (1.0 mmol, 1.0 molar equivalent) in methanol, add the substrate amine R3’NH2 (3.0 molar equivalents relative to II-b), stir at room temperature for 0.5 h, add sodium cyanoborohydride (3.0 molar equivalents relative to II-b) and stir at room temperature for 8 - 24 h; after detecting the completion of the reaction by TLC, add saturated sodium carbonate solution to the reaction solution to adjust the pH to 7.0 - 8.0, extract with dichloromethane 2 - 4 times (10 ml each time), combine the organic phases, dry and then concentrate, and purify by column chromatography to obtain the target product II-d; Reaction G Dissolve II-b (1.0 mmol, 1.0 molar equivalent) in tetrahydrofuran (2 - 20 ml), add methylmagnesium bromide (3.0 molar equivalents relative to II-b) under ice bath, and stir at room temperature for 8 - 24 h; after detecting the completion of the reaction of the raw materials by TLC, add saturated sodium carbonate solution to the reaction solution to adjust the pH to 7.0 - 8.0, extract with dichloromethane 2 - 4 times (10 ml each time), combine the organic phases, dry and then concentrate, and purify by column chromatography to obtain the target product II-e; Synthesis Method 3 Reaction H Dissolve SM2 (1.0 mmol, 1.0 molar equivalent) in toluene (2 - 20 ml), add MnO2 (5.0 molar equivalents relative to SM2), reflux and stir at 110 °C for 8 - 24 h; after detecting the completion of the reaction by TLC, cool the reaction solution to room temperature, filter, and concentrate the filtrate to obtain the target product II-f; Reaction I Dissolve II-f (1.0 mmol, 1.0 molar equivalent) and the substrate amine (3.0 molar equivalents relative to II-f) in dioxane (2 - 20 ml), add Pd2(dba)3 (0.1 molar equivalent relative to II-f), BINAP (0.2 molar equivalent relative to II-f), and sodium tert-butoxide (3.0 molar equivalents relative to II-f), protect with nitrogen, and stir at 90 °C for 8 - 24 h; after detecting the completion of the reaction by TLC, cool the reaction solution to room temperature, filter, concentrate the filtrate, and purify by column chromatography to obtain the target product II-g; Synthesis method 4 R4 refers to one or more of H, methyl, ethyl, methoxy, ethoxy, F, Cl, Br substituted at any position of the phenyl group; Reaction J Dissolve SM3 (1.0 mmol, 1.0 molar equivalent) in acetic acid (2 - 20 ml), dropwise add a solution of bromine (3.0 molar equivalents relative to SM3) in acetic acid at 0 - 5 °C, heat to 65 °C and stir for 12 h, after detecting the completion of the reaction by LCMS; add saturated sodium bisulfite solution (2 - 10 ml) to quench the reaction in the reaction solution, then adjust to pH = 7.0 - 8.0 with saturated sodium carbonate solution, extract with ethyl acetate 2 - 4 times (10 ml each time), combine the organic phases, dry and concentrate, and purify by column chromatography to obtain the target product II-h; Synthesis method 5 When compound I or II forms a salt with a pharmaceutically acceptable acid (HX) (these acids refer to various pharmaceutically acceptable acids, such as: one or more of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, acetic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, citric acid, camphorsulfonic acid, malic acid, benzoic acid, gluconic acid), the synthesis method is as follows: Dissolve the substrate I or II (1.0 mmol, 1.0 molar equivalent) in dry tetrahydrofuran and / or dichloromethane (1.0 mmol substrate is dissolved in 2 - 10 ml), add various pharmaceutically acceptable acids (0.5 - 2.0 mmol), stir for 0.5 - 3.0 h, then concentrate by rotary evaporation to remove the solvent to obtain the corresponding acid salt; Or, the product resolution method in the above synthesis methods 1 - 5 When compound I or II is a chiral monomer, chiral chromatography can be used to resolve the racemate: Dissolve the racemic compound I or II in methanol, and separate and purify it by supercritical fluid chromatography through a BH (chiral) chromatographic column. The mobile phase A is CO2, B is triethylamine - methanol (volume concentration 0.1% - 2%), the volume ratio of A / B is in the range of 90 / 10 to 60 / 40, the elution time is 0 - 12 or 0 - 24 minutes, isocratic elution, and collect according to the chromatographic peaks to obtain the chiral monomer.

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