WO2024130689A1 - 2-fluorobiphenyl-4-acetic acid derivative, preparation method therefor, and use thereof - Google Patents

Abstract

Disclosed are a 2-fluorobiphenyl-4-acetic acid derivative, a preparation method therefor, and use thereof. The structural formula of the 2-fluorobiphenyl-4-acetic acid derivative is set forth in formula I. The compound can be prepared by means of an artificial synthesis method, having a broad-spectrum anti-tumor effect, prolonging the survival period of tumor patients and improving their survival quality. The compound has stable therapeutic effects, low toxicity and easy acceptance by a human body, and is applicable to the treatment of most cancers, thus exhibiting certain advantages over currently available anti-tumor drugs.

Description

2-Fluorobiphenyl-4-acetic acid derivatives and preparation methods and applications thereof Technical Field

The invention belongs to the field of medicine, and specifically relates to a 2-fluorobiphenyl-4-acetic acid derivative and a preparation method and application thereof.

Background technique

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 metalloproteinase (MMP) activity.

Both B1R and B2R are 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), promote the hydrolysis of inositol triphosphate (IP3) and the mobilization of intracellular Ca ²⁺ to produce NO, and inhibit adenylate cyclase (AC) through the G protein subunit Gα-i to activate the mitogen-activated protein kinase pathway (MAPK), increase the expression of MMP-2/9, and promote tumor occurrence, development and metastasis. Therefore, BK receptor can be used as a new anti-tumor target, and BK receptor antagonists are considered to be a promising tumor treatment method.

Based on the above strategy, a series of compounds have been reported, such as PL-AC-15, PL-AC-202, etc. Among them, PL-AC-15 is an amino acid derivative provided by Jiangsu Pulai Pharmaceutical Biotechnology Co., Ltd. (see Chinese patent CN107382827B), which has good anti-tumor effect. 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), and further structural modification is expected to obtain a compound with better anti-tumor effect.

Invention Disclosure

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).

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

In Formula I, R ₁ and R ₂ are independently selected from any of the following groups: hydrogen, -OR ⁴ , -SR ⁴ , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, C _6-12 aryl, 5-12 membered heteroaryl; or R ₁ and R ₂ can be combined to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclic group; wherein R ⁴ is selected from any 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 the above groups in which hydrogen is substituted by any one or more halogens;

The R ₃ 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 the R ₃ and Linker, including but not limited to the following groups:

and each hydrogen on R ₃ is arbitrarily replaced by R ⁵ ;

Wherein, 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 heterocyclyl, C _6-14 aryl, oxy C _6-14 aryl or oxy C _5-14 aromatic heteroyl, nitrogen C _6-14 aryl or nitrogen C _5-14 aromatic heteroyl, 5-14 membered heteroaryl, partially or fully halogenated C _1-5 alkyl.

The linker is selected from any of the following groups: C _1-8 alkylene (such as -CH ₂ CH ₂ -), C _2-8 alkenylene (such as -CH ₂ =CH-CH ₂ -), C _2-8 alkynylene (such as -C≡C-CH ₂ -), C _3-12 cycloalkylene, 3-12 membered heterocyclylene, C _6-12 arylene, 5-12 membered heteroarylene.

The C _3-12 cycloalkylene group includes but is not limited to the following groups:

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

The C _6-12 arylene group includes but is not limited to the following groups:

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

and each hydrogen on the Linker is arbitrarily replaced by R ⁶ ;

Wherein, ^R6 is selected from the following groups: halogen, _C1-10 alkyl, _{C2-8 alkenyl, C2-8 alkynyl} , _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl, oxy _C6-14 aryl or oxy _C5-14 aromatic heteroyl, nitrogen _C6-14 aryl or nitrogen _C5-14 aromatic heteroyl, 5-14 membered heteroaryl. -CN, _-NO2 , _-CF2H ^, -CF2OH, _-CF3 , ^{-OCF3 ,} -CR7R8R9 _, ^-OR7 _, -O(C=O) ^R7 , ^-O (C=O) ^OR7 , -O(C=O) ^NR8R9 , -(C=O) ^R7 , -(C=O)OR7, -(C=O) ^{NR8R9 , -SR7 ,} -(S=O) _mR7 , ^{-NR8R9 , -NR7} (C=O) ^{R8 , -NR7C} (=O) ^{NR8R9 , -NR7C} (=O) ^{OR8 , -NR7S ( =} O) ^{mNR8R9 ,} _-NR7S (=O) _mOR8 , or ^-NR7S (=O) _mR8 , or the groups of adjacent atoms on R ₆ can be combined to form a C _3-12 cycloalkyl group, a C _6-12 aryl group, a 3-12 membered heterocyclic group, and a 5-12 membered heteroaromatic ring group;

wherein R ⁷ , R ⁸ , and 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 heterocyclyl, C _6-14 aryl, oxy C 6-14 aryl or oxy C 5-14 heteroaromatic group, nitrogen C _6-14 aryl or nitrogen C _5-14 heteroaromatic group, _5-14 membered heteroaryl, or any two of R ⁷ , R ⁸ , and R ⁹ bound to the same nitrogen atom can be combined with the nitrogen to which they are bound to form a _3-12 membered heterocyclyl or 5-12 membered heteroaryl, which optionally contains 1 to 3 additional heteroatoms selected from N, O and S, or any two of R 7 , R 8 , and R 9 bound to the same carbon atom can be combined to form a C 3-12 cycloalkyl, C 6-14 aryl, or C 5-14 heteroaromatic group, or any two of R ⁷ , R ⁸ , and R ⁹ bound to the same carbon atom can be combined to form a C _3-12 cycloalkyl, C _6-12 membered aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and each hydrogen atom in R ⁷ , R ⁸ and R ⁹ is optionally substituted by R ¹⁰ , or two hydrogen atoms on the same carbon atom in R ⁷ , R ⁸ and R ⁹ are optionally oxo substituents.

The R ¹⁰ may 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 heterocyclyl, C _6-14 aryl, oxy C _6-14 aryl or oxy C _5-14 heteroaromatic group, nitrogen C _6-14 aryl or nitrogen C _5-14 heteroaromatic group, 5-14 membered heteroaryl; -CN, -NO ₂ , -OH, -NH ₂ , partially or fully halogenated C _1-5 alkyl, -C(＝O)(CH ₂ ) _n CH ₃ , -C(＝O)O(CH ₂ ) _n CH ₃ , -C(＝O)OH, -C(＝O)N[(CH ₂ ) _n CH ₃ ] ₂ , -C(＝O)NH ₂ , -C(＝O)NH(CH ₂ ) _n CH ₃ , -NH(CH ₂ ) _n CH ₃ , -N[(CH ₂ ) _n CH ₃ ] ₂ , -N(CH ₂ ) _n CH ₃ C(═O)(CH ₂ ) _n CH ₃ , -N(CH ₂ ) _n CH ₃ C(═O)NH(CH ₂ ) _n CH ₃ , -N(CH ₂ ) _n CH ₃ C(═O)N[(CH ₂ ) _n CH ₃ ] ₂ , -N(CH ₂ ) _n CH ₃ C(═O)NH ₂ , -N(CH ₂ ) _n CH ₃ C(═O)O(CH ₂ ) _n CH ₃ , -N(CH ₂ ) _n CH ₃ C(═O)OH , -NHC(═O)(CH ₂ ) _n CH ₃ , -NHC(═O)NH(CH ₂ ) _n CH ₃ , -NHC(＝O)N[(CH ₂ ) _n CH ₃ ] ₂ , -NHC(＝O)NH ₂ , -NHC(＝O)O(CH ₂ ) _n CH ₃ , -NHC(＝O)OH, -N(CH ₂ ) _n CH ₃ S(＝O) _m (CH ₂ ) _n CH ₃ , -NHS(＝O) _m (CH ₂ ) _n CH ₃ , -O(CH ₂ ) _n CH ₃ , ＝O, -OC(＝O)(CH ₂ ) _n CH ₃ , OC(＝O)O(CH ₂ ) _n CH ₃ , -OC(＝O)N[(CH ₂ ) _n CH ₃ ] ₂ , -OC(＝O)NH(CH ₂ ) _n CH ₃ , -OC(＝O)NH ₂ , -S(＝O)m(CH ₂ ) _n CH ₃ , -OS(=O)m(CH ₂ ) _n CH ₃ , -S(=O) _mNH (CH ₂ ) _n CH ₃ , -S(=O) _mN [(CH ₂ ) _n CH ₃ ] ₂ ;

The m is selected from 1 or 2;

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

Preferably, R ₁ and R ₂ are independently selected from any of the following groups: hydrogen, C _1-4 alkyl (such as methyl, ethyl), C _3-6 cycloalkyl, R ₁ and R ₂ form a C _3-6 cycloalkyl;

Preferably, R ₃ is selected from any of the following groups: hydrogen, C _1-4 alkyl, or a 5-12 membered heterocyclic aliphatic group formed by said R ₃ and Linker;

Preferably, the linker is selected from any one of the following groups: -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CHR ¹¹ CH ₂ -, -CH ₂ CHR ¹¹ -, -CH ₂ CH ₂ CHR ¹¹ -, -CHR ¹¹ O-, -CHR ¹¹ NH-, -CHNR ¹¹ -;

Preferably, R ¹¹ is 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 group, C _6-12 aryl (such as phenyl, biphenyl), 5-12 membered heteroaryl, aniline, benzylamino, benzyloxyphenyl, wherein the hydrogen on R ¹¹ is arbitrarily replaced by R ¹² .

R ¹² is the same as defined above for R ¹⁰ .

Furthermore, the Linker in Formula I includes but is not limited to the following groups:

The 5-12 membered heterocyclic aliphatic group formed by _R3 and Linker includes but is not limited to the following groups:

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):

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.

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 a common edge and a common carbon atom.

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.

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 cited: 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.

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 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.

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

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

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 or intermediate 2 or intermediate 3 at room temperature to obtain the corresponding final product of formula I.

Wherein, R ₁ and R ₂ in Formula II are defined as those in Formula I; Linker and R ₃ in Intermediate 1 are defined as those in Formula I (excluding the case where R ₃ in Formula I is hydrogen and Linker is -CH ₂ CHR ¹¹ - and

R ¹³ in the intermediate 2 is defined as R ¹¹ in the above formula I.

The synthetic route of 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 K ₂ CO ₃ and HBTU to obtain compound 5; compound 5 is deprotected under the conditions of TFA/DCM to obtain intermediate 1.

The synthesis route of chiral intermediate 2 is as follows:

The specific preparation method of chiral intermediate 2 is as follows: carboxylic acid 6 is activated by oxalyl chloride (COCl) ₂ to obtain acid chloride 7, which is amidated under n-BuLi conditions to obtain chiral compound 8; compound 8 is reacted with N-bromomethylphthalimide in the presence of lithium hexamethyldisilazide (LiHMDS) at -70°C to obtain chiral compound 9; compound 9 is deprotected under H ₂ O ₂ and LiOH conditions to obtain carboxylic acid 10; compound 10 is then condensed with 4-amino-2,2,6,6-tetramethylpiperidine under HBTU and K ₂ CO ₃ to obtain compound 11; compound 11 is deprotected under N ₂ H ₄ and EtOH conditions to obtain chiral intermediate 2.

The synthetic route of 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.

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

The applications provided by the present invention include the following aspects: 1) application of the 2-fluorobiphenyl-4-acetic acid derivative shown in formula I or its pharmaceutically acceptable salt, ester, solvate or isomer (including stereoisomer, enantiomer, tautomer or mixture thereof) in the preparation of drugs for preventing and/or treating cancer; 2) application of the 2-fluorobiphenyl-4-acetic acid derivative shown in formula I or its pharmaceutically acceptable salt, ester, solvate or isomer (including stereoisomer, enantiomer, tautomer or mixture thereof) in the preparation of drugs for inhibiting the proliferation of cancer cells.

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.

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).

Drugs for preventing and/or treating cancer prepared with the peptide 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.

The novel compound of the present invention can be prepared by an artificial synthesis method, and the novel compound 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 to treat most cancers, and has certain advantages over currently marketed anti-tumor drugs.

Best Mode for Carrying Out the Invention

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.

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

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

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

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

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

The details of its preparation refer to Chinese patent CN113620862A.

1. Preparation and characterization of compounds

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)

The preparation method 1 of the racemic compound Cpd001 is as follows:

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 K ₂ CO ₃ (0.45 g, 3.22 mmol) were added to dry acetonitrile (50 ml) in sequence. The reaction solution was stirred at room temperature overnight to precipitate a large amount of white solid. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the residual solid was added with 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×2). The organic layers were combined and washed with saturated NaHCO ₃ solution (30 mL×3) and brine (30 mL×3) in sequence, dried over anhydrous magnesium sulfate, separated and purified by silica gel column chromatography, and eluted with dichloromethane/methanol (20:1, v/v) to obtain white solid compound 16 (1.33 g) with a yield of 95%.

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 the reaction was completed, the mixture was concentrated under reduced pressure, and the residual syrup was dissolved with an appropriate amount of methanol. About 10 ml of saturated HCl/EtOAc solution was added dropwise under ice-cooling and stirring. After stirring for 10 min, the mixture was concentrated under reduced pressure and pumped to constant weight with an oil pump to obtain nearly white solid compound 17 (0.658 g) with a yield of 93%.

3) Compound 18 (0.5 g, 2.05 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 (0.52 g, 4.10 mmol) was added dropwise. After the addition, the mixture was stirred for 20 minutes at room temperature. The mixture was allowed to react for 5 hours at room temperature. The mixture was then dried and used to obtain intermediate 19.

4) Dissolve the intermediate 19 (0.54 g, 2.05 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 (compound 17) (0.93 g, 2.05 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 by column chromatography (methanol/dichloromethane elution) to obtain 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, yield 87%). ¹ H-NMR (DMSO-d ₆ ): 1.05-1.15 (m, 2H, CH ₂ ), 1.23-1.31 (s, 15H, CH ₃ ), 1.56-1.57 (m, 1H, CH ₂ ), 1.67-1.68 (m, 1H, CH ₂ ), 2.83-2.89 (m, 2H, CH ₂ ), 3.83 (q, 1H, CH), 3.29 (s, 1H, 3.8) (s, 3H, OCH ₃ ),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).MS m/z:592.25(M+H)

The preparation method 2 of the chiral intermediate 2S and the chiral compound Cpd001 (RS, SS) is as follows:

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

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-butyl lithium (9.5 mL) was added dropwise for 1 h, and the addition process was maintained at -78 °C. Compound 21 was added dropwise for 1 h. The reaction was carried out for 5 hours, and the reaction was complete after TLC monitoring. After returning to room temperature, the system was poured into 30 ml of saturated sodium bicarbonate, stirred for half an hour, and filtered to obtain yellow solid compound 22R (5.6 g) with a yield of 71%.

3) Compound 22R (8.60 g, 0.024 mol) was dissolved in tetrahydrofuran (200 mL), cooled to about -70 ° C, and 28 mL of lithium bis(trimethylsilyl)amide was added dropwise. After 2 hours of dropping, the mixture was kept warm and stirred at -70 ° C for 1 hour. N-bromomethylphthalimide (6.72 g, 0.028 mol) was dissolved in tetrahydrofuran and added dropwise. After 1 hour of dropping, the mixture was reacted at -70 ° C for 5 hours. The reaction was complete after TLC monitoring. The reaction was returned to room temperature. It was quenched with ammonium chloride and filtered to obtain a pink solid. DCM column chromatography was used to obtain solid compound 23S (5.33 g) with a yield of 43%.

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 completed, lithium hydroxide (0.5 g, 21 mol) was dissolved in 4 mL of water and added dropwise to the reaction solution. The addition was completed in half an hour, and the mixture was stirred for 2 hours. The mixture was quenched with sodium sulfite, extracted with ethyl acetate, dried, and concentrated to obtain yellow oily compound 24S (0.28 g) with a yield of 77.7%.

5) Compound 24S (0.28 g, 0.75 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (0.22 g, 1.59 mmol) and HBTU (0.32 g, 0.84 mmol) were added, and after stirring for 10 min, 4-amino-2,2,6,6-tetramethylpiperidine (0.15 g, 0.96 mmol) was added dropwise, and the mixture was reacted at room temperature for 15 hours. The system was spin-dried, extracted with ethyl acetate 3 times, dried, and concentrated to obtain solid compound 25S (0.27 g) with a yield of 70%.

6) Compound 25S (0.27 g, 0.53 mmol) was dissolved in ethanol (8 mL), hydrazine hydrate (0.5 mL) was added, and the mixture was heated to 75°C and stirred for 4 hours. After the reaction was completed, the reaction system was dried by spin-drying, and ethanol was added to precipitate a white solid, which was filtered and the mother liquor was dried by spin-drying to obtain a yellow oily chiral intermediate 2S (0.11 g), with a yield of 55%.

7) Using R-configuration raw material 18R and intermediate 2S as reaction raw materials, the method of steps 3 and 4 in the above Example 1 can be used to synthesize 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). The compound is a white solid (201 mg) with a yield of 39%.

8) Using the S-configuration raw material 18S and the intermediate 2S as reaction raw materials, the method of steps 3 and 4 in the above Example 1 can be 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) with a yield of 17%.

The preparation method 3 of the chiral intermediate 2R and the chiral compound Cpd001 (RR, SR) is as follows:

Preparation method of intermediate 2R: Use corresponding raw materials and follow the preparation method of intermediate 2S to obtain intermediate 2R.

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

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), a 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) can be obtained with a yield of 22%.

2) Using S-configuration raw material 18S 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-SR) (23 mg) can be obtained with a yield of 21%.

Other compounds of formula I (Examples 2-5, 7-9) were synthesized using 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.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29–8.09 (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, 4.0 Hz, 1H), 3.75–3.59 (m, 2H), 3.50–3.38 (m, 1H), 1.67 (q, J=14.3, 13.0 Hz, 1H), 1.44–1.08 (m, 18H). MS m/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)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.93 (s, 1H), 7.73 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.7 Hz, 3H), 7.49 (s, 2H), 7.37 (s, 0H), 7.11 (s, 2H), 7.03 (s, 1H), 6.39 (d, J=16.2 Hz, 1H), 5.28 (s, 2H), 5.22 (d, J=7.7 Hz, 1H), 1.99 (s, 1H), 1.24 (s, 6H), 1.06 (s, 1H), 0.85 (s, 1H). MS m/z: 705.7 (M+H).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.81 (d, J＝7.4 Hz, 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, 4.6 Hz, 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).MS m/z:493.1(M +H).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (dd, J＝7.8, 2.1 Hz, 1H), 7.80–7.73 (m, 1H), 7.63–7.41 (m, 7H), 7.28 (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=11.1Hz, 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). MS m/z: 507.3 (M+H).

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

1) Compound 12 (0.5 g, 3.2 mmol) and ethyl acetate (20 mL) were added to a 100 mL two-necked bottle, and the reaction system was stirred and cooled to -10°C. Then 4-nitrophenyl chloroformate (0.71 g, 3.52 mmol) was added dropwise to the reaction system over a period of 20 minutes, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was filtered and the filter cake was dried to obtain a white solid compound 13 (0.8 g, yield 78%).

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 to a 100 mL two-necked bottle in sequence. The reaction system was heated to 73 ° C in an oil bath under stirring and the reaction was maintained for 10 hours. After the reaction was complete, 30 mL of water was added to the system, and the organic layer was washed with water 5 times after extraction with ethyl acetate. The organic layer was dried and concentrated to obtain an oily compound 14 (157 mg) with a yield of 66%.

3) The compound 14 was placed in a 50 mL single-mouth bottle, and dichloromethane (5 mL) and TFA (0.3 mL) were added. After stirring at room temperature for 3 hours, the reaction solvent was concentrated to dryness to obtain intermediate 3, which was directly carried out to the next step.

4) Using the intermediate 3 and the acyl chloride 19 in Example 1 as raw materials, the compound of Example 6 (35 mg, the yield of the last two steps is 17%) can be obtained by referring to Step 4 in the preparation method of the racemic compound Cpd001 in Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.44 (s, 1H), 7.99 (dd, J＝7.8,1.7 Hz, 1H), 7.64 (s, 1H), 7.57–7.45 (m, 3H), 7.48–7.43 (m, 1H), 7.39 (t, J＝7.3 Hz, 1H), 7.28–7.19 (m, 2H), 6.38 (dd, J = 11.6, 7.3 Hz, 1H), 3.82 (ddd, J = 32.8, 12.6, 4.0 Hz, 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 = 8.7 Hz, 2H), 1.62 (d, J = 16.8 Hz, 1H), 1.43–1.21 (m, 16H). MS m/z: 508.3 (M+H).

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

¹ H NMR (400 MHz, DMSO-d ₆ )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).MS m/z:467.2(M+H).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (q, J = 5.2 Hz, 1H), 7.91 (s, 1H), 7.54–7.35 (m, 7H), 7.29 (dd, J = 5.4, 2.0 Hz, 4H), 7.26–7.18 (m, 3H), 4.11 (s, 1H), 3.63 (dp, J＝10.7, 3.9, 3.4 Hz, 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, 3.5 Hz, 9H), 1.30 (s, 9H), 1.24 (d, J = 3.4 Hz, 1H). MS m/z: 572.3 (M+H).

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)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74–7.20 (m, 11H), 4.73 (dd, J=9.5, 5.6 Hz, 1H), 4.16–3.98 (m, 1H), 3.87 (dd, J=16.7, 4.7 Hz, 1H), 1.85 (t, J=16.4 Hz, 1H), 1.47 (d, J=6.7 Hz, 1H), 1.45–1.27 (m, 11H), 1.23 (s, 1H). MS m/z: 605.3 (M+H).

II. Biological Activity Test of the Compounds of the Invention

Example 10: In vitro antitumor activity test of representative 2-fluorobiphenyl-4-acetic acid derivatives of formula I

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, 100U/ml penicillin and 100U/ml streptomycin at 37°C and 5% CO ₂ incubator. Using the MTT method, cells in logarithmic growth phase were inoculated in 96-well plates (100μl/well, 2×10 ⁴ cells), and blank wells were set up at the same time. After overnight culture, 100μl of drug solution (final concentration of 25μM was diluted to 0.39μM), and the blank control wells were added with an equal volume of culture medium, and 3 replicate wells were set up for each drug concentration. After continuing to culture for 48h, the supernatant was discarded, PBS was washed twice, and 100μl MTT (5mg/ml) was added to each well, and culture was continued for 2h. The absorbance (A _492nm value) was measured using an enzyme marker to calculate the inhibition rate of the drug on tumor cells.

GraphPad software was used to calculate the IC ₅₀ values of the compounds against tumor cells, and the results are shown in Table 2-1 and Table 2-2. The results show that the in vitro antitumor activity of the new molecules Cpd001, Cpd002, and Cpd003 against prostate cancer, lung cancer, and liver cancer is comparable to that of the compound PL-AC-202, and is superior to cisplatin. The compounds Cpd001-Cpd009 used in Table 2-1 and Table 2-2 are all racemates.

Table 2-1. In vitro antitumor activity IC ₅₀ values of example compounds (uM)

Table 2-2. In vitro antitumor activity IC ₅₀ values of example compounds (uM)

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

BALB/c nude mice were used to construct an in vivo antitumor efficacy evaluation model, and 0.15 mL of tumor cell suspension (A549, 2×10 ⁷ cells/ml) was subcutaneously inoculated in the axilla of the right forelimb of each mouse. Administration began when the inoculated cells grew to 300 mm ^3. On the 22nd day after inoculation, intraperitoneal injection (20 mg/kg) was given once every 2 days for a total of 10 times. On the second day after the last administration, all tumor-bearing mice were killed, the tumor weight was weighed, and the tumor inhibition rate was calculated. The results showed that the new compounds represented by Cpd001 (S, S) have better in vivo antitumor efficacy against lung cancer than PL-AC-202.

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

The above description is only the 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.

Industrial Applications

The 2-fluorobiphenyl-4-acetic acid derivatives shown in formula I provided by the present invention are brand-new compounds designed from scratch. The compounds in the present invention are 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.

Claims (12)

1. The compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt, ester, solvate or isomer thereof:

   

   In Formula I, R ₁ and R ₂ are independently selected from any of the following groups: hydrogen, -OR ⁴ , -SR ⁴ , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, C _6-12 aryl, 5-12 membered heteroaryl; or R ₁ and R ₂ can be combined to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclic group; wherein R ⁴ is selected from any 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 the above groups in which hydrogen is substituted by any one or more halogens;

   The R ₃ 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 the R ₃ and Linker, and each hydrogen on R ₃ is arbitrarily replaced by R ⁵ ;

   Wherein, ^R5 can be independently selected from: hydrogen, halogen, _C1-10 alkyl, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl, oxy _C6-14 aryl or oxy _C5-14 aromatic heteroyl, nitrogen _C6-14 aryl or nitrogen _C5-14 aromatic heteroyl, 5-14 membered heteroaryl, partially or fully halogenated _C1-5 alkyl;

   The linker is selected from any of the following groups: C _1-8 alkylene, C _2-8 alkenylene, C _2-8 alkynylene, C _3-12 cycloalkylene, 3-12 membered heterocyclylene, C _6-12 arylene, 5-12 membered heteroarylene, and each hydrogen on the linker is arbitrarily replaced by R ⁶ ;

   Wherein, ^R6 is selected from the following groups: halogen, _C1-10 alkyl, _{C2-8 alkenyl, C2-8 alkynyl} , _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl, oxy _C6-14 aryl or oxy _C5-14 aromatic heteroyl, nitrogen _C6-14 aryl or nitrogen _C5-14 aromatic heteroyl, 5-14 membered heteroaryl. -CN, _-NO2 , _-CF2H ^, -CF2OH, _-CF3 , ^{-OCF3 ,} -CR7R8R9 _, ^-OR7 _, -O(C=O) ^R7 , ^-O (C=O) ^OR7 , -O(C=O) ^NR8R9 , -(C=O) ^R7 , -(C=O)OR7, -(C=O) ^{NR8R9 , -SR7 ,} -(S=O) _mR7 , ^{-NR8R9 , -NR7} (C=O) ^{R8 , -NR7C} (=O) ^{NR8R9 , -NR7C} (=O) ^{OR8 , -NR7S ( =} O) ^{mNR8R9 ,} _-NR7S (=O) _mOR8 , or ^-NR7S (=O) _mR8 , or the groups of adjacent atoms on R ₆ can be combined to form a C _3-12 cycloalkyl group, a C _6-12 aryl group, a 3-12 membered heterocyclic group, and a 5-12 membered heteroaromatic ring group;

   wherein R ⁷ , R ⁸ , and R ⁹ are 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 heterocyclyl, C _6-14 aryl, oxy C 6-14 aryl or oxy C 5-14 heteroaromatic group, nitrogen C _6-14 aryl or nitrogen C _5-14 heteroaromatic group, _5-14 membered heteroaryl, or any two of R ⁷ , R ⁸ , and R ⁹ bound to the same nitrogen atom may be combined with the nitrogen to which they are bound to form a _3-12 membered heterocyclyl or 5-12 membered heteroaryl, which optionally contains 1 to 3 additional heteroatoms selected from N, O and S, or any two of R 7 , R 8 , and R 9 bound to the same carbon atom may be combined to form a C 3-12 cycloalkyl, C 6-14 aryl, or C 5-14 heteroaromatic group, or any two of R ⁷ , R ⁸ , and R ⁹ bound to the same carbon atom may be combined to form a C _3-12 cycloalkyl, C _6-12 membered aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and each hydrogen atom in R ⁷ , R ⁸ and R ⁹ is optionally substituted by R ¹⁰ , or two hydrogen atoms on the same carbon atom in R ⁷ , R ⁸ and R ⁹ are optionally oxo substituents;

   The ^R10 is independently selected from: hydrogen, halogen, _C1-10 alkyl, _{C2-8 alkenyl, C2-8 alkynyl} , _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl, oxy _C6-14 aryl or oxy _C5-14 heteroaromatic group, nitrogen _C6-14 aryl or nitrogen _C5-14 heteroaromatic group, 5-14 membered heteroaryl; -CN, _-NO2 , -OH, _-NH2 , partially or fully halogenated _C1-5 alkyl, -C(=O)( _CH2 ) _nCH3 , -C(=O)O( _CH2 ) _nCH3 , -C(= _O )OH, -C(=O)N[( _CH2 ) _nCH3 ] ₂ , _-C (=O) _NH2 , -C ₍ =O)NH( _{CH2 ) nCH3} , -NH(CH ₂ ) _n CH ₃ , -N[(CH ₂ ) _n CH ₃ ] ₂ , -N(CH ₂ ) _n CH ₃ C(═O)(CH ₂ ) _n CH ₃ , -N(CH ₂ ) _n CH ₃ C(═O)NH(CH ₂ ) _n CH ₃ , -N(CH ₂ ) _n CH ₃ C(═O)N[(CH ₂ ) _n CH ₃ ] ₂ , -N(CH ₂ ) _n CH ₃ C(═O)NH ₂ , -N(CH ₂ ) _n CH ₃ C(═O)O(CH ₂ ) _n CH ₃ , -N(CH ₂ ) _n CH ₃ C(═O)OH , -NHC(═O)(CH ₂ ) _n CH ₃ , -NHC(═O)NH(CH ₂ ) _n CH ₃ , -NHC(＝O)N[(CH ₂ ) _n CH ₃ ] ₂ , -NHC(＝O)NH ₂ , -NHC(＝O)O(CH ₂ ) _n CH ₃ , -NHC(＝O)OH, -N(CH ₂ ) _n CH ₃ S(＝O) _m (CH ₂ ) _n CH ₃ , -NHS(＝O) _m (CH ₂ ) _n CH ₃ , -O(CH ₂ ) _n CH ₃ , ＝O, -OC(＝O)(CH ₂ ) _n CH ₃ , OC(＝O)O(CH ₂ ) _n CH ₃ , -OC(＝O)N[(CH ₂ ) _n CH ₃ ] ₂ , -OC(＝O)NH(CH ₂ ) _n CH ₃ , -OC(＝O)NH ₂ , -S(＝O)m(CH ₂ ) _n CH ₃ , -OS(=O)m(CH ₂ ) _n CH ₃ , -S(=O) _mNH (CH ₂ ) _n CH ₃ , -S(=O) _mN [(CH ₂ ) _n CH ₃ ] ₂ ;

   The m is selected from 1 or 2;

   The n is selected from 1, 2, 3, 4 or 5.
2. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate or isomer thereof, characterized in that:

   The 5-12 membered heterocyclic aliphatic group formed by _R3 and Linker includes but is not limited to the following groups:

   

   The C _3-12 cycloalkylene group includes but is not limited to the following groups:

   

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

   

   The C _6-12 arylene group includes but is not limited to the following groups:

   

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

   
3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, ester, solvate or isomer thereof, characterized in that:

   The R ₁ and R ₂ are independently selected from any of the following groups: hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, R ₁ and R ₂ form a C _3-6 cycloalkyl;

   The R ₃ is selected from any of the following groups: hydrogen, C _1-4 alkyl, or a 5-12 membered heterocyclic aliphatic group formed by the R ₃ and Linker;

   The linker is selected from any one _of the following groups: _-CH2- , ^-CH2CH2- _{, -CH2CH2CH2- ,} ^-CHR11CH2- _, ^-CH2CHR11- _{, -CH2CH2CHR11- ,} ^-CHR11O- _, -CHR11NH- ^{, -CHNR11-} ;

   Preferably, R ¹¹ is 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 group, C _6-12 aryl, 5-12 membered heteroaryl, phenylamino, benzylamino, benzyloxyphenyl, wherein any hydrogen on R ¹¹ is replaced by R ¹² ; the definition of R ¹² is the same as that of R ¹⁰ ;

   Preferably, the Linker includes but is not limited to the following groups:

   

   The 5-12 membered heterocyclic aliphatic group formed by _R3 and Linker includes but is not limited to the following groups:

   
4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester, solvate or isomer thereof, characterized in that:

   
5. The method for preparing the compound of formula I according to any one of claims 1 to 3 comprises the following steps:

   The carboxylic acid represented by formula II is activated by oxalyl chloride (COCl) ₂ , and then reacted with intermediate 1, intermediate 2 or intermediate 3 at room temperature to obtain the corresponding final product compound represented by formula I;

   

   Wherein, R ₁ and R ₂ in Formula II are defined as those in Formula I; Linker and R ₃ in Intermediate 1 are defined as those in Formula I, except that R ₃ in Formula I is hydrogen, and Linker is -CH ₂ CHR ¹¹ - and

   

   The definition of R ¹³ in intermediate 2 is the same as R ¹¹ in the above formula I.
6. The preparation method according to claim 5, characterized in that: the synthesis 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 K ₂ CO ₃ and HBTU to obtain compound 5; compound 5 is deprotected under the conditions of TFA/DCM to obtain intermediate 1;

   The synthesis route of the chiral intermediate 2 is as follows:

   

   The specific preparation method of chiral intermediate 2 is as follows: carboxylic acid 6 is activated by oxalyl chloride (COCl) ₂ to obtain acid chloride 7, which is amidated under n-BuLi to obtain chiral compound 8; compound 8 is reacted with N-bromomethylphthalimide in the presence of lithium hexamethyldisilazide (LiHMDS) at -70°C to obtain chiral compound 9; compound 9 is deprotected under H ₂ O ₂ and LiOH to obtain carboxylic acid 10; compound 10 is then condensed with 4-amino-2,2,6,6-tetramethylpiperidine under HBTU and K ₂ CO ₃ to obtain compound 11; compound 11 is deprotected under N ₂ H ₄ and EtOH to obtain chiral intermediate 2;

   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.
7. Use of the compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, ester, solvate or isomer in the preparation of a drug for preventing and/or treating cancer or in the preparation of a drug for inhibiting cancer cell proliferation;

   Preferably, the cancer is solid cancer or non-solid cancer, including liver cancer, lung cancer, prostate cancer, and colorectal cancer;

   The cancer cells include liver cancer cells, lung cancer cells, prostate cancer cells, and colorectal cancer cells.
8. A drug or pharmaceutical composition for preventing and/or treating cancer, characterized in that the drug or pharmaceutical composition comprises an effective dose of a compound of formula I as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester, solvate or isomer thereof.
9. The medicine or pharmaceutical composition according to claim 8, characterized in that the cancer is solid cancer or non-solid cancer, including liver cancer, lung cancer, prostate cancer, and colorectal cancer.
10. The medicine or pharmaceutical composition according to claim 8 or 9 is characterized in that the dosage form of the medicine or pharmaceutical composition includes capsules, powders, oral liquids, granules, and tablets.
11. A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester, solvate or isomer thereof, or administering a therapeutically effective amount of a medicament or pharmaceutical composition according to claim 9 or 10.
12. The method according to claim 11 is characterized in that: the cancer is solid cancer or non-solid cancer, including liver cancer, lung cancer, prostate cancer, and colorectal cancer.