Ethylenediamine derivatives and preparation methods and applications thereof

Abstract

The present invention discloses an ethylenediamine derivative and a preparation method and application thereof. The structural formula of the ethylenediamine derivative is shown in Formula I. The compound can be prepared by an artificial synthesis method, has a broad-spectrum anti-tumor effect, can prolong the survival period of tumor patients, and improve the quality of life of tumor patients. The compound has stable efficacy, low toxicity, is easily accepted by the human body, can be used in the treatment of most cancers, and has certain advantages over the currently marketed anti-tumor drugs.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to an ethylenediamine derivative and a preparation method and application thereof. Background Art

[0002] Studies have found that bradykinin (BK) is an important growth factor for many cancers. It can promote angiogenesis by stimulating the secretion of vascular endothelial growth factor, and can also stimulate cancer cell migration and invasion by activating matrix metalloproteinase (MMP) activity enzymes.

[0003] BK acts on the body by binding to the B1 receptor (B1R) and B2 receptor (B2R) on the cell membrane. Both B1R and B2R are G protein-coupled receptors. Studies on cancer have found that B1R is not only abnormally upregulated in malignant prostate tumors, but can also stimulate the activation of macrophages and dendritic cells in the tumor microenvironment; B2R is not only overexpressed in human brain gliomas, but has also been detected in gastric cancer, duodenal cancer, prostate cancer, lung cancer and liver cancer.

[0004] Whether BK binds to B1 receptor or B2 receptor, the final result is mainly through the Gq subunit in the G protein-coupled receptor family to stimulate phospholipase C-β (PLC-β), promote the hydrolysis of inositol triphosphate (IP3) and the intracellular Ca 2+ The mobilization of mitogen activated protein kinase (MAPK) pathway can promote cancer cell proliferation, migration and invasion by inhibiting adenylate cyclase (AC) through G protein subunit Gα-i. The MAPK pathway involves P38, JNK and ERK.

[0005] A series of inhibitors have been developed based on this target, such as compounds PL-AC-15 and PL-AC-202. PL-AC-15 is an amino acid derivative developed by Jiangsu Pulai Pharmaceutical Biotechnology Co., Ltd. (see Chinese patent CN107382827B), which has good anti-tumor effects. PL-AC-202 is a compound obtained by Jiangsu Pulai Pharmaceutical Biotechnology Co., Ltd. through further structural optimization and modification on the basis of PL-AC-15 (see Chinese patent application No. 202010386293.7). Further structural modification is expected to obtain a compound with better anti-tumor effect. Summary of the invention

[0006] One object of the present invention is to provide a class of ethylenediamine derivatives and pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof).

[0007] The structural formula of the ethylenediamine derivative provided by the present invention is as follows:

[0008]

[0009] Wherein, R1 is selected from any of the following groups: C 1-10 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, oxy C 6-14 Aryl or oxy C 5-14 Aromatic hetero groups, nitrogen groups C 6-14 Aryl or nitrogen C 5-14 Heteroaromatic group, 5-14 membered heteroaryl group.

[0010] The hydrogen on R1 can be arbitrarily replaced by one or more of the following substituents: halogen, C 1-10 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, oxy C 6-14 Aryl or oxy C 5-14 Aromatic hetero groups, nitrogen groups C 6-14 Aryl or nitrogen C 5-14 Aromatic heteroaryl, 5-14 membered heteroaryl, -CN, -NO2, -CF2H, -CF2OH, -CF3, -OCF3, -CR 1 R 2 R 3 、-OR 1 , -O(C=O)R 1 、-O(C=O)OR 1 、-O(C=O)NR 2 R 3 、-(C=O)R 1 、-(C=O)OR 1 、-(C=O)NR 2 R 3 、-SR 1 、-(S=O) m R 1 、-NR 2 R 3 、-NR 4 (C=O)R 1 、-NR 4 C(=O)NR 2 R 3 、-NR 4 C(=O)OR 1 、-NR 4 S(=O) m NR2 R 3 、-NR 4 S(=O) m OR 1 or -NR 4 S(=O) m R 1 , or groups of adjacent atoms on R1 can be combined to form C 3-12 Cycloalkyl, C 6-12 Aryl, 3-12 membered heterocyclic ring and 5-12 membered heteroaromatic ring;

[0011] Where R 1 , R 2 , R 3 , R 4 Can be independently selected from hydrogen, halogen or any of the following groups: C 1-10 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, oxy C 6-14 Aryl or oxy C 5-14 Aromatic hetero groups, nitrogen groups C 6-14 Aryl or nitrogen C 5-14 heteroaryl, 5-14 membered heteroaryl, or R bound to the same nitrogen atom 1 , R 2 , R 3 , R 4 Any two of the may be combined together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which optionally contains 1 to 3 additional heteroatoms selected from N, O and S, or R attached to the same carbon atom 1 , R 2 , R 3 Any two of them can be combined to form C 3-12 Cycloalkyl, C 6-12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and R 1 , R 2 , R 3 , R 4 Each hydrogen in is optionally replaced by R 5 Replace, or R 1 , R 2 , R 3 , R 4 Two hydrogen atoms on the same carbon atom in are optionally oxo substituents.

[0012] R 5 Can be independently selected from the following groups: hydrogen, halogen, C 1-10 Alkyl, C 2-8 Alkenyl, C2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, oxy C 6-14 Aryl or oxy C 5-14 Aromatic hetero groups, nitrogen groups C 6-14 Aryl or nitrogen C 5-14 Heteroaromatic group, 5-14 membered heteroaryl group; -CN, -NO2, -OH, -NH2, partially or fully halogenated C 1-5 Alkyl, -C(=O)(CH2) n CH3, -C(=O)O(CH2) n CH3, -C(=O)OH, -C(=O)N[(CH2) n CH3]2, -C(=O)NH2, -C(=O)NH(CH2) n CH3, -NH(CH2) n CH3, -N[(CH2) n CH3]2, -N(CH2) n CH3C(=O)(CH2) n CH3, -N(CH2) n CH3C(=O)NH(CH2) n CH3, -N(CH2) n CH3C(=O)N[(CH2) n CH3]2, -N(CH2) n CH3C(=O)NH2 、-N(CH2) n CH3C(=O)O(CH2) n CH3, -N(CH2) n CH3C(=O)OH, -NHC(=O)(CH2) n CH3, -NHC(=O)NH(CH2) n CH3, -NHC(=O)N[(CH2) n CH3]2, -NHC(=O)NH2, -NHC(=O)O(CH2) n CH3,-NHC(=O)OH,-N(CH2) n CH3S(=O) m (CH2) n CH3, -NHS(=O) m (CH2) n CH3, -O(CH2) n CH3, =O, -OC(=O)(CH2) n CH3、OC(=O)O(CH2) nCH3, -OC(=O)N[(CH2) n CH3]2, -OC(=O)NH(CH2) n CH3, -OC(=O)NH2, -S(=O) m (CH2) n CH3, -OS(=O) m (CH2) n CH3, -S(=O) m NH(CH2) n CH3, -S(=O) m N[(CH2) n CH3]2;

[0013] The m is selected from 1 or 2;

[0014] The n is selected from 1, 2, 3, 4 or 5.

[0015] R2 is selected from any of the following groups: H, halogen, C 1-10 Alkyl, oxy C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, oxy C 6-14 Aryl, oxy C 5-14 Aromatic hetero groups, nitrogen groups C 6-14 Aryl, nitrogen C 5-14 Heteroaromatic group, 5-14 membered heteroaryl group.

[0016] The hydrogen on R2 can be arbitrarily replaced by one or more of the following substituents: halogen, -CN, -NO2, -CF2H, -CF2OH, -CF3, -OCF3, -CR 6 R 7 R 8 、-OR 6 、-O(C=O)R 6 、-O(C=O)OR 6 、-O(C=O)NR 7 R 8 、-(C=O)R 6 、-(C=O)OR 6 、-(C=O)NR 7 R 8 、-SR 6 、-(S=O)R 6 、-S(=O)2R 6 、-NR 7 R 8 、-NR 9 (C=O)R6 、-NR 9 C(=O)NR 7 R 8 、-NR 9 C(=O)OR 6 、-NR 9 S(=O) m NR 7 R 8 、-NR 9 S(=O) m OR 6 or -NR 9 S(=O) m R 6 , or groups of adjacent atoms on R2 can be combined to form C 3-12 Cycloalkyl, C 6-12 Aryl, 3-12 membered heterocyclic ring and 5-12 membered heteroaromatic ring;

[0017] Where R 6 , R 7 , R 8 , R 9 It can be hydrogen or any one of C 1-10 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, oxy C 6-14 Aryl or oxy C 5-14 Aromatic hetero groups, nitrogen groups C 6-14 Aryl or nitrogen C 5-14 an aromatic heterocyclic group, a 5-14 membered heteroaryl group, or any two of R1, R2, R3, and R4 bonded to the same nitrogen atom may be combined together with the nitrogen to which they are bonded to form a 3-12 membered heterocyclic group or a 5-12 membered heteroaryl group, which optionally contains 1 to 3 additional heteroatoms selected from N, O, and S; or R bonded to the same carbon atom 6 , R 7 , R 8 R 9 Any two of them can be combined to form C 3-12 Cycloalkyl, C 6-12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and R 6 , R 7 , R 8 Each hydrogen in is optionally replaced by R 10 Replace, or R 6 , R 7 , R 8 , R 9 Two hydrogen atoms on the same carbon atom in are optionally oxo substituents.

[0018] R 10 Can be independently selected from: hydrogen, halogen, C 1-10 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, oxy C 6-14 Aryl or oxy C 5-14 Aromatic hetero groups, nitrogen groups C 6-14 Aryl or nitrogen C 5-14 Heteroaromatic, 5-14 membered heteroaryl, -CN, -NO2, -OH, -NH2, partially or fully halogenated C 1-5 Alkyl, -C(=O)(CH2) n CH3, -C(=O)O(CH2) n CH3, -C(=O)OH, -C(=O)N[(CH2) n CH3]2, -C(=O)NH2, -C(=O)NH(CH2) n CH3, -NH(CH2) n CH3, -N[(CH2) n CH3]2, -N(CH2) n CH3C(=O)(CH2) n CH3, -N(CH2) n CH3C(=O)NH(CH2) n CH3, -N(CH2) n CH3C(=O)N[(CH2) n CH3]2, -N(CH2) n CH3C(=O)NH2、-N(CH2) n CH3C(=O)O(CH2) n CH3, -N(CH2) n CH3C(=O)OH, -NHC(=O)(CH2) n CH3, -NHC(=O)NH(CH2) n CH3, -NHC(=O)N[(CH2) n CH3]2, -NHC(=O)NH2, -NHC(=O)O(CH2) n CH3,-NHC(=O)OH,-N(CH2) n CH3S(=O) m (CH2) n CH3, -NHS(=O) m (CH2) n CH3, -O(CH2) nCH3, =O, -OC(=O)(CH2) n CH3、OC(=O)O(CH2) n CH3, -OC(=O)N[(CH2) n CH3]2, -OC(=O)NH(CH2) n CH3, -OC(=O)NH2, -S(=O)m(CH2) n CH3, -OS(=O)m(CH2) n CH3, -S(=O) m NH(CH2) n CH3, -S(=O) m N[(CH2) n CH3]2;

[0019] The m is selected from 1 or 2;

[0020] The n is selected from 1, 2, 3, 4 or 5.

[0021] W represents a bond or any group selected from the following: C 1-8 Alkylene (such as -CH2CH2-), C 2-8 Alkenylene (such as -CH2=CH-CH2-), C 2-8 Alkyne (e.g. -C≡C-CH2-), C 3-8 Cycloalkylene, 3-8 membered heterocyclylene, oxy C 1-8 Alkylene, -O-, -NH-, amino C 1-8 Alkylene, or any one or more hydrogen atoms of the above groups are replaced by halogen, and any hydrogen atoms are replaced by R 11 The above-mentioned groups substituted, wherein R 11 Same definition as R 1 .

[0022] The C 3-8 Cycloalkylene includes but is not limited to the following groups:

[0023]

[0024] The 3-8 membered heterocyclylene group includes but is not limited to the following groups:

[0025]

[0026] The oxygen group C 1-8 Alkylene, such as: -OCH2-, -CH2O-,

[0027] The amino C 1-8 Alkylene, such as: -NHCH2-, -CH2NH-, -NCH3CH2-, -CH2 CH3N-,

[0028] X represents a chemical bond or any group selected from the following: C 1-8 Alkylene (such as -CH2-, -CH2CH2-, -CHCH3CH2-), -O-, oxy 1-8 Alkylene (such as: -OCH2-, -CH2O-), -NH-, amino C 1-8 Alkylene (such as -NHCH2-, -CH2NH-, -NCH3CH2-), mercapto 1-8 Alkylene (eg. -SCH2-, -CH2S-), oxidized mercapto C 1-8 Alkylene (e.g., -S(=O)CH2-, -CH2S(=O)2-), -S(=O)NH-, -S(=O)2NH-, or any one or more hydrogen atoms on X are replaced by halogen, and any hydrogen atoms on X are replaced by R 12 The above groups substituted. 12 Same definition as R 1 .

[0029] Preferably R1 is selected from any of the following groups: 1-4 Alkyl, C 2-4 Alkenyl, C 3-7 Cycloalkyl (such as cyclohexyl), phenyl, phenoxy, fluorenyl, pyridyl, substituted pyridyl, and any hydrogen on R1 replaced by R 13 A substituted group, wherein R 13 Definition and R 10 same;

[0030] Preferably, R2 is selected from any of the following groups: H, halogen, phenyl, biphenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, and any hydrogen on R2 is replaced by R 14 A substituted group, wherein R 14 Definition and R 10 same:

[0031] Preferably W represents a chemical bond or is selected from any of the following groups: C 1-4 Alkylene, C 2-6 Alkenylene, -OCH2-, -CH2O-;

[0032] Preferably X represents a chemical bond or any group selected from the following: -CH2-, -CH2CH2-, oxy-C 1-4 Alkylene,

[0033] Furthermore, the R1 combined with the W group in Formula I includes but is not limited to the following fragments:

[0034]

[0035] In Formula I, X combined with R2 includes but is not limited to the following fragments:

[0036]

[0037] In some embodiments, the ethylenediamine derivatives of the present invention can be listed as follows, but are not limited to the following structures (all compound structures are shown in Table 1):

[0038] Table 1 List of ethylenediamine derivatives of the present invention

[0039]

[0040]

[0041]

[0042]

[0043] The term "alkyl" used in the present invention refers to a group consisting of only carbon atoms and hydrogen atoms and not having a degree of unsaturation (such as a double bond, a triple bond or a ring), which encompasses various possible geometric isomer groups and stereoisomer groups. The group is connected to the rest of the molecule by a single bond. As the limiting examples of alkyl, the following straight or branched groups can be enumerated: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, the tert-butyl, n-pentyl and other seven isomers thereof, n-hexyl and other 16 isomers thereof, n-heptyl and various isomers thereof, n-octyl and various isomers thereof, n-nonyl and various isomers thereof, n-decyl and various isomers thereof.

[0044] The term "cycloalkyl" used in the present invention refers to a saturated non-aromatic ring system consisting of at least 3 carbon atoms, which can be a monocyclic, bicyclic, polycyclic, or condensed, bridged, or spirocyclic ring. As non-limiting examples of cycloalkyl, the following groups can be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; and condensed, bridged, or spirocyclic groups formed by two or more of the above monocyclic rings through common edges and common carbon atoms.

[0045] The term "aryl" used in the present invention can be used alone or as part of "arylalkyl" and refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members and has only one attachment point to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring", such as aromatic rings can include phenyl, naphthyl, anthracenyl.

[0046] The term "heteroaryl" used in the present invention refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, and the ring system can be monocyclic, bicyclic or polycyclic, wherein the bicyclic and polycyclic rings can be formed by a monocyclic ring connected by a single bond or by fusion. As non-limiting examples of the heteroaryl group, the following groups can be mentioned: oxazolyl, isoxazolyl, imidazolyl, furanyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, coumarinyl, pyrazolopyridinyl, pyridopyridazinyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridazinyl; and groups formed by the above heteroaryl groups connected by a single bond or condensed.

[0047] The compounds of the present invention may also be used in the form of pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof).

[0048] Another object of the present invention is to provide a method for preparing the ethylenediamine derivative shown in Formula I.

[0049] The synthesis route of the ethylenediamine derivative compounds represented by formula I provided by the present invention is as follows:

[0050]

[0051] The specific preparation method comprises the following steps: activating R1-W-COOH with oxalyl chloride [(COCl)2)], and then reacting with intermediate 1 or intermediate 2 at room temperature to obtain the corresponding final product of formula I.

[0052]

[0053] In the intermediate 1, R is -X-R2, wherein X is defined as in Formula I (excluding the case where X is -OCH2-), and R2 in the intermediate 1 is defined as in Formula I.

[0054]

[0055] In the intermediate 2, Y represents that the hydrogen in the benzene ring connected to Y is replaced by one or more R 15 The substituted group, wherein R 15 The definition of R is the same as that of Formula I 1 .

[0056] Specifically, the synthetic route of the intermediate 1 is as follows:

[0057]

[0058] The specific preparation method of the intermediate 1 is as follows: NaBH4 is used to reduce carboxylic acid 1 under Lewis acid catalysis to obtain compound 2; compound 2 is oxidized under the conditions of NaBr, NaClO and TEMPO to obtain compound 3; and then amino reduction with 4-amino-2,2,6,6-tetramethylpiperidine under the conditions of NaBH(OAc)3 to obtain compound 4; compound 4 is deprotected by TFA in DCM to obtain intermediate 1.

[0059] The synthetic route of the intermediate 2 is as follows:

[0060]

[0061] The specific preparation method of the intermediate 2 is as follows: phenol 5 and bromide undergo substitution reaction under K2CO3 to obtain compound 6; in MeOH / THF / H2O solution, compound 6 is hydrolyzed by NaOH to obtain compound 7; under NaBH4, compound 7 is reduced to obtain compound 8; compound 8 is then oxidized by NaBr, TEMPO and NaClO to obtain compound 9; the compound 9 undergoes reductive amination reaction with 4-amino-2,2,6,6-tetramethylpiperidine to obtain compound 10; compound 10 is deprotected by TFA to obtain intermediate 2.

[0062] Another object of the present invention is to provide the use of the ethylenediamine derivative represented by the above formula I or its pharmaceutically acceptable salt, ester, solvate or isomer (including stereoisomer, enantiomer, tautomer or mixture thereof).

[0063] The applications provided by the present invention include the following aspects: 1) application of the ethylenediamine derivatives shown in formula I or their pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof) in the preparation of drugs for preventing and / or treating cancer; 2) application of the ethylenediamine derivatives shown in formula I or their pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof) in the preparation of drugs for inhibiting the proliferation of cancer cells.

[0064] The cancer includes various cancers (solid cancer or non-solid cancer) known in the art, including but not limited to: liver cancer, lung cancer, and prostate cancer.

[0065] The cancer cells include liver cancer cells (such as Bel-7402 cells, HepG-2 cells, SK-hep1 cells), lung cancer cells (such as A549 cells, H460 cells, H1299 cells, H292 cells), and prostate cancer cells (such as PC-3 cells).

[0066] Drugs for preventing and / or treating cancer prepared with the ethylenediamine derivatives shown in Formula I or their pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof) as active ingredients also fall within the scope of protection of the present invention.

[0067] The tripeptide compound of formula I provided by the present invention is a brand-new compound designed from scratch. The compound in the present invention is a class of bradykinin receptor antagonists, which inhibit the growth and invasion of tumor cells by inhibiting the binding of bradykinin to its receptor, and further inhibit the occurrence of tumors. Compounds with similar structures may have the same mechanism of action. Understanding the mechanism of action of different compounds is helpful to fully understand the clinical application prospects of the compounds and their analogs in the present invention and possible problems, so that research and development are more targeted. DETAILED DESCRIPTION

[0068] The present invention is described below by means of specific embodiments, but the present invention is not limited thereto, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

[0069] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0070] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0071] The structural formula of the PL-AC-15 compound involved in the following examples is as follows:

[0072]

[0073] For details of its preparation, please refer to Chinese patent CN107382827B.

[0074] The structural formula of the PL-AC-202 compound involved in the following examples is as follows:

[0075]

[0076] The details of its preparation refer to Chinese patent CN113620862A.

[0077] 1. Preparation and characterization of compounds

[0078] Example 1: (S,E)-N-(1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-4-phenyl-3-enamide (Cpd001)

[0079]

[0080] The preparation method of intermediate 16 (corresponding to Y=2,6-dichloro in intermediate 2) is as follows:

[0081]

[0082] 1) Compound 5 (47.8 g, 170 mmol) was dissolved in acetonitrile, potassium carbonate (48.4 g, 350 mmol) was added, and 2,6-dichlorobenzyl bromide (33.6 g, 140 mmol) was added after stirring for 10 minutes, and the mixture was reacted at 80°C for 15 hours. After TLC showed that compound 5 was completely reacted (EA / PE=1 / 5, v / v), the system was spin-dried, 300 mL of water was added to obtain white insoluble matter, and a white solid was obtained by suction filtration, which was compound 11 (45 g).

[0083] 2) Compound 11 (35.0 g, 79 mmol) was dissolved in tetrahydrofuran and methanol (350 mL: 350 mL, v / v), and sodium hydroxide aqueous solution was slowly added, and the reaction was carried out at room temperature for 15 hours. After TLC showed that compound 11 was completely reacted (EA / PE = 1 / 5, v / v), the system was spin-dried, an appropriate amount of water was added, and the pH of the system was adjusted to 3-4 with dilute hydrochloric acid, and a white solid was obtained by suction filtration, which was compound 12 (23 g, yield 68.4%).

[0084] 3) Compound 12 (21.3 g, 50 mmol) was dissolved in methanol, cooled to 0-5°C, NiCl2.6H2O (11.9 g, 50 mmol) was added under stirring, and then NaBH4 (7.6 g, 200 mmol) was added in batches. After the addition was completed and the reaction was kept warm for more than 1 hour, TLC showed that compound 12 was completely reacted (EA / PE = 1 / 3, v / v). The system was directly filtered to obtain a gray-black filtrate, and a saturated sodium bicarbonate solution was added to the filtrate to adjust the pH of the system to 7-8. It was then extracted with ethyl acetate, and the organic phase was dried and spin-dried to obtain a light yellow oil, which was purified by column chromatography (EA / PE = 1 / 5, v / v) to obtain compound 13 (9.4 g, yield 45.6%)

[0085] 4) Compound 13 (8.5 g, 20 mmol) was dissolved in isopropyl acetate, sodium bromide (206 mg, 2 mmol) and TEMPO (31.3 mg, 0.2 mmol) were added, cooled to -5-5°C, and sodium hypochlorite (2.2 g, 30 mmol) aqueous solution adjusted to pH 9-10 with sodium bicarbonate was added dropwise. About 1 hour after the addition, TLC showed that the reaction was complete (EA / PE = 1 / 3, v / v). The reaction was returned to room temperature, 10% sodium sulfite solution was added to quench the reaction, and then extracted with ethyl acetate. The organic phase was dried and vortexed to obtain a light yellow oil 14 (6.2 g, yield 75.2%).

[0086] 5) Compound 14 (14.0 g, 34 mmol) was dissolved in dichloromethane, 4-amino-2,2,6,6-tetramethylpiperidine (5.3 g, 34 mmol) was added, and the mixture was cooled to about 0°C. NaBH(OAc)3 (14.4 g, 68 mmol) was added in batches. After the addition was completed, the mixture was slowly returned to room temperature and reacted for 15 hours. After TLC showed that the reaction was complete (EA / PE=1 / 3, v / v), a saturated sodium bicarbonate solution was added, the pH of the system was adjusted to 7-8, and then the mixture was extracted with dichloromethane. The organic phase was dried and spin-dried to obtain a light yellow oil 15 (15.8 g, yield 84.3%).

[0087] 6) Compound 15 (15.0 g, 27 mmol) was dissolved in 500 mL of dichloromethane, cooled to 0-5°C, and 100 mL of TFA was added dropwise. After the addition was completed, the mixture was stirred for 30 minutes and returned to room temperature for reaction for 3 hours. After TLC showed that the reaction was complete (methanol / dichloromethane = 1 / 10, v / v), the system was directly spin-dried, saturated sodium bicarbonate solution was added, the pH of the system was adjusted to 7-8, and then extracted with ethyl acetate. After the organic phase was dried and spin-dried, it was purified by column chromatography (methanol / dichloromethane = 1 / 20, v / v) to obtain a light reddish brown clear oil intermediate 16 (4.3 g, yield 36.4%).

[0088]

[0089] 1) Compound 17 (0.73 g, 4.5 mmol) was dissolved in 10 mL of dichloromethane, 3 drops of DMF were added, and the mixture was cooled to 0-5°C. Oxalyl chloride (1.14 g, 9 mmol) was added dropwise. After the addition, the mixture was stirred for 20 minutes at room temperature. The mixture was returned to room temperature for reaction for 5 hours, and the mixture was dried to obtain intermediate 18.

[0090] 2) Dissolve the intermediate 18 (0.81 g, 4.5 mmol) in 10 mL of dichloromethane, add triethylamine, cool to 0-5 ° C, slowly dropwise add 10 mL of dichloromethane solution of the product from the previous step (intermediate 16, 2.03 g, 4.5 mmol), keep warm for 30 minutes after the dropwise addition, return to room temperature and react for 10 hours. TLC (methanol / dichloromethane = 1 / 10, v / v) shows that the reaction is complete. Wash the reaction solution with water, dry the organic phase, and purify it by column chromatography (methanol / dichloromethane = 1 / 15, v / v) to obtain the product Cpd001 (S, E) -N- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -4-phenyl-3-enamide (530 mg, yield 19.4%).

[0091] Structure confirmation data: 1 H NMR (400MHz, DMSO-d6) δ8.12(s,2H),7.74(d,J=8.2Hz,1H),7.59–7.53(m,2H),7.47(dd,J=8.9,7.1Hz,1H),7.39(d,J=7 .2Hz,2H),7.36–7.28(m,2H),7.26–7.16(m,1H),7.19–7.12(m,2H),6.96–6.88(m,2H),6.44(d,J=15.9Hz,1H),6.28(dt ,J=15.8,7.0Hz,1H),5.20–5.08(m,2H),3.95(s,1H),3.30(s,1H),3.11(s,1H),3.00(d,J=7.1Hz,2H),2.94(s,1H),2.7 8(dd,J=13.8,5.3Hz,1H),2.61(t,J=7.0Hz,3H),1.85(t,J=16.1Hz,2H),1.34–1.21(m,13H),1.13(d,J=12.2Hz,2H).MS m / z:608.2(M+H).

[0092] Other compounds of formula I were prepared according to the preparation method of Example 1 (Cpd001) (racemic) above using the corresponding intermediates and carboxylic acids.

[0093] Example 2: (S)-N-((S)-1-([1,1'-biphenyl]-4-yl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanamide (Cpd002)

[0094]

[0095] 1 H NMR(400MHz, CDCl3)δ7.58–7.29(m,13H),7.20(d,J=7.9Hz,2H),7.16–7.08(m,2H),6.26(s,1H) ,4.24(d,J=7.0Hz,1H),3.61(q,J=7.1Hz,1H),3.48(s,2H),2.92(dd,J=13.7,6.7Hz,1H),2.81( dd,J=13.8,7.1Hz,1H),2.69(s,1H),1.78(d,J=13.1Hz,1H),1.65(d,J=13.1Hz,1H),1.52–1.44 (m,7H),1.40(d,J=8.3Hz,6H),1.33(s,3H),1.25(t,J=3.5Hz,1H),0.86(s,1H),0.07(s,1H).MS m / z:592.4(M+H).

[0096] Example 3: (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)-N-((S)-1-phenyl-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)propanamide (Cpd003)

[0097]

[0098] 1 H NMR(400MHz,DMSO-d6)δ7.83(d,J=8.4Hz,1H),7.57–7.45(m,4H),7.47–7.34(m,2H),7.1 5–7.04(m,5H),7.02(dd,J=7.3,2.2Hz,2H),3.93(d,J=6.3Hz,1H),3.62(q,J=7.0Hz,1H) ,2.86–2.74(m,2H),2.57(dd,J=13.4,7.6Hz,3H),1.70(t,J=13.9Hz,2H),1.32(d,J=7.0 Hz,3H),1.28–1.21(m,2H),1.15(s,6H),1.08(s,6H),1.04(s,0H),0.89–0.82(m,3H).MS m / z:592.4(M+H).

[0099] Example 4: (S)-N-((S)-1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propaneamide (Cpd004)

[0100]

[0101] 1 H NMR(400MHz,DMSO-d6)δ7.85(d,J=8.7Hz,1H),7.60–7.49(m,4H),7.53–7.42(m,4H),7.46–7.35(m,1H) ,7.27–7.19(m,2H),7.18–7.11(m,2H),7.01–6.92(m,2H),5.18(s,2H),3.95(d,J=7.1Hz,1H),3.63(q, J=7.0Hz,1H),3.29(s,1H),2.83(s,1H),2.79(dd,J=13.7,5.3Hz,1H),2.66–2.56(m,2H),2.53(s,1H), 1.82–1.73(m,1H),1.58(d,J=13.1Hz,1H),1.30–1.24(m,6H),1.23(d,J=16.0Hz,10H),1.03(s,2H).MS m / z:690.3(M+H).

[0102] Example 5: (S)-N-((S)-1-(4-chlorophenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanamide (Cpd005)

[0103]

[0104] 1H NMR(400MHz,DMSO-d6)δ7.85(dd,J=12.4,8.6Hz,1H),7.58–7.29(m,10H),7.31(s,1H),7.25–7.17(m,3H),7.14–6 .99(m,3H),3.95(s,2H),3.60(dd,J=7.2,3.9Hz,1H),2.82(dt,J=11.8,5.7Hz,2H),2.70(s,1H),2.67–2.53(m,3H) ,2.05–1.95(m,1H),1.72(t,J=15.9Hz,1H),1.61(d,J=12.4Hz,1H),1.50–1.41(m,1H),1.31(d,J=7.5Hz,3H),1.29 –1.21(m,8H),1.17(s,4H),1.10(d,J=5.8Hz,6H),1.05(s,4H),1.00(s,3H),0.85(t,J=6.6Hz,1H),0.75(s,2H).MS m / z:550.25(M+H).

[0105] Example 6: (9H-fluoren-9-yl)methyl-(1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)carbamate (Cpd006)

[0106]

[0107] 1 H NMR (400MHz, DMSO-d6) δ7.88(t,J=8.6Hz,3H),7.64(t,J=7.7Hz,2H),7.55(d,J=7.4Hz,2H),7.52–7.27(m,5H) ,7.19(d,J=8.7Hz,1H),7.14(d,J=8.3Hz,2H),6.93(d,J=8.0Hz,2H),5.22–5.09(m,2H),4.27(dd,J=8.6,4.7Hz ,1H),4.22–4.12(m,2H),3.65(d,J=6.5Hz,1H),2.86(s,1H),2.78(dd,J=13.6,5.2Hz,1H),2.59(s,12H),1.98 (s,1H),1.76(t,J=12.3Hz,2H),1.47(s,1H),1.32–1.17(m,22H),1.01(s,4H),0.95(dd,J=13.8,6.6Hz,1H).MS m / z:686.25(M+H).

[0108] Example 7: (S)-N-(1-([1,1'-biphenyl]-4-yl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-3,3-dimethylbutylamine (Cpd007)

[0109]

[0110] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.69–7.56(m,3H),7.59–7.53(m,3H),7.45(dd,J=8.3,7 .0Hz,2H),7.34(t,J=7.4Hz,1H),7.30(d,J=8.1Hz,2H),4.05(s,1H),3.30(s,2H),2.95(s,2H) ,2.88(dd,J=13.8,5.5Hz,1H),2.65(dd,J=13.8,8.3Hz,1H),2.60(d,J=6.2Hz,2H),1.93–1.82 (m,4H),1.41–1.30(m,12H),1.24(s,1H),1.16(s,1H),1.12(d,J=11.7Hz,1H),0.87(s,9H).MS m / z:464.3(M+H).

[0111] Example 8: (S)-N-(1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-3,3-dimethylbutylamine (Cpd008)

[0112]

[0113] 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.59–7.54(m,2H),7.53(s,1H),7.47(dd,J=8.9 ,7.1Hz,1H),7.15(d,J=8.6Hz,2H),6.99–6.92(m,2H),5.18(s,2H),4.06–3.97(m,1H ),3.30(s,1H),2.97(s,1H),2.78(dd,J=13.9,5.6Hz,1H),2.61–2.52(m,3H),1.96–1 .82(m,4H),1.37–1.31(m,11H),1.28–1.17(m,1H),1.20–1.12(m,1H),0.87(s,8H).MS m / z:562.45(M+H).

[0114] Example 9: N-((S)-1-([1,1'-biphenyl]-4-yl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-2-cyclohexylbutylamine (Cpd009)

[0115]

[0116] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.68–7.51(m,6H),7.44(t,J=7.6Hz,2H),7.32(ddd,J=18.0,7.7,1.9 Hz,4H),4.12(s,1H),2.98(d,J=12.6Hz,1H),2.90(dt,J=20.0,7.0Hz,1H),2.70–2.54(m,4H),1.87(s,2H), 1.77–1.65(m,1H),1.65–1.49(m,2H),1.33(t,J=7.4Hz,17H),1.27–1.21(m,2H),1.10(t,J=14.2Hz,5H),0. 96–0.87(m,1H),0.87–0.74(m,1H),0.73(d,J=7.3Hz,1H),0.62(t,J=12.6Hz,1H),0.47(t,J=7.3Hz,2H).MS m / z:518.55(M+H).

[0117] Example 10: 2-cyclohexyl-N-((S)-1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)butanamide (Cpd010)

[0118]

[0119] 1H NMR(400MHz, DMSO-d6)δ8.32(s,1H),7.59–7.50(m,3H),7.47(dd,J=9.0,7.1Hz,1H),7.15(d,J=8.5Hz,2H),6 .97–6.90(m,2H),5.15(s,2H),4.06(s,1H),2.95(s,1H),2.85(dd,J=13.8,4.5Hz,1H),2.58(d,J=6.3Hz,2H), 1.86(t,J=14.0Hz,2H),1.73–1.55(m,3H),1.49(d,J=9.2Hz,2H),1.40(d,J=7.7Hz,1H),1.36–1.21(m,14H),1 .14(s,7H),1.04(d,J=12.0Hz,1H),0.95(dd,J=10.9,7.9Hz,1H),0.74(t,J=7.3Hz,3H),0.65–0.55(m,1H).MS m / z:618.25(M+H).

[0120] Example 11: (S,E)-N-(1-([1,1'-biphenyl]-4-yl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-4-phenyl-3-enamide (Cpd011)

[0121]

[0122] 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.79(d,J=8.5Hz,1H),7.60–7.49(m,4H),7.43(dd,J=8.3,6.9H z,2H),7.41–7.29(m,3H),7.33–7.23(m,4H),7.26–7.17(m,1H),6.41(d,J=15.9Hz,1H),6.24(dt,J= 15.8,7.0Hz,1H),4.04–3.98(m,1H),3.07–2.92(m,2H),2.95(s,1H),2.90(dd,J=13.7,5.2Hz,1H),2 .72–2.58(m,3H),1.87(ddd,J=21.3,13.0,3.3Hz,2H),1.35–1.21(m,13H),1.14(q,J=11.8Hz,2H).MS m / z:510.45(M+H).

[0123] Example 12: (S)-N-(1-([1,1'-biphenyl]-4-yl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-2-chloronicotinamide (Cpd012)

[0124]

[0125] 1 H NMR (400MHz, DMSO-d6) δ8.52–8.42(m,2H),7.70(dd,J=7.6,2.0Hz,1H),7.66(dd, J=7.2,1.8Hz,2H),7.63–7.58(m,2H),7.52–7.42(m,3H),7.36(d,J=7.8Hz,3H),4. 26–4.16(m,1H),2.98(dd,J=13.7,5.5Hz,2H),2.90(s,0H),2.77(dd,J=13.7,8.4H z,1H),2.73(s,1H),2.72(s,1H),1.85(s,2H),1.30–1.21(m,14H),1.06(s,3H).MS m / z:505.3(M+H).

[0126] Example 13: (S)-2-chloro-N-(1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)nicotinamide (Cpd013)

[0127]

[0128] 1 H NMR (400MHz, DMSO-d6) δ8.49–8.40(m,2H),8.32(s,1H),7.69(dd,J=7.5,2.0Hz,1H),7.57(d,J=8. 0Hz,2H),7.48(ddd,J=9.0,6.0,4.0Hz,2H),7.21(d,J=8.2Hz,2H),7.00(d,J=8.5Hz,2H),5.20(s, 2H),4.15(d,J=7.7Hz,1H),3.30(s,1H),3.01(s,1H),2.93–2.83(m,1H),2.69(dt,J=13.7,9.1Hz, 3H),2.03–1.85(m,2H),1.35(dd,J=7.9,2.7Hz,11H),1.28–1.17(m,2H),1.14(d,J=13.1Hz,1H).MS m / z:605.35(M+H).

[0129] Example 14: (S)-N-(1-([1,1'-biphenyl]-4-yl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)cinnamamide (Cpd014)

[0130]

[0131] 1 H NMR(400MHz,DMSO-d6)δ8.03(d,J=8.3Hz,1H),7.79(s,4H),7.69–7.61(m,2H),7.56(d d,J=18.4,7.5Hz,4H),7.51–7.29(m,9H),6.63(d,J=15.8Hz,1H),4.14(dt,J=8.1,5.3H z,1H),2.96(dd,J=13.9,5.8Hz,2H),2.76(dd,J=13.8,8.0Hz,1H),2.68(d,J=6.2Hz,2 H),2.58(s,0H),1.88(t,J=11.2Hz,2H),1.33–1.21(m,13H),1.12(d,J=11.3Hz,2H).MS m / z:496.35(M+H).

[0132] Example 15: (S)-N-(1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)cinnamamide (Cpd015)

[0133]

[0134] 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=8.4Hz,1H),7.62–7.51(m,4H),7.50–7.34(m,5H),7 .22–7.15(m,2H),7.01–6.94(m,2H),6.62(d,J=15.8Hz,1H),5.18(s,2H),4.08(q,J=6. 7Hz,1H),2.97(s,1H),2.85(dd,J=13.8,5.7Hz,1H),2.67(dd,J=13.5,7.4Hz,3H),1.97 –1.84(m,2H),1.33(d,J=7.9Hz,11H),1.24(d,J=3.4Hz,1H),1.16(q,J=11.7Hz,2H).MS m / z:594.25(M+H).

[0135] Example 16: (S)-N-(1-([1,1'-biphenyl]-4-yl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)-2,2-bis(4-chlorophenoxy)acetamide (Cpd016)

[0136]

[0137] 1 H NMR (400MHz, DMSO-d6) δ8.41(d,J=8.7Hz,1H),7.64(d,J=7.6Hz,2H),7.56(d,J=7.9Hz,2H),7.46(t,J= 7.6Hz,2H),7.39–7.25(m,8H),7.04–6.92(m,5H),6.17(s,1H),4.09(d,J=8.3Hz,1H),2.98–2.89(m,2H ),2.77(dd,J=13.8,8.9Hz,1H),2.68(d,J=6.4Hz,2H),1.87(d,J=13.3Hz,1H),1.77(d,J=13.8Hz,1H), 1.61(s,1H),1.32(d,J=6.6Hz,6H),1.30(s,6H),1.25(d,J=8.7Hz,1H),1.13(q,J=11.3,10.8Hz,2H).MS m / z:660.15(M+H).

[0138] Example 17: (S)-2,2-bis(4-chlorophenoxy)-N-(1-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)propan-2-yl)acetamide (Cpd017)

[0139]

[0140] 1H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.7Hz,1H),7.56(d,J=8.0Hz,2H),7.51–7.43(m,1H),7.35( t,J=9.1Hz,4H),7.16(d,J=8.2Hz,2H),7.05–6.93(m,7H),6.16(s,1H),5.20(s,2H),4.01(q,J =7.3Hz,1H),2.91(s,2H),2.83(dd,J=13.7,5.1Hz,1H),2.67(dd,J=23.6,7.6Hz,3H),1.85(d, J=13.4Hz,1H),1.76(d,J=13.0Hz,1H),1.35–1.27(m,12H),1.24(s,1H),1.21–1.03(m,2H).MS m / z:760.35(M+H).

[0141] II. Biological Activity Test of the Compounds of the Invention

[0142] Example 18. In vitro antitumor activity test of the example compounds

[0143] Five human tumor cell lines were selected and cultured in RPMI-1640 (Gibco) or DMEM (Gibco) or GMEM / F12 medium (Gibco) containing 10% inactivated fetal bovine serum, 100 U / ml penicillin and 100 U / ml streptomycin at 37°C in a 5% CO2 incubator. The cells in the logarithmic growth phase were seeded in 96-well plates (100 μl per well, 2×10 4 After overnight incubation in the incubator, 100 μl of drug was added (final concentration 25 μM was diluted to 0.39 μM, a total of 7 groups of drug concentrations), and an equal volume of culture medium was added to the blank control wells. Three replicate wells were set for each drug concentration. After 48 h of culture, the supernatant was discarded, and 100 μl of MTT (5 mg / ml) was added to each well after washing twice with PBS, and culture was continued for 2 h. The absorbance (A 492nm The inhibition rate of the drug on tumor cells was calculated.

[0144] GraphPad software was used to calculate the IC of compounds against tumor cells. 50 The in vitro activity results of the three example compounds are shown in Table 2. The inhibition rates of the compounds on different cancer cells are comparable to those of PL-AC-15 and PL-AC-202, and are superior to those of cisplatin.

[0145] Table 2. In vitro antitumor activity IC of the compounds in the examples 50 (μM)

[0146]

[0147] Example 19. In vivo antitumor efficacy test of the example compound (Cpd014)

[0148] BALB / c nude mice were used to construct an in vivo drug efficacy evaluation model. 0.15 mL of tumor cell suspension (A549 lung cancer cells, 2×10 7 / ml). When the inoculated cells grow to a tumor of 300mm 3 At 14:00, administration began. On the 22nd day after inoculation, intraperitoneal administration (20 mg / kg) was performed once every 2 days for a total of 10 times. On the 2nd day after the last administration, all tumor-bearing mice were killed, the tumor weight was weighed, and the tumor inhibition rate was calculated. The experimental results showed that the tumor inhibition rate of compound Cpd014 in vivo was higher than that of PL-AC-202 and docetaxel.

[0149] Table 3 In vivo antitumor activity results of the compounds in the examples

[0150]

[0151] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound having a structural formula as shown in Formula I or a pharmaceutically acceptable salt thereof: In the formula I, R1 and W groups are selected from any of the following groups: In the formula I, X and R2 are selected from any of the following groups: 。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula I is selected from any of the following compounds:

3. A method for preparing the compound of formula I according to claim 1 or 2, comprising the following steps: R1-W-COOH is activated by oxalyl chloride, and then reacted with intermediate 1 or intermediate 2 at room temperature to obtain the corresponding final product of formula I; In the R1-W-COOH, R1 and W are defined as the same as Formula I in claim 1; In the intermediate 1, R is -X-R2, wherein X is defined as in Formula I, but excluding the case where X is -OCH2; in the intermediate 1, R2 is defined as in Formula I in Claim 1; 。 4. The preparation method according to claim 3, characterized in that: The synthetic route of the intermediate 1 is as follows: The specific preparation method is as follows: reducing carboxylic acid 1 under the condition of NaBH4 to obtain compound 2; oxidizing compound 2 under the condition of NaClO and TEMPO to obtain compound 3; Then, the compound 4 was reduced with 1,1,2,2-4-methyl-4-aminopiperidine under the condition of NaBH4; the compound 4 was deprotected by TFA in DCM to obtain the intermediate 1; Wherein, the definition of R in compound 1-4 is the same as that of intermediate 1; The synthetic route of the intermediate 2 is as follows: The specific preparation method of the intermediate 2 is as follows: carboxylic acid 5 and 2,6-dichloro-benzyl bromide undergo substitution reaction under K2CO3 to obtain compound 6; compound 6 is hydrolyzed with NaOH under MeOH / THF / H2O to obtain compound 7; compound 7 is reduced under NaBH4 to obtain compound 8, and then oxidized with TEMPO and NaClO to obtain compound 9; the compound 9 is subjected to reductive amination reaction with 1,1,2,2-4-methyl-4-aminopiperidine to obtain compound 10; the compound 10 is deprotected using TFA in DCM solvent to obtain intermediate 2.

5. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating cancer or in the preparation of a drug for inhibiting cancer cell proliferation; The cancer is at least one of liver cancer, lung cancer, and prostate cancer; The cancer cells are at least one of liver cancer cells, lung cancer cells and prostate cancer cells.

6. A drug or pharmaceutical composition for preventing and / or treating cancer, characterized in that: The medicine or pharmaceutical composition comprises an effective dose of the compound of formula I according to claim 1 or 2 or a pharmaceutically acceptable salt thereof; The cancer is at least one of liver cancer, lung cancer and prostate cancer.

Images