2-Fluorobiphenyl-4-acetic acid derivatives and their preparation methods and applications

Abstract

The present invention discloses a 2-fluorobiphenyl-4-acetic acid derivative, its preparation method, and its application. The structural formula of the 2-fluorobiphenyl-4-acetic acid derivative is shown in Formula I. This compound can be prepared by synthetic methods and exhibits broad-spectrum anti-tumor effects, potentially prolonging the survival of cancer patients and improving their quality of life. The compound has stable efficacy, low toxicity, and is well tolerated by the human body. It can be used to treat most cancers and offers certain advantages over currently available anti-tumor drugs. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a 2-fluorobiphenyl-4-acetic acid 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 not only promote angiogenesis by stimulating the secretion of vascular endothelial growth factor, but also stimulate the formation of new blood vessels by activating matrix metalloproteinases (MMPs).

[0003] B1R and B2R are both G protein coupled receptors. 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), promoting the hydrolysis of inositol triphosphate (IP3) and the intracellular Ca 2+ The BK receptor is a key target for tumorigenesis and metastasis. It is a key target for tumorigenesis and metastasis. BK receptors are activated by the Gα-i subunit Gα-i, which inhibits adenylate cyclase (AC) and activates the mitogen-activated protein kinase (MAPK) pathway, thereby increasing the expression of MMP-2 / 9. Therefore, BK receptors can be used as a new anti-tumor target, and BK receptor antagonists are considered a promising tumor treatment.

[0004] Based on the above strategy, a series of compounds have been reported, including PL-AC-15 and PL-AC-202. PL-AC-15 is an amino acid derivative provided by Jiangsu Pulai Pharmaceutical Biotechnology Co., Ltd. (see Chinese Patent CN107382827B) and exhibits promising anti-tumor effects. PL-AC-202 is a compound derived from PL-AC-15 through further structural optimization and modification by Jiangsu Pulai Pharmaceutical Biotechnology Co., Ltd. (see Chinese Patent Application No. 202010386293.7). This further structural modification aims to yield a compound with even better anti-tumor efficacy. Summary of the Invention

[0005] One object of the present invention is to provide a 2-fluorobiphenyl-4-acetic acid derivative and a pharmaceutically acceptable salt, ester, solvate or isomer (including stereoisomers, enantiomers, tautomers or mixtures thereof).

[0006] The structural formula of the 2-fluorobiphenyl-4-acetic acid derivative provided by the present invention is as follows:

[0007]

[0008] In formula I, R1 and R2 are independently selected from any of the following groups: hydrogen, -OR 4 , -SR 4 、C 1-8Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl; or R1 and R2 may be combined to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group; wherein, R 4 Any one of the following groups: hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, and any of the above groups in which hydrogen is replaced by one or more halogens;

[0009] The R3 is selected from any of the following groups: hydrogen, C 1-8 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, or 5-12 membered heterocyclic aliphatic group formed by R3 and Linker, including but not limited to the following groups:

[0010]

[0011] And each hydrogen on R3 is arbitrarily replaced by R 5 replace;

[0012] Among them, R 5 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, partially or fully halogenated C 1-5 alkyl.

[0013] The linker is selected from any of the following groups: C 1-8 Alkylene (such as -CH2CH2-), C 2-8 Alkenylene (such as -CH2=CH-CH2-), C 2-8 Alkynylidene (such as -C≡C-CH2-), C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene, 5-12 membered heteroarylene.

[0014] The C 3-12Cycloalkylene groups include but are not limited to the following groups:

[0015]

[0016] The 3-12 membered heterocyclylene group includes but is not limited to the following groups:

[0017]

[0018] The C 6-12 Arylene groups include but are not limited to the following groups:

[0019]

[0020] The 5-12 membered heteroarylene group includes but is not limited to the following groups:

[0021]

[0022] And each hydrogen on the Linker is arbitrarily R 6 replace;

[0023] Among them, R 6 Selected from the following groups: 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 group, 5-14 membered heteroaryl group. -CN, -NO2, -CF2H, -CF2OH, -CF3, -OCF3, -CR 7 R 8 R 9 、-OR 7 、-O(C=O)R 7 、-O(C=O)OR 7 、-O(C=O)NR 8 R 9 、-(C=O)R 7 、-(C=O)OR 7 、-(C=O)NR 8 R 9 、-SR 7 、-(S=O) m R 7 、-NR 8 R 9 、-NR 7 (C=O)R 8、-NR 7 C(=O)NR 8 R 9 、-NR 7 C(=O)OR 8 、-NR 7 S(=O) m NR 8 R 9 、-NR 7 S(=O) m OR 8 or -NR 7 S(=O) m R 8 , or adjacent atoms on R6 can be combined to form C 3-12 Cycloalkyl, C 6-12 Aryl, 3-12 membered heterocyclic ring and 5-12 membered heteroaromatic ring;

[0024] Among them, R 7 、R 8 、R 9 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 7 、R 8 、R 9 Any two of the R groups 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 group, which optionally contains 1 to 3 additional heteroatoms selected from N, O and S, or R groups attached to the same carbon atom. 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 7 、R 8 、R 9 Each hydrogen in is optionally replaced by R 10 Replace, or R 7 、R 8 、R 9 Two hydrogen atoms on the same carbon atom in are optionally oxo substituents.

[0025] The 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;

[0026] The m is selected from 1 or 2;

[0027] The n is selected from 1, 2, 3, 4 or 5.

[0028] Preferably, R1 and R2 are independently selected from any of the following groups: hydrogen, C 1-4 Alkyl (such as methyl, ethyl), C 3-6 Cycloalkyl, R1 and R2 form C 3-6 Cycloalkyl;

[0029] Preferably, R3 is selected from any of the following groups: hydrogen, C 1-4 Alkyl, or a 5-12 membered heterocyclic aliphatic group formed by R3 and Linker;

[0030] Preferably, Linker is selected from any of the following groups: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CHR 11 CH2-、-CH2CHR 11 -、-CH2CH2CHR 11 -、-CHR 11 O-、-CHR 11 NH-, -CHNR 11 -;

[0031] Preferably, R 11 Selected from any of the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heteroalicyclic, C 6-12 Aryl (such as phenyl, biphenyl), 5-12 membered heteroaryl, phenylamino, benzylamino, benzyloxyphenyl, wherein R 11 Any hydrogen on the 12 replace.

[0032] R 12 The definition of R is the same as above 10 same.

[0033] Furthermore, the linker in Formula I includes but is not limited to the following groups:

[0034]

[0035] The 5-12 membered heterocyclic aliphatic group formed by R3 and Linker includes but is not limited to the following groups:

[0036]

[0037] In some embodiments, the 2-fluorobiphenyl-4-acetic acid 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

[0039]

[0040]

[0041]

[0042] 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 via a single bond. As non-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 its other seven isomers, n-hexyl and its other sixteen isomers, n-heptyl and its various isomers, n-octyl and its various isomers, n-nonyl and its various isomers, n-decyl and its various isomers.

[0043] The term "cycloalkyl" as used in the present invention refers to a saturated non-aromatic ring system consisting of at least three carbon atoms, which may be monocyclic, bicyclic, polycyclic, or condensed, bridged, or spirocyclic. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl; and condensed, bridged, or spirocyclic groups formed by two or more of the above monocyclic rings through a common edge and common carbon atom.

[0044] As used herein, the term "aryl" may be used alone or as part of the term "arylalkyl" and refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing a total of 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 point of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring," and aromatic rings may include, for example, phenyl, naphthyl, and anthracenyl.

[0045] The term "heteroaryl" as 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 monocyclic rings connected by single bonds or fused. 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 connecting the above heteroaryl groups by a single bond or by condensation.

[0046] The compounds of this invention can also be used in the form of its pharmaceutically acceptable salt, ester, solvate or isomer (including stereoisomer, enantiomer, tautomer or its mixture). The physiologically acceptable salt of compound shown in Formula I comprises the conventional salt formed by pharmaceutically acceptable inorganic acid or organic acid or inorganic base or organic base and the acid addition salt of quaternary ammonium. The more specific example of suitable acid salt comprises the salt of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, stearic acid, tannic acid etc. More specific examples of suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.

[0047] Another object of the present invention is to provide a method for preparing the 2-fluorobiphenyl-4-acetic acid derivative shown in Formula I.

[0048] The synthetic route of the 2-fluorobiphenyl-4-acetic acid derivative represented by Formula I provided by the present invention is as follows:

[0049]

[0050] The specific preparation method comprises the following steps: activating the carboxylic acid represented by formula II with oxalyl chloride (COCl) 2, and then reacting with intermediate 1, intermediate 2 or intermediate 3 at room temperature to obtain the corresponding final product of formula I.

[0051]

[0052] Wherein, the definitions of R1 and R2 in Formula II are the same as those in Formula I; the definitions of Linker and R3 in Intermediate 1 are the same as those in Formula I (excluding that R3 in Formula I is hydrogen and Linker is -CH2CHR 11 -and In the case of intermediate 2, R 13 The definition is the same as R in the above formula I 11 .

[0053] The synthetic route of intermediate 1 is as follows:

[0054]

[0055] The specific preparation method of intermediate 1 is as follows: carboxylic acid 4 is condensed with 4-amino-2,2,6,6-tetramethylpiperidine under the conditions of K2CO3 and HBTU to obtain compound 5; compound 5 is deprotected under the conditions of TFA / DCM to obtain intermediate 1.

[0056] The synthesis route of chiral intermediate 2 is as follows:

[0057]

[0058] The specific preparation method of chiral intermediate 2 is as follows: carboxylic acid 6 is activated with oxalyl chloride (COCl)2 to obtain acid chloride 7, which is amidated under n-BuLi conditions to obtain chiral compound 8; compound 8 reacts with N-bromomethylphthalimide in the presence of lithium hexamethyldisilazide (LiHMDS) at -70°C to obtain chiral compound 9; compound 9 is deprotected in the presence of H2O2 and LiOH to obtain carboxylic acid 10; compound 10 is then condensed with 4-amino-2,2,6,6-tetramethylpiperidine in the presence of HBTU and K2CO3 to obtain compound 11; compound 11 is deprotected in the presence of N2H4 and EtOH to obtain chiral intermediate 2.

[0059] The synthetic route of intermediate 3 is as follows:

[0060]

[0061] The specific preparation method of intermediate 3 is as follows: compound 12 reacts with 4-nitrophenyl chloroformate to obtain intermediate 13; under DIPEA conditions, compound 13 is condensed with tert-butyl piperidin-3-ylcarbamate to obtain compound 14; compound 14 is deprotected under TFA conditions to obtain intermediate 3.

[0062] Another object of the present invention is to provide the use of the 2-fluorobiphenyl-4-acetic acid derivative represented by the above formula I or its pharmaceutically acceptable salt, ester, solvate or isomer (including stereoisomers, enantiomers, tautomers or mixtures thereof).

[0063] The applications provided by the present invention include the following aspects: 1) use of the 2-fluorobiphenyl-4-acetic acid derivative shown in Formula I or its 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) use of the 2-fluorobiphenyl-4-acetic acid derivative shown in Formula I or its pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof) in the preparation of drugs for inhibiting cancer cell proliferation.

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

[0065] The cancer cells include but are not limited to 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 peptide derivatives represented by Formula I or 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 novel compound of the present invention can be prepared by artificial synthesis and exhibits broad-spectrum anti-tumor activity, potentially prolonging the survival of cancer patients and improving their quality of life. The compound exhibits stable efficacy, low toxicity, and is readily accepted by the human body, making it suitable for the treatment of most cancers and offering advantages over currently marketed anti-tumor drugs.

[0068] The 2-fluorobiphenyl-4-acetic acid derivatives represented by Formula I provided herein are novel compounds designed from scratch. These compounds are bradykinin receptor antagonists that inhibit the growth and invasion of tumor cells by inhibiting the binding of bradykinin to its receptor, further suppressing tumorigenesis. Compounds with similar structures may share the same mechanism of action. Understanding the mechanism of action of different compounds helps to fully understand the clinical application prospects and potential problems of the compounds and their analogs, thereby making research and development more targeted. DETAILED DESCRIPTION

[0069] The present invention is described below by means of specific embodiments, but the present invention is not limited thereto. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

[0070] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0071] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0072] The structural formula of the PL-AC-15 compound involved in the following examples is as follows:

[0073]

[0074] The details of its preparation can be found in Chinese patent CN107382827B.

[0075] The structural formula of the PL-AC-202 compound involved in the following examples is as follows:

[0076]

[0077] The details of its preparation can be found in Chinese patent CN113620862A.

[0078] 1. Preparation and characterization of compounds

[0079] Example 1: 2-([1,1'-biphenyl]-4-yl)-3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd001)

[0080]

[0081] Preparation method 1 of the racemic compound Cpd001 is as follows:

[0082]

[0083] 1) Compound 15 (1.0 g, 2.93 mmol), HBTU (1.11 g, 2.93 mmol), 4-amino-2,2,6,6-tetramethylpiperidine (0.46 g, 2.93 mmol), and K2CO3 (0.45 g, 3.22 mmol) were added sequentially to dry acetonitrile (50 mL). The reaction mixture was stirred at room temperature overnight, and a large amount of white solid precipitated. The reaction mixture was concentrated under reduced pressure using a rotary evaporator. The residual solid was added to 50 mL of water and 50 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (50 mL x 2). The combined organic layers were washed sequentially with saturated NaHCO3 solution (30 mL x 3) and brine (30 mL x 3), dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography eluting with dichloromethane / methanol (20:1, v / v) to obtain Compound 16 (1.33 g) as a white solid in a 95% yield.

[0084] 2) Compound 16 (0.75 g, 1.56 mmol) was added to 25% TFA / DCM (50 ml) and stirred at 0-5°C for 30 min. After completion of the reaction, the mixture was concentrated under reduced pressure. The residual syrup was dissolved in an appropriate amount of methanol and approximately 10 ml of saturated HCl / EtOAc solution was added dropwise with stirring in an ice bath. After stirring for 10 min, the mixture was concentrated under reduced pressure and pumped to constant weight using an oil pump to obtain compound 17 (0.658 g) as an off-white solid in a 93% yield.

[0085]

[0086] 3) Compound 18 (0.5 g, 2.05 mmol) was dissolved in 10 mL of dichloromethane, and 3 drops of DMF were added dropwise. The mixture was cooled to 0-5°C, and oxalyl chloride (0.52 g, 4.10 mmol) was added dropwise. After stirring for 20 minutes, the mixture was returned to room temperature and reacted for 5 hours. The mixture was then dried to obtain intermediate 19.

[0087] 4) Intermediate 19 (0.54 g, 2.05 mmol) was dissolved in 10 mL of dichloromethane. Triethylamine was added, and the mixture was cooled to 0-5°C. A 10 mL solution of the product from the previous step (Compound 17) (0.93 g, 2.05 mmol) in dichloromethane was slowly added dropwise. The mixture was incubated for 30 minutes, then returned to room temperature and allowed to react for 10 hours. TLC (methanol / dichloromethane = 1 / 10, v / v) indicated the reaction was complete. The reaction solution was washed with water, and the organic phase was dried and spin-dried. Purification by column chromatography (methanol / dichloromethane elution) afforded Example 1: 2-([1,1'-biphenyl]-4-yl)-3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd001) (1.08 g, 87% yield). 1H-NMR(DMSO-d6):1.05-1.15(m,2H,CH2),1.23-1.31(s,15H,CH3),1.56-1.57(m,1 H,CH2),1.67-1.68(m,1H,CH2),2.83-2.89(m,2H,CH2),3.83(q,1H,CH),3.29(s,1H ,3.8)(s,3H,OCH3),3.92-3.94(m,1H,CH),4.49-4.51(m,1H,CH),7.25-7.76(m,15H ,NH,ArH),7.96(d,1H,ArH),8.24(d,1H,ArH),8.44(m,1H,NH).MSm / z:592.25(M+H)

[0088] Preparation method 2 of chiral intermediate 2S and chiral compound Cpd001 (RS, SS) is as follows:

[0089]

[0090] 1) Compound 20 (5.30 g, 0.025 mol) was dissolved in dichloromethane (50 mL), and three drops of DMF were added. The mixture was cooled to 0-5°C, and oxalyl chloride (3.80 g, 0.03 mol) was added dropwise over 0.5 hours. The mixture was stirred for 3 hours and filtered to obtain a clear solution of compound 21 for later use.

[0091] 2) Compound (R)-4-phenyl-2-oxazolidinone (3.59 g, 0.022 mol) was dissolved in tetrahydrofuran (50 ml), cooled to -78°C, and 2.5 M n-butyllithium (9.5 mL) was added dropwise over 1 hour, maintaining the temperature at -78°C. The clear solution of compound 21 was added dropwise over 1 hour. The reaction was allowed to proceed for 5 hours, and the reaction was monitored for completion by TLC. After returning to room temperature, the mixture was poured into 30 ml of saturated sodium bicarbonate, stirred for half an hour, and filtered to obtain compound 22R (5.6 g) as a yellow solid in a 71% yield.

[0092]

[0093] 3) Compound 22R (8.60 g, 0.024 mol) was dissolved in tetrahydrofuran (200 mL) and cooled to approximately -70°C. 28 mL of lithium bis(trimethylsilyl)amide was added dropwise over 2 h. The mixture was then stirred at -70°C for 1 h. N-bromomethylphthalimide (6.72 g, 0.028 mol) was dissolved in tetrahydrofuran and added dropwise over 1 h. The reaction was incubated at -70°C for 5 h. The reaction was complete as monitored by TLC, and the reaction mixture was allowed to return to room temperature. The mixture was quenched with ammonium chloride and filtered to obtain a pink solid. DCM column chromatography afforded solid compound 23S (5.33 g) in a 43% yield.

[0094] 4) Compound 23S (0.50 g, 0.97 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to about 0-5°C, and hydrogen peroxide (0.67 g, 0.02 mol) was added dropwise. After the addition was complete, lithium hydroxide (0.5 g, 21 mol) was dissolved in 4 mL of water and added dropwise to the reaction solution over a period of half an hour. The mixture was stirred at this temperature for 2 hours. The mixture was quenched with sodium sulfite, extracted with ethyl acetate, dried, and concentrated to afford Compound 24S (0.28 g) as a yellow oil in a yield of 77.7%.

[0095]

[0096] 5) Compound 24S (0.28 g, 0.75 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (0.22 g, 1.59 mmol) and HBTU (0.32 g, 0.84 mmol) were added. After stirring for 10 min, 4-amino-2,2,6,6-tetramethylpiperidine (0.15 g, 0.96 mmol) was added dropwise. The mixture was reacted at room temperature for 15 hours. The solution was spin-dried, extracted three times with ethyl acetate, dried, and concentrated to obtain solid compound 25S (0.27 g) in a 70% yield.

[0097] 6) Compound 25S (0.27 g, 0.53 mmol) was dissolved in ethanol (8 mL), and hydrazine hydrate (0.5 mL) was added. The mixture was heated to 75°C and stirred for 4 hours. After completion of the reaction, the reaction system was spin-dried. Ethanol was added to precipitate a white solid, which was filtered and the mother liquor was spin-dried to give the chiral intermediate 2S (0.11 g) as a yellow oil in a 55% yield.

[0098]

[0099] 7) Using the R-configuration raw material 18R and the intermediate 2S as reaction raw materials, the compound 2-([1,1'-biphenyl]-4-yl)-3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd001-RS) was synthesized as a white solid (201 mg) in a yield of 39%.

[0100] 8) Using the S-configuration raw material 18S and the intermediate 2S as reaction raw materials, the method of steps 3 and 4 in Example 1 above was used to synthesize the compound 2-([1,1'-biphenyl]-4-yl)-3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd001-SS) (38 mg) in a yield of 17%.

[0101]

[0102] Preparation method 3 of chiral intermediate 2R and chiral compound Cpd001 (RR, SR) is as follows:

[0103]

[0104] Preparation method of intermediate 2R: Intermediate 2R is obtained by using the corresponding raw materials and following the preparation method of intermediate 2S.

[0105] Preparation of Chiral Cpd001: Using the corresponding raw materials, referring to steps 7 and 8 of the preparation of chiral Cpd001 (RS, SS), chiral Cpd001 (RR) and (SR) can be obtained:

[0106] 1) Using R-configuration raw material 18R and chiral intermediate 2R as reactants, referring to steps 7 and 8 of the preparation method of chiral compound Cpd001 (RS, SS), the chiral compound 2-([1,1'-biphenyl]-4-yl)-3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd001-RR) (80 mg) was obtained in a yield of 22%.

[0107]

[0108] 2) Using the S-configuration raw material 18S and the chiral intermediate 2R as reactants, referring to steps 7 and 8 of the preparation method of the chiral compound Cpd001 (RS, SS), the chiral compound 2-([1,1'-biphenyl]-4-yl)-3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd001-SR) (23 mg) was obtained in a yield of 21%.

[0109]

[0110] Other compounds of formula I (Examples 2-5, 7-9) were synthesized using the corresponding intermediates and carboxylic acids according to the preparation method of the racemic compound of Example 1 (Cpd001) or the preparation method of the chiral compound.

[0111] Example 2: 3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-2-phenyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd002)

[0112]

[0113] 1H NMR (400MHz, DMSO-d6) δ8.29–8.09(m,2H),7.57–7.44(m,4H),7.48–7.36(m,2H),7.33–7.13(m,7H),4.06(ddt,J=12.0,8. 0,4.0Hz,1H),3.75–3.59(m,2H),3.50–3.38(m,1H),1.67(q,J=14.3,13.0Hz,1H),1.44–1.08(m,18H).MSm / z:530.4(M+H). Example 3: 2-(4-((2,6-dichlorobenzyl)oxy)phenyl)-3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)propionamide (Cpd003)

[0114]

[0115] 1 H NMR (400MHz, DMSO-d6) δ7.93(s,1H),7.73(s,1H),7.65(d,J=8.0Hz,1H),7.57(d,J=7.7Hz,3H),7.49(s,2H),7.37(s,0H),7.11(s,2H),7.03 (s,1H),6.39(d,J=16.2Hz,1H),5.28(s,2H),5.22(d,J=7.7Hz,1H),1.99(s,1H),1.24(s,6H),1.06(s,1H),0.85(s,1H).MSm / z:705.7(M+H).

[0116] Example 4: 1-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)piperidine-3-carboxamide (Cpd004)

[0117]

[0118] 1H NMR(400MHz, DMSO-d6)δ7.81(d,J=7.4Hz,1H),7.66–7.41(m,7H),7.35–7.20(m,2H),4.49–4.41(m,1H) ,4.39(s,1H),4.38–4.15(m,1H),4.05(dtd,J=19.5,11.5,9.4,5.7Hz,2H),2.84(t,J=12.4Hz,1H),2.77 –2.62(m,1H),2.05(q,J=5.9,4.6Hz,1H),1.72(s,1H),1.70–1.56(m,2H),1.59–1.47(m,1H),1.39(q,J =4.1Hz,2H),1.37(s,1H),1.36–1.27(m,1H),1.27–1.15(m,6H),1.14–0.87(m,8H).MSm / z:493.1(M+H).

[0119] Example 5: 3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)cyclohexane-1-carboxamide (Cpd005)

[0120]

[0121] 1 H NMR(400MHz,DMSO-d6)δ8.05(dd,J=7.8,2.1Hz,1H),7.80–7.73(m,1H),7.63–7.41(m,7H),7.2 8(d,J=9.9Hz,2H),4.06(ddt,J=16.1,8.0,4.3Hz,1H),3.68(q,J=7.0Hz,1H),3.59(d,J=11.1H z,2H),2.75(s,1H),2.25–2.13(m,1H),1.86(t,J=12.3Hz,1H),1.75(s,5H),1.41(d,J=7.1Hz, 3H),1.38–1.26(m,9H),1.26–1.18(m,8H),1.18–1.14(m,1H),1.12(s,1H).MSm / z:507.3(M+H).

[0122] Example 6: 3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)piperidine-1-carboxamide (Cpd006)

[0123]

[0124] 1) Compound 12 (0.5 g, 3.2 mmol) and ethyl acetate (20 mL) were added sequentially to a 100 mL two-necked flask and the reaction system was stirred and cooled to -10°C. 4-Nitrophenyl chloroformate (0.71 g, 3.52 mmol) was then added dropwise over 20 minutes, followed by stirring at room temperature for 3 hours. After completion of the reaction, the mixture was filtered and the filter cake was dried to afford Compound 13 (0.8 g, 78% yield) as a white solid.

[0125] 2) Compound 13 (0.20 g, 0.62 mmol), DMF (6 mL), tert-butyl piperidin-3-ylcarbamate (0.124 g, 0.62 mmol), and DIPEA (0.22 g, 1.7 mmol) were added sequentially to a 100 mL two-necked flask. The reaction system was heated to 73°C in an oil bath with stirring for 10 hours. After the reaction was complete, 30 mL of water was added to the system. After extraction with ethyl acetate, the organic layer was washed five times with water, dried, and concentrated to afford Compound 14 (157 mg) as an oil in a 66% yield.

[0126] 3) Compound 14 was added to a 50 mL single-necked bottle, followed by dichloromethane (5 mL) and TFA (0.3 mL). The mixture was stirred at room temperature for 3 hours, and the reaction solvent was concentrated to dryness to obtain intermediate 3, which was directly used for the next step.

[0127] 4) Using the intermediate 3 and the acid chloride 19 in Example 1 as starting materials, the compound of Example 6 (35 mg, 17% yield in the last two steps) was obtained by referring to Step 4 of the preparation method of the racemic compound Cpd001 in Example 1. 1 H NMR(400MHz, DMSO-d6)δ8.44(s,1H),7.99(dd,J=7.8,1.7Hz,1H),7.64(s,1H),7.57–7.45(m,3H) ,7.48–7.43(m,1H),7.39(t,J=7.3Hz,1H),7.28–7.19(m,2H),6.38(dd,J=11.6,7.3Hz,1H),3.82( ddd,J=32.8,12.6,4.0Hz,1H),3.73(s,1H),3.71–3.62(m,1H),3.53(s,1H),3.30(s,1H),2.78–2. 67(m,1H),1.83(t,J=8.7Hz,2H),1.62(d,J=16.8Hz,1H),1.43–1.21(m,16H).MSm / z:508.3(M+H).

[0128] Example 7: 4-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionamide)-N-(2,2,6,6-tetramethylpiperidin-4-yl)butanamide (Cpd007)

[0129]

[0130] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.04(t,J=5.5Hz,1H),7.89(d,J=7.4Hz,1H),7.56–7 .35(m,7H),7.27–7.19(m,2H),4.07(dtt,J=11.8,7.3,3.7Hz,1H),3.64(q,J=7.0Hz,1H),3 .30(s,1H),3.03(dhept,J=20.0,6.9Hz,2H),2.09–1.99(m,2H),1.85(dd,J=13.6,3.7Hz, 2H),1.61(p,J=7.3Hz,2H),1.40–1.28(m,16H),1.24(d,J=3.6Hz,1H).MSm / z:467.2(M+H).

[0131] Example 8: 2-(Benzylamino)-4-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propylamino)-N-(2,2,6,6-tetramethylpiperidin-4-yl)butanamide (Cpd008)

[0132]

[0133] 1 H NMR(400MHz, DMSO-d6)δ8.03(q,J=5.2Hz,1H),7.91(s,1H),7.54–7.35(m,7H),7.29(dd,J=5.4 ,2.0Hz,4H),7.26–7.18(m,3H),4.11(s,1H),3.63(dp,J=10.7,3.9,3.4Hz,2H),3.46(dd,J=13. 4,4.9Hz,1H),3.18–3.01(m,2H),2.94(t,J=6.8Hz,1H),1.83(s,2H),1.59(ddd,J=29.1,13.3,6 .7Hz,1H),1.35(dd,J=7.1,3.5Hz,9H),1.30(s,9H),1.24(d,J=3.4Hz,1H).MSm / z:572.3(M+H).

[0134] Example 9: N-([1,1'-biphenyl]-4-ylmethyl)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)-N-(2-oxo-2-((2,2,6,6-tetramethylpiperidin-4-yl)amino)ethyl)propionamide (Cpd009)

[0135]

[0136] 1 H NMR(400MHz, DMSO-d6)δ7.74–7.20(m,11H),4.73(dd,J=9.5,5.6Hz,1H),4.16–3.98(m,1H),3.87(dd,J=16.7,4 .7Hz,1H),1.85(t,J=16.4Hz,1H),1.47(d,J=6.7Hz,1H),1.45–1.27(m,11H),1.23(s,1H).MSm / z:605.3(M+H).

[0137] II. Biological Activity Test of the Compounds of the Invention

[0138] Example 10: In vitro antitumor activity test of representative 2-fluorobiphenyl-4-acetic acid derivatives represented by formula I

[0139] 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. Using the MTT assay, cells in the logarithmic growth phase were seeded in 96-well plates (100 μl / well, 2 × 10 4 After overnight culture, 100 μl of drug solution was added (the final concentration was 25 μM and diluted to 0.39 μM), 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 continuous culture, the supernatant was discarded, and 100 μl of MTT (5 mg / ml) was added to each well after washing twice with PBS. The cells were cultured for another 2 h. The absorbance (A) was measured using an enzyme-labeled instrument. 492nm The inhibition rate of the drug on tumor cells was calculated.

[0140] GraphPad software was used to calculate the IC of compounds against tumor cells. 50The results are shown in Tables 2-1 and 2-2. The results indicate that the new molecules Cpd001, Cpd002, and Cpd003 exhibited comparable in vitro antitumor activity against prostate, lung, and liver cancers to that of the compound PL-AC-202, and superior to cisplatin. The compounds Cpd001-Cpd009 used in Tables 2-1 and 2-2 are all racemates.

[0141] Table 2-1. In vitro antitumor activity IC of the example compounds 50 Value (μM)

[0142]

[0143] Table 2-2. In vitro antitumor activity IC of the example compounds 50 Value (μM)

[0144]

[0145] Example 11: In vivo antitumor efficacy study of representative compound Cpd001(S,S)

[0146] BALB / c nude mice were used to establish an in vivo anti-tumor drug efficacy evaluation model. 0.15 mL of tumor cell suspension (A549, 2×10 7 The inoculated cells grow into a tumor that grows to 300mm. 3 Dosing began at 1:00 p.m. Twenty-two days after inoculation, the mice were intraperitoneally injected (20 mg / kg) once every two days for a total of 10 doses. Two days after the last dose, all tumor-bearing mice were sacrificed, tumor weights were weighed, and tumor inhibition rates were calculated. The results demonstrated that new compounds, represented by Cpd001(S,S), exhibited superior in vivo antitumor efficacy against lung cancer compared to PL-AC-202.

[0147] Table 3. Effects of intraperitoneal administration of Cpd001(S,S) on tumor weight and tumor inhibition rate in BALB / c tumor-bearing mice

[0148]

[0149] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt thereof: The compound represented by formula I is selected from any one of the following compounds:

2. The method for preparing the compound of formula I according to claim 1, comprising the following steps: The carboxylic acid represented by formula II is activated by oxalyl chloride (COCl) 2 and then reacted with intermediate 1 or intermediate 3 at room temperature to obtain the corresponding final product compound represented by formula I; in, In formula II, R1 and R2 are defined the same as in formula I; The definitions of Linker and R3 in the intermediate 1 are the same as those in Formula 1, except that Linker is situation.

3. The preparation method according to claim 2, wherein: The synthetic route of the intermediate 1 is as follows: The specific preparation method of intermediate 1 is as follows: carboxylic acid 4 is condensed with 4-amino-2,2,6,6-tetramethylpiperidine under the conditions of K2CO3 and HBTU to obtain compound 5; compound 5 is deprotected under the conditions of TFA / DCM to obtain intermediate 1; The synthetic route of the intermediate 3 is as follows: The specific preparation method of intermediate 3 is as follows: compound 12 reacts with 4-nitrophenyl chloroformate to obtain intermediate 13; under DIPEA conditions, compound 13 is condensed with tert-butyl piperidin-3-ylcarbamate to obtain compound 14; compound 14 is deprotected under TFA conditions to obtain intermediate 3.

4. Use of the compound according to claim 1 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 and prostate cancer; The cancer cells are at least one of liver cancer cells and prostate cancer cells.

5. 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 a pharmaceutically acceptable salt thereof; The cancer is at least one of liver cancer and prostate cancer.

6. The drug or pharmaceutical composition according to claim 5, characterized in that: The dosage forms of the medicine or pharmaceutical composition include capsules, powders, oral liquids, granules, and tablets.

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