Triphenylphosphine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a triphenylphosphine compound as well as a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is shown as a formula I. The compound not only has good selectivity on HDAC3 protein, but also has a good inhibition effect on fat cells, and has wide application prospects in the aspect of treating and / or preventing various diseases related to mitochondrial targeting HDAC3 activity inhibition. Meanwhile, the preparation method of the compound is convenient, efficient, high in universality and easy in structure expansion. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a triphenylphosphine compound, a preparation method thereof, a pharmaceutical composition and an application, and particularly relates to a triphenylphosphine compound having HDAC3 inhibitory activity, a preparation method thereof, a pharmaceutical composition and an application. Background Art

[0002] Obesity is a complex metabolic disease caused by multiple factors, characterized by excessive accumulation of body fat, resulting in overweight and a series of health problems, such as type 2 diabetes, cardiovascular diseases and non-alcoholic fatty liver disease, etc. Currently, the drugs used for the treatment of obesity mainly control body weight by inhibiting absorption and reducing energy intake, which can play a role in reducing body weight to a certain extent, but long-term use will lead to malnutrition and even cause damage to the body. Therefore, researching and developing new, efficient and low-toxic treatment methods for the pathogenesis of obesity is an important scientific problem that urgently needs to be solved in this field.

[0003] HDAC (histone deacetylase) is mainly involved in regulating processes such as gene expression, cell proliferation and differentiation. Among them, HDAC3 plays an important role in the pathogenesis of obesity, and its mechanism mainly affects the differentiation of adipocytes, lipid metabolism and insulin sensitivity by regulating epigenetic modifications.

[0004] HDAC3 plays a key role in the expression of genes related to mitochondrial oxidative metabolism. Research shows that HDAC3 can act on key genes involved in mitochondrial biosynthesis, such as nuclear respiratory factor (NRF) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). HDAC3 can deacetylate the histones in the regions where these genes are located, making the chromatin structure become compact, thereby inhibiting their transcription, and further affecting the quantity and quality of mitochondria.

[0005] Another study shows that overactivation of HDAC3 will inhibit the expression of fatty acid transporter genes, such as carnitine / organic cation transporter 2 (OCTN2) and fatty acid transport protein (FATP) family members, reducing the amount of fatty acids entering mitochondria. At the same time, overactivation of HDAC3 inhibits the expression of fatty acid oxidase genes, such as acyl-CoA oxidase (ACOX) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and other genes. This will result in insufficient amounts of enzymes involved in fatty acid oxidation inside mitochondria, leading to a decrease in fatty acid oxidation efficiency, thereby affecting mitochondrial oxidative metabolism.

[0006] HDAC3 is widely distributed in the body. Existing HDAC3 inhibitors have insufficient inhibitory activity against HDAC3, low selectivity, and require high doses to achieve ideal therapeutic effects. This may increase the risk of adverse drug reactions and is not conducive to the clinical application of drugs. At the same time, existing HDAC3 inhibitors lack targeting. HDAC3 also plays an important role in processes such as cell cycle regulation and DNA damage repair. Non-targeted inhibition of HDAC3 may lead to cell cycle disorders and abnormal DNA damage repair, increasing the risk of disease treatment or exacerbating existing diseases. Summary of the Invention

[0007] Objectives of the Invention: The first objective of the present invention is to provide a triphenylphosphine compound, the second objective is to provide a preparation method of the compound, the third objective is to provide a pharmaceutical composition containing the compound, and the fourth objective is to provide a pharmaceutical application of the compound and its pharmaceutical composition.

[0008] Technical Solution: The triphenylphosphine compound described in the present invention has the structure of Formula I, and also includes its stereoisomers, diastereoisomers, enantiomers, tautomers, solvates, isotopic compounds, pharmaceutically acceptable salts, prodrugs, or mixtures thereof:

[0009]

[0010] Wherein:

[0011] n is selected from 1, 2, 3, 4, 5, 6, 7;

[0012] Q and G are L-Z;

[0013] L is selected from a chemical bond, -O-, -S-, -SO-, -SO2-, -N(R 6 )SO2-, -SO2N(R 6 )-, -N(R 6 )-, -CO-, -C(O)O-, -N(R 6 )CO-, -N(R 6 )CO2-, -N(R 6 )CON(R 6 )-, -N(R 6 )SO2N(R 6 )-, -N(R 6 )N(R 6 )-, -CON(R 6 )-, -OCON(R 6 )-, -C(R 6 )2O-, -C(R 6 )2S-, -C(R6 )2SO−, −C(R 6 )2SO2−, −C(R 6 )2SO2N(R 6 )−, −C(R 6 )2N(R 6 )−, −C(R 6 )2N(R 6 )CO−, −C(R 6 )2N(R 6 )CO2−, −C(R 6 )=NN(R 6 )−, −C(R 6 )=N−O−, −C(R 6 )2N(R 6 )N(R 6 )−, −C(R 6 )2N(R 6 )SO2N(R 6 )− or −C(R 6 )2N(R 6 )CON(R 6 )−;

[0014] Z is selected from hydrogen, a 5- to 7-membered monocyclic group or an 8- to 10-membered bicyclic group, and the 5- to 7-membered monocyclic group or 8- to 10-membered bicyclic group is selected from aryl, heteroaryl, heterocyclic or carbocyclic groups, wherein the heteroaryl or heterocyclic group contains 1 to 4 nitrogen, oxygen or sulfur ring heteroatoms; any ring carbon atom on the 5- to 7-membered monocyclic group or 8- to 10-membered bicyclic group that can be substituted is oxo, T-R 4 or V-W-R 4 substituted; any ring nitrogen atom on the 5- to 7-membered monocyclic group or 8- to 10-membered bicyclic group that can be substituted is R 5 substituted;

[0015] T is selected from a chemical bond or C 1-4 alkylene chain;

[0016] V is selected from -O-, -S-, -SO-, -SO2-, -N(R 6 )SO2-, -SO2N(R 6 )-, -N(R 6 )-, -CO-, -C(O)O-, -N(R 6 )CO-, -N(R 6 )CO2-, -N(R 6 )CON(R 6 )-, -N(R 6 )SO2N(R 6 )-, -N(R 6 )N(R6 )-, -C(O)N(R 6 )-, -OC(O)N(R 6 )-, -C(R 6) 2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C(R 6 )2SO2-, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )CO-, -C(R 6 )2N(R 6 )CO2-, -C(R 6 )=NN(R 6 )-, -C(R 6 )=N-O-, -C(R 6 )2N(R 6 )N(R 6 )-, -C(R 6 )2N(R 6 )SO2N(R 6 )- or -C(R 6 )2N(R 6 )CON(R 6 )-;

[0017] W is selected from -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C(R 6 )2SO2-, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -C(O)O-, -C(R 6 )OCO-, -C(R 6 )OCON(R 6 )-, -C(R 6 )2N(R 6 )CO-, -C(R 6 )2N(R 6 )C(O)O-, -C(R 6 )=NN(R 6 )-, -C(R 6 )=N-O-, -C(R 6 )2N(R 6)N(R 6 )-, -C(R 6 )2N(R 6 )SO2N(R 6 )-, -C(R 6 )2N(R 6 )CON(R 6 )- or -CON(R 6 )-;

[0018] R 4 is selected from R 2 , halogen, -O(R 2 ), -CO(R 2 ), -CO2(R 2 ), -COCO(R 2 ), -NO2, -CN, -SO(R 2 ), -SO2(R 2 ), -S(R 2 ), -N(R 3 ),2, -CON(R 3 ),2, -SO2N(R 3 ),2, -OCOR 2 , -N(R 3 ),CO(R 2 ), -N(R 3 ),CO(halogen, nitro, cyano, alkoxy-substituted C1-C6 aliphatic group), -N(R 3 ),N(R 3 ),2, -C=NN(R 3 ),2, -C=N, -O(R 2 ), -N(R 3 ),CON(R 3 ),2, -N(R 3 ),SO2N(R 3 ),2, -N(R 3 ),SO2(R 2 ) or -OCON(R 3 ),2;

[0019] R 2 is selected from hydrogen, C1-C6 alkyl, 6-10 membered aryl, 5-10 membered heteroaryl ring or 5-10 membered heterocyclic ring, wherein the 5-10 membered heteroaryl or 5-10 membered heterocyclic ring contains 1-4 nitrogen, oxygen or sulfur ring heteroatoms;

[0020] R 3 is selected from hydrogen, C1-C6 alkyl, cyano, halogen, C1-C6 haloalkyl, hydroxy, mercapto, C1-C6 alkoxy, R 5 , -COR 5, -C(O)O-(C1-C6 alkyl substituted by halogen, nitro, cyano, C1-C4 alkoxy), -CON(R 5 )2 or -SO2R 5 ;

[0021] R 5 is selected from hydrogen or C1-C6 alkyl substituted by halogen, nitro, cyano, C1-C4 alkoxy, or two Rs attached to the same nitrogen atom 5 form a 5-8 membered heterocyclic ring or a 5-8 membered heteroaromatic ring with the nitrogen atom to which they are attached;

[0022] R 6 is selected from hydrogen or C1-C4 alkyl substituted by halogen, nitro, cyano, C1-C4 alkoxy.

[0023] Preferably, in the structure:

[0024] n is selected from 1, 2, 3, 4, 5;

[0025] L in Q is selected from -N(R 6 )-, -CON(R 6 )- or -N(R 6 )CO-;

[0026] Z in Q is selected from 5-7 membered monocyclic groups, and the 5-7 membered monocyclic groups are selected from aryl, heteroaryl, heterocyclic or carbocyclic groups, wherein the heteroaryl or heterocyclic group contains 1-4 nitrogen, oxygen or sulfur ring heteroatoms; any ring carbon atom on the 5-7 membered monocyclic group that can be substituted is substituted by R 5 ;

[0027] R 5 is selected from hydrogen or C1-C4 alkyl substituted by halogen, nitro, cyano, C1-C4 alkoxy;

[0028] R 6 is selected from hydrogen or C1-C4 alkyl substituted by halogen, nitro, cyano, C1-C4 alkoxy.

[0029] More preferably, in the structure:

[0030] L in G is selected from chemical bond, -O- or -NR 6 -;

[0031] Z in G is selected from 5-7 membered monocyclic groups, and the 5-7 membered monocyclic groups are selected from aryl, heteroaryl, heterocyclic or carbocyclic groups, wherein the heteroaryl or heterocyclic group contains 1-4 nitrogen, oxygen or sulfur ring heteroatoms; any ring carbon atom on the 5-7 membered monocyclic group that can be substituted is substituted by R 5 ;

[0032] R5 Selected from hydrogen or a C1-C4 alkyl group substituted by a halogen, nitro group, cyano group, or C1-C4 alkoxy group;

[0033] R 6 Selected from hydrogen or a C1-C4 alkyl group substituted by a C1-C4 alkoxy group.

[0034] Preferably, in the said structure:

[0035] L in Q is selected from a chemical bond, -CONH-, or -NHCO-;

[0036] Z in Q is selected from any one of the following structures:

[0037]

[0038] L in G is selected from a chemical bond, -O-, -NH(CH2)3-, or -NH(CH2)4-;

[0039] Z in G is selected from any one of the following structures:

[0040]

[0041] Preferably, the said triphenylphosphine compound is characterized in that it is selected from any one of the following compounds:

[0042]

[0043]

[0044] The designed mitochondrial-targeted selective HDAC3 inhibitor of the present invention has a good therapeutic effect on obesity. Therefore, the development of new mitochondrial-targeted selective HDAC3 inhibitors is of great significance for improving the treatment of obesity and reducing the side effects caused by pan-HDAC inhibitors.

[0045] Preferably, the said pharmaceutically acceptable salt is a salt formed by the said compound and any one of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid.

[0046] "Pharmaceutically acceptable salts" refer to salts of a compound prepared from a compound having specific substituents with a relatively non-toxic acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates), sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids; organic acid salts also include salts of amino acids (such as arginine, etc.), glucuronic acid and other organic acids. When certain specific compounds contain both basic and acidic functional groups, they can thus be converted into either base or acid addition salts. Preferably, the salt is contacted with a base or an acid in a conventional manner, and then the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0047] "Pharmaceutically acceptable salts" can be synthesized from parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of both, these compounds in the free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0048] Preferably, the tautomer is an isomer formed by the conjugation and interconversion of double bonds in an unsaturated heterocycle, including carbon-carbon double bond interconversion, carbon-heteroatom, heteroatom-heteroatom double bond interconversion, such as the tautomers formed by the double bond interconversion in an imidazole ring system, a pyrazole ring.

[0049] Preferably, the prodrug is an ester or amide prodrug introduced by carboxyl, hydroxyl, amino groups, and more preferably a C1-C4 alkyl ester, a C1-C4 carboxylic acid ester, a C1-C4 alkyl amide.

[0050] Preferably, the solvate is a small molecule bound state formed by the compound and solvent molecules, and more preferably a hydrate, an alcoholate; its solvate can further form a salt with the corresponding acid to obtain the salt of the solvate.

[0051] Preferably, the isotope compound is a compound in which hydrogen in the compound is replaced by deuterium.

[0052] Preferably, the crystal is a specific crystal structure formed during the crystallization of the compound, including different crystal forms of the compound itself, as well as different crystal forms of its salts, solvates, and salts of solvates.

[0053] The preparation method of the triphenylphosphine compound of the present invention is selected from any one of the following methods:

[0054] Method 1:

[0055] (1) Acid amide condensation of triphenylphosphine alkyl carboxylic acid with Q-methyl ester to obtain intermediate 2;

[0056] (2) Alkaline hydrolysis of intermediate 2 to obtain intermediate 3;

[0057] (3) Reacting intermediate 3 with amino-G to generate the triphenylphosphine compound I;

[0058]

[0059] Method 2:

[0060] (1) Acid amide condensation / coupling reaction of triphenylphosphine alkylamine with Q-methyl ester to obtain intermediate 6;

[0061] (2) Hydrolysis of intermediate 6 to obtain intermediate 7;

[0062] (3) Acid amide condensation of intermediate 7 with NH2-G to obtain the triphenylphosphine compound I;

[0063]

[0064] Method 3:

[0065] (1) Reacting (3-propylcarboxyl) triphenylphosphonium bromide with methyl 5-aminopyridine-2-carboxylate to obtain intermediate 10;

[0066] (2) Condensation reaction of intermediate 10 with hydrazine hydrate to obtain intermediate 11;

[0067] (3) Imine reduction of intermediate 11 to obtain the triphenylphosphine compound I;

[0068]

[0069] Among them, the definitions of n, Q, and G are as described above;

[0070] The corresponding acid is salted with the compound I obtained by any of the above methods to obtain the pharmaceutically acceptable salt described above.

[0071] The pharmaceutical composition described in the present invention comprises the triphenylphosphine compound described in the present invention and a pharmaceutically acceptable carrier.

[0072] "Pharmaceutically acceptable carrier" can be an excipient widely used in the field of drug production. The excipient is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the active ingredient to dissolve at the desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the administration of the composition. The pharmaceutical excipient can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipient can include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesive agent, glidant, wetting agent, gelling agent, absorption delaying agent, dissolution inhibitor, enhancer, adsorbent, buffer, chelating agent, preservative, colorant, flavoring agent and sweetening agent.

[0073] The pharmaceutical composition described in the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0074] The pharmaceutical composition described in the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be in a controlled-release or sustained-release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include but are not limited to powders, capsules, cachets, soft gelatin capsules and tablets. Examples of liquid preparations for oral or mucosal administration include but are not limited to suspensions, emulsions, elixirs and solutions. Examples of topical preparations include but are not limited to emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include but are not limited to injection solutions, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspensions and injection emulsions. Examples of other suitable preparations of the pharmaceutical composition include but are not limited to eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0075] The triphenylphosphine compound described in the present invention and its pharmaceutical composition are used in the preparation of drugs for treating and / or preventing diseases related to HDAC3 inhibition.

[0076] Preferably, the drug is a drug for treating and / or preventing obesity, Alzheimer's disease, acute liver injury, liver fibrosis, multiple myeloma, lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastric cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin-dependent diabetes or autoimmune disease.

[0077] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0078] The compound designed by the present invention can effectively inhibit HDAC3 activity at the nanomolar concentration level, and has good selectivity for HDAC3 protein, reducing side effects; it also has a good inhibitory effect on fat cells, and can effectively inhibit obesity. It has broad application prospects in the treatment and / or prevention of various diseases related to the inhibition of HDAC3 activity. At the same time, the preparation method of the compound is simple, efficient, highly versatile, and easy to expand the structure. DETAILED DESCRIPTION

[0079] The technical solution of the present invention is further described below in conjunction with embodiments.

[0080] (1) Reagents and materials

[0081] (3-Propanylcarboxyl)triphenylphosphonium bromide, methyl para-aminomethylbenzoate, o-phenylenediamine, N,N-diisopropylethylamine, HATU, and hydroxylamine hydrochloride are from Shanghai Bid Pharmaceutical Technology Co., Ltd., Titan Technology Co., Ltd., and Shanghai Haohong Biopharmaceutical Technology Co., Ltd.

[0082] (2) Instruments

[0083] 1 H NMR was measured using a BRUKERAVANCE-300 or BRUKERAVANCE-400 nuclear magnetic resonance instrument (Brucker, Switzerland), with TMS as the internal standard and the unit of shift value (δ) was ppm. Low-resolution mass spectrometry was measured using an expression compact Fourier transform mass spectrometer.

[0084] Method 1:

[0085] Triphenylphosphine alkyl carboxylic acid and Q-formate undergo acid-amine condensation to generate intermediate 2; intermediate 2 is hydrolyzed with alkali in methanol aqueous solution, and the pH is adjusted to precipitate a solid to obtain intermediate 3; intermediate 3 reacts with amino-G to obtain compound I.

[0086]

[0087] Reaction conditions: (a) HATU, DIPEA, DMF, r.t.; (b) LiOH, MeOH:H2O = 3:1, r.t.; (c) HATU, DIPEA, DMF, r.t.

[0088] Example 1: Synthesis of N-(2-aminophenyl)-4-((5-(triphenylphosphino)butyramido)methyl)benzamide (Compound I-1)

[0089]

[0090] (1) Preparation of methyl 4-((5-(triphenylphosphino)-butylaminomethyl)benzoate) (1-2)

[0091] At room temperature, 5-(triphenylphosphino)butyric acid (1 g, 2.74 mmol) and HATU (1.15 g, 3.01 mmol) were dissolved in 10 mL of anhydrous DMF. DIPEA (1.45 mL, 8.22 mmol) was added and stirred for 30 min. Then methyl 4-(aminomethyl)benzoate was added and the reaction was carried out at room temperature for 3 h. After monitoring the reaction by TLC until completion, 50 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 3), washed with water (50 mL × 2) and saturated brine (50 mL × 2). After drying, it was filtered and concentrated, and purified by column chromatography (DCM:MeOH = 50:1) to obtain 1.25 g of a pale yellow oil, with a yield of 89%. ESI-MS m / z: 510.2 [M-H] + 。

[0092] (2) Preparation of 4-((5-(triphenylphosphino)butyryl)methyl)benzoic acid (1-3)

[0093] At room temperature, 1-2 (1 g, 2.01 mmol) and LiOH (0.19 g, 8.04 mmol) were dissolved in 12 mL of 75% methanol and stirred at room temperature for 6 h. After monitoring the reaction by TLC until completion, the reaction solution was evaporated to dryness, 15 mL of water was added, and the pH was adjusted to 5 - 6 with 1N dilute hydrochloric acid until the product precipitated. After filtration and drying, 0.9 g of a white powdery substance was obtained, with a yield of 90%. ESI-MS m / z: 496.2 [M-H] + 。

[0094] (3) Preparation of N-(2-aminophenyl)-4-((5-(triphenylphosphino)butyramido)methyl)benzamide (I-1)

[0095] At room temperature, using 1-3 (150 mg, 0.3 mmol) and o-phenylenediamine (39 mg, 0.36 mmol) as raw materials, the method was the same as that of 1-2, and 130 mg of a white powdery substance was obtained, with a yield of 74%. 11H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.53 (s, 1H), 7.91 - 7.72 (m, 17H), 7.36 (d, J = 7.9 Hz, 2H), 7.19 - 7.12 (m, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 4.88 (s, 2H), 4.35 (d, J = 5.9 Hz, 2H), 3.56 (s, 2H), 2.43 (d, J = 7.0 Hz, 2H), 1.77 (d, J = 10.7 Hz, 2H). ESI-MS m / z: 572.2 [M-H] + 。

[0096] Using an operation similar to that in Example 1, the following compounds were prepared:

[0097]

[0098]

[0099]

[0100]

[0101] Method 2:

[0102] Triphenylphosphine alkylamine undergoes an acid amide condensation / coupling reaction with Q-methyl ester to form intermediate 6; intermediate 6 is hydrolyzed with LiOH at room temperature in water to obtain intermediate 7; 7 undergoes an acid amide condensation with NH2-G to form Compound I.

[0103]

[0104] Reaction conditions: (a) HATU, DIPEA, DMF, r.t. / Pd(dppf)Cl2, Brettphos, K2CO3, 1,4-Dioxane, 100 °C; (b) LiOH, MeOH:H2O = 3:1, r.t.; (c) HATU, DIPEA, DMF, r.t.

[0105] Example 2: N 1 -(2-Aminophenyl)-N 4 -(2-(Triphenylphosphino)ethyl)terephthalamide (Compound I-29) Synthesis

[0106]

[0107] (1) Methyl 4-((2-(Triphenylphosphino)ethyl)carbamoyl)benzoate (29-6)

[0108] At room temperature, using 2-(triphenylphosphino)ethylamine (1 g, 3.25 mmol) as the raw material, following the same method as in 1-2, 1.12 g of a pale yellow oil was obtained, with a yield of 80%. ESI-MS m / z: 468.2 [M-H] + 。

[0109] (2) 4-((2-(Triphenylphosphino)ethyl)carbamoyl)benzoic acid (29-7)

[0110] At room temperature, using 29-6 (1 g, 2.2 mmol) as the raw material, following the same method as in 1-3, 0.9 g of a white powdery substance was obtained, with a yield of 90%. ESI-MS m / z: 454.2 [M-H] + 。

[0111] (3) N-(2-Aminophenyl)-4-(2-(triphenylphosphoranylidene)ethyl)benzamide (I-29)

[0112] At room temperature, using 29-7 (150 mg, 0.34 mmol) and o-phenylenediamine (44 mg, 0.36 mmol) as the raw materials, following the same method as in 1-2, 160 mg of a white powdery substance was obtained, with a yield of 86%. 1 HNMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.99 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.98–7.63 (m, 18H), 7.17 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 7.5 Hz, 1H), 4.93 (s, 2H), 3.89 (d, J = 14.2, 7.5 Hz, 2H), 3.61 (s, 2H). ESI-MS m / z: 544.2 [M-H] + 。

[0113] Example 3: Synthesis of N 1 -(2-Aminophenyl)-N 4 -(2-(Triphenylphosphino)ethyl)terephthalamide (Compound I-31)

[0114]

[0115] (1) Methyl 4-((3-(Triphenylphosphino)propyl)amino)benzoate (31-6)

[0116] Using 2-(triphenylphosphino)propylamine (1 g, 3.12 mmol) as the raw material, successively add methyl 4-(bromomethyl)benzoate (714.97 mg, 3.12 mmol), Pd(dppf)Cl2 (1.14 g, 1.56 mmol), Brettphos (837.69 mg, 1.56 mmol), and K2CO3 (1.29 g, 9.36 mmol) dissolved in dioxane. Under nitrogen protection, heat to 100 °C and react for 4 h. After monitoring the reaction by TLC until it is completed, add 50 mL of water to the reaction solution, extract with ethyl acetate (50 mL × 3), wash with water (50 mL × 2), wash with saturated brine (50 mL × 2), dry, filter, and concentrate. Purify by column chromatography (DCM:MeOH = 50:1) to obtain 1.25 g of a pale yellow oily substance with a yield of 86%. ESI-MS m / z: 468.3 [M-H] + 。

[0117] (2) Methyl 4-((3-(triphenylphosphino)propyl)amino)benzoate (31-7)

[0118] At room temperature, using 31-6 (1 g, 2.2 mmol) as the raw material, the method is the same as in 1-3, to obtain 0.8 g of a white powdery substance with a yield of 84%. ESI-MS m / z: 454.2 [M-H] + 。

[0119] (3) N-(2-Aminophenyl)-4-(2-(triphenylphosphoranylidene)ethyl)benzamide (I-31)

[0120] At room temperature, using 31-7 (150 mg, 0.34 mmol) and o-phenylenediamine (39 mg, 0.36 mmol) as the raw materials, the method is the same as in 1-2, to obtain 132 mg of a white powdery substance with a yield of 82%. 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.51 (s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.58 (s, 3H), 7.50 (d, J = 20.0 Hz, 8H), 7.40 (s, 1H), 6.98 (d, J = 20.0 Hz, 7H), 6.85 (s, 1H), 5.12 (s, 3H), 3.66 (s, 3H), 2.54 (s, 3H), 1.50 (s, 3H), 1.30 (s, 3H). ESI-MS m / z: 544.4 [M-H] + 。

[0121] Using operations similar to those in Example 2 and Example 3, the following compounds were prepared:

[0122]

[0123] Method 3:

[0124] Using (3 - propylcarboxyl) triphenylphosphonium bromide as the raw material, react with methyl 5 - aminopyridine - 2 - carboxylate to generate intermediate 10; intermediate 10 undergoes a condensation reaction with hydrazine hydrate to obtain intermediate 11; finally, it is reduced by imine to generate compound I;

[0125]

[0126] Reaction conditions: (a) HATU, DIPEA, DMF, r.t.; (b) NH2NH2·H2O, MeOH, reflux; (c) 1) catalytic PTSA, MeOH, r.t.; 2) NaBH3CN, MeOH, pH = 5, r.t.

[0127] Example 4: Synthesis of N-(6-(2 - propylhydrazine - 1 - carbonyl)pyridin - 3 - yl)-4-(triphenylphosphonium)butanamide (Compound I - 34)

[0128]

[0129] (1) Preparation of methyl 5-(4-(triphenylphosphino)butanamido)pyridine - 2 - carboxylate (34 - 10)

[0130] At room temperature, dissolve 5-(triphenylphosphino)butyric acid (1 g, 2.74 mmol) and HATU (1.15 g, 3.01 mmol) in 10 mL of anhydrous DMF, add DIPEA (1.45 mL, 8.22 mmol), stir for 30 min, and then add methyl 5 - aminopyridine - 2 - carboxylate and react at room temperature for 3 h. After monitoring the reaction by TLC until it is completed, add 50 mL of water to the reaction solution, extract with ethyl acetate (50 mL × 3), wash with water (50 mL × 2), wash with saturated brine (50 mL × 2), dry, filter, and concentrate. Purify by column chromatography (DCM / MeOH = 50:1) to obtain 0.87 g of a pale yellow oily substance with a yield of 72%. ESI - MS m / z: 483.3[M - H] + 。

[0131] (2) Preparation of N-(6-(hydrazinecarbonyl)pyridin - 3 - yl)-4-(triphenylphosphino)butanamide (34 - 11)

[0132] At room temperature, dissolve 34 - 10 (150 mg, 0.31 mmol) in 10 mL of methanol in a 50 mL eggplant - shaped flask, add hydrazine hydrate (155 mg, 3.1 mmol), react at 65 °C for 6 h. After monitoring the reaction by TLC and confirming its completion, rotary - evaporate the reaction solution to obtain 0.8 g of a pale yellow powdery substance, which can be directly used for the next step with a yield of 54%. ESI - MS m / z: 483.0[M - H]+ .

[0133] (3) Preparation of N-(6-(2-Propylhydrazine-1-carbonyl)pyridin-3-yl)-4-(triphenylphosphonium)butanamide (I-34)

[0134] At room temperature, dissolve 34-11 (150 mg, 0.31 mmol) in 8 mL of anhydrous DCM in a 25 mL eggplant-shaped flask. Add propionaldehyde (18.58 mg, 0.37 mmol) and DIPEA (163 μL, 0.93 mmol). Stir at room temperature for 2 h. After monitoring the reaction by TLC until completion, add 20 mL of water to the reaction solution. Extract with dichloromethane (20 ml × 3), wash with water (20 mL × 2), and wash with saturated brine (20 mL × 2). After drying, filter by suction and concentrate. Dissolve it in 6 mL of methanol in a 25 mL eggplant-shaped flask. Add sodium cyanoborohydride (38.87 mg, 0.62 mmol), and adjust the pH to 4 - 5 by dropping glacial acetic acid. Stir at room temperature for 10 min. After monitoring and confirming the completion of the reaction by TLC, adjust the pH to 6 - 7 by dropping saturated sodium bicarbonate solution. Rotavaporize the reaction solution, add 20 mL of water, extract with dichloromethane (20 ml × 3), wash with water (20 mL × 2), and wash with saturated brine (20 mL × 2). After drying, filter by suction and concentrate. Purify by column chromatography (DCM:MeOH = 40:1) to obtain 65 mg of a white powdery substance with a yield of 40%. 1 HNMR(500MHz,DMSO-d6)δ10.95(s,1H),9.95(s,1H),8.85(s,1H),8.23(s,1H),7.98 - 7.66(m,16H),5.05(s,2H),3.65(s,2H),2.72(d,J = 21.9Hz,2H),1.84(s,2H),1.43(s,2H),1.23(s,2H),0.88(s,3H). ESI-MS m / z: 525.2[M-H] + .

[0135] Using an operation similar to that in Example 4, the following compounds were prepared:

[0136]

[0137] Example 5: Test for the inhibitory activity of the compound against HDAC3 enzyme

[0138] 1. Experimental method

[0139] All enzymatic reactions were carried out at 37 °C for 30 min. The 50 mL reaction mixture contained 25 mmol / L Tris (pH 8.0), 1 mmol / L MgCl2, 0.1 mg / mL bovine serum albumin, 137 mmol / L NaCl, 2.7 mmol / L NaCl, histone deacetylase (HDAC), and the enzyme substrate. The compound was diluted in 10% dimethyl sulfoxide (DMSO), and 5 μL of the dilution was added to 50 μL of the reaction system to make the final DMSO concentration 1% in all reactions. The assay was performed by quantifying the amount of fluorescent product in the solution after the enzymatic reaction. Fluorescence was then analyzed on a SpectraMax M5 microplate reader at an excitation wavelength of 350 - 360 nm and an emission wavelength of 450 - 460 nm. Using Prism GraphPad software, the single concentration inhibition rate was calculated by nonlinear regression with normalized dose - response fitting.

[0140] 2. Experimental Results

[0141] Table 1 Inhibitory Activities of Compounds against HDAC3 and HDAC1 Enzymes

[0142]

[0143]

[0144] As shown in Table 1, compounds I - 4, I - 5, I - 6, I - 11, I - 12, I - 13, I - 14, I - 15, I - 28, I - 30, I - 31, I - 33, I - 34, I - 35 all had excellent inhibitory effects on HDAC3 enzyme activity (inhibition rate ≥ 60%), and the inhibitory activity was at the nanomolar concentration level.

[0145] Example 6: Determination of the Anti - Obesity Activity of Compounds in Vitro

[0146] The inhibitory effect of the compound on lipid droplet formation in 3T3 - L1 cell line was determined using Oil Red O.

[0147] 1. Experimental Principle

[0148] 3T3 - L1 is a mouse pre - adipocyte cell line that can differentiate into mature adipocytes under the action of specific inducers (such as insulin, dexamethasone, IBMX), accompanied by the formation of a large number of lipid droplets. Oil Red O is a fat - soluble azo dye, and its lipophilic groups (such as benzene rings and long - chain alkanes) can dissolve in the neutral lipids (triglycerides, cholesterol esters) of lipid droplets to form a stable physical adsorption, thus staining the fat. This staining method is an important method for evaluating the fat level.

[0149] 2. Experimental Procedures and Methods

[0150] Cell culture and induced differentiation: 3T3-L1 cells are a commonly used preadipocyte cell line. First, they are cultured in high-glucose DMEM medium containing 10% calf serum. After 2 days when the cells reach a confluent state (contact inhibition), they are treated with induction medium I prepared with low-glucose DMEM containing 10 μg / mL insulin, 1 μM dexamethasone (Dex), and 0.5 mM 3-isobutyl-1-methylxanthine (IBMX) for 2 - 3 days. Subsequently, they are changed to induction medium II (low-glucose DMEM containing only 10 μg / mL insulin) and cultured for another 4 - 6 days to complete the differentiation of the cells into mature adipocytes.

[0151] Testing the inhibitory effect of the test compound on differentiation: During the induced differentiation process, the test compound is added. The formation of lipid droplets can be observed by Oil Red O staining. Mature adipocytes contain a large number of lipid droplets, and Oil Red O can specifically stain the lipid droplets red. After staining, the lipid droplets stained with Oil Red O are extracted with 100% isopropanol, and the absorbance is measured at a specific wavelength (such as 500 nm) using an enzyme-linked immunosorbent assay (ELISA) reader. The absorbance is proportional to the lipid droplet content. By comparing the absorbance of the drug-treated group and the control group, the inhibitory activity of the drug on adipocyte differentiation is evaluated.

[0152] 3. Experimental results

[0153] Table 2 Inhibition rate of compounds on 3T3L1 cell line (%)

[0154] Compound 3T3L1 single concentration inhibition rate (100 nM) 3T3L1 single concentration inhibition rate (200 nM) I-4 45 78 I-5 78 98 I-6 36 64 I-11 67 90 I-12 53 86 I-13 28 46 I-14 79 91 I-15 35 79 I-28 42 68 I-31 69 70 I-33 43 74 I-34 46 77 I-35 47 80 BG45 58 92

[0155] As shown in Table 2, the compounds with excellent HDAC3 inhibitory activity also have excellent inhibitory effects on the 3T3L1 cell line. Among them, compounds I-5, I-11, I-14, and I-31 have obvious inhibitory effects (inhibition rate ≥ 60%).

Claims

1. A triphenylphosphine compound, characterized in that, It has the structure of formula I, and also includes its stereoisomers, diastereoisomers, enantiomers, tautomers, solvates, isotopic compounds, pharmaceutically acceptable salts, prodrugs or mixtures thereof: Wherein: n is selected from 1, 2, 3, 4, 5, 6, 7; Q, G are L-Z; L is selected from a chemical bond, -O-, -S-, -SO-, -SO2-, -N(R 6 )SO2-, -SO2N(R 6 )-, -N(R 6 )-, -CO-, -C(O)O-, -N(R 6 )CO-, -N(R 6 )CO2-, -N(R 6 )CON(R 6 )-, -N(R 6 )SO2N(R 6 )-, -N(R 6 )N(R 6 )-, -CON(R 6 )-, -OCON(R 6 )-, -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C(R 6 )2SO2-, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )CO-, -C(R 6 )2N(R 6 )CO2-, -C(R 6 )=NN(R 6 )-, -C(R 6 )=N-O-, -C(R 6 )2N(R 6 )N(R 6 )-, -C(R 6 )2N(R 6 )SO2N(R 6 )- or -C(R 6 )2N(R 6 )CON(R 6 )-; Z is selected from hydrogen, a 5- to 7-membered monocyclic group or an 8- to 10-membered bicyclic group, and the 5- to 7-membered monocyclic group or 8- to 10-membered bicyclic group is selected from aryl, heteroaryl, heterocyclic group or carbocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 nitrogen, oxygen or sulfur ring heteroatoms; any ring carbon atom on the 5- to 7-membered monocyclic group or 8- to 10-membered bicyclic group that can be substituted is oxo, T-R 4 or V-W-R 4 substituted; any ring nitrogen atom on the 5- to 7-membered monocyclic group or 8- to 10-membered bicyclic group that can be substituted is substituted by R 5 substituted; T is selected from a chemical bond or C 1-4 an alkylene chain; V is selected from -O-, -S-, -SO-, -SO2-, -N(R 6 )SO2-, -SO2N(R 6 )-, -N(R 6 )-, -CO-, -C(O)O-, -N(R 6 )CO-, -N(R 6 )CO2-, -N(R 6 )CON(R 6 )-, -N(R 6 )SO2N(R 6 )-, -N(R 6 )N(R 6 )-, -C(O)N(R 6 )-, -OC(O)N(R 6 )-, -C(R 6) 2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C(R 6 )2SO2-, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )CO-, -C(R 6 )2N(R 6 )CO2-, -C(R 6 )=NN(R 6 )-, -C(R 6 )=N-O-, -C(R 6 )2N(R 6 )N(R 6 )-, -C(R 6 )2N(R 6 )SO2N(R 6 )- or -C(R 6 )2N(R 6 )CON(R 6 )-; W is selected from -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C(R 6 )2SO2-, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -C(O)O-, -C(R 6 )OCO-, -C(R 6 )OCON(R 6 )-, -C(R 6 )2N(R 6 )CO-, -C(R 6 )2N(R 6 )C(O)O-, -C(R 6 )=NN(R 6 )-, -C(R 6 )=N-O-, -C(R 6 )2N(R 6 )N(R 6 )-, -C(R 6 )2N(R 6 )SO2N(R 6 )-, -C(R 6 )2N(R 6 )CON(R 6 )- or -CON(R 6 )-; R 4 Selected from R 2 、halogen, -O(R 2 ), -CO(R 2 ), -CO2(R 2 ), -COCO(R 2 ), -NO2, -CN, -SO(R 2 ), -SO2(R 2 ), -S(R 2 ), -N(R 3 )2, -CON(R 3 )2, -SO2N(R 3 )2, -OCOR 2 , -N(R 3 )CO(R 2 ), -N(R 3 )CO(halogen, nitro, cyano, alkoxy-substituted C1-C6 aliphatic group), -N(R 3 )N(R 3 )2, -C=NN(R 3 )2, -C=N, -O(R 2 ), -N(R 3 )CON(R 3 )2, -N(R 3 )SO2N(R 3 )2, -N(R 3 )SO2(R 2 ) or -OCON(R 3 )2; R 2 selected from hydrogen, C1-C6 alkyl, 6-10 membered aryl, 5-10 membered heteroaryl ring or 5-10 membered heterocyclic ring, wherein the 5-10 membered heteroaryl or 5-10 membered heterocyclic ring contains 1-4 nitrogen, oxygen or sulfur ring heteroatoms; R 3 selected from hydrogen, C1-C6 alkyl, cyano, halogen, C1-C6 haloalkyl, hydroxy, mercapto, C1-C6 alkoxy, R 5 , -COR 5 , -C(O)O-(C1-C6 alkyl substituted by halogen, nitro, cyano, C1-C4 alkoxy), -CON(R 5 )2 or -SO2R 5 ; R 5 selected from hydrogen or a C1-C6 alkyl group substituted by a halogen, nitro, cyano, C1-C4 alkoxy group, or two Rs attached to the same nitrogen atom 5 forming a 5- to 8-membered heterocyclic ring or 5- to 8-membered heteroaromatic ring with the attached nitrogen atom; R 6 Selected from hydrogen or a C1-C4 alkyl group substituted by a halogen, nitro, cyano, or C1-C4 alkoxy group.

2. The triphenylphosphine compound according to claim 1, wherein In the said structure: n is selected from 1, 2, 3, 4, 5; L in Q is selected from -N(R 6 )-, -CON(R 6 )- or -N(R 6 )CO-; Z in Q is selected from 5- to 7-membered monocyclic groups, and the 5- to 7-membered monocyclic groups are selected from aryl, heteroaryl, heterocyclic or carbocyclic groups, wherein the heteroaryl or heterocyclic group contains 1 to 4 nitrogen, oxygen or sulfur ring heteroatoms; any ring carbon atom on the 5- to 7-membered monocyclic group that can be substituted is substituted by R 5 substituted; R 5 selected from hydrogen or a C1-C4 alkyl group substituted by a halogen, nitro, cyano, or C1-C4 alkoxy group; R 6 selected from hydrogen or a C1-C4 alkyl group substituted by a halogen, nitro, cyano or C1-C4 alkoxy group.

3. The triphenylphosphine compound according to claim 2, wherein In the said structure: L in G is selected from a chemical bond, -O- or -NR 6 -; Z in G is selected from 5- to 7-membered monocyclic groups, and the 5- to 7-membered monocyclic groups are selected from aryl, heteroaryl, heterocyclic or carbocyclic groups, wherein the heteroaryl or heterocyclic group contains 1 to 4 nitrogen, oxygen or sulfur ring heteroatoms; any ring carbon atom on the 5- to 7-membered monocyclic group that can be substituted is substituted by R 5 substituted; R 5 selected from hydrogen or a C1-C4 alkyl group substituted by a halogen, nitro, cyano, or C1-C4 alkoxy group; R 6 Selected from hydrogen or a C1-C4 alkyl group substituted with a C1-C4 alkoxy group.

4. The triphenylphosphine compound according to claim 3, wherein In the said structure: L in Q is selected from a chemical bond, -CONH- or -NHCO-; Z in Q is selected from any one of the following structures: L in G is selected from a chemical bond, -O-, -NH(CH2)3- or -NH(CH2)4-; Z in G is selected from any one of the following structures:

5. The triphenylphosphine compound according to claim 1, wherein It is selected from any one of the following compounds: N-(2-Aminophenyl)-4-((4-(triphenylphosphonium)butyrylamino)methyl)benzamide I-1, N-(2-Aminophenyl)-4-((5-(triphenylphosphonium)valerylamino)methyl)benzamide I-2, N-(2-Aminophenyl)-4-((6-(triphenylphosphonium)hexanoylamino)methyl)benzamide I-3, N-(2-Aminophenyl)-4-(4-(triphenylphosphonium)butyrylamino)benzamide I-4, N-(2-Aminophenyl)-4-(4-(triphenylphosphonium)valerylamino)benzamide I-5, N-(2-Aminophenyl)-4-(4-(triphenylphosphonium)hexanoylamino)benzamide I-6, N-(2-Aminophenyl)-4-(N-methyl-4-(triphenylphosphonium)butanamido)benzamide I-7, N-(2-Aminophenyl)-3-methyl-4-(4-(triphenylphosphonium)butanamido)benzamide I-8, N-(2-Aminophenyl)-3-methoxy-4-(4-(triphenylphosphonium)butanamido)benzamide I-9, N-(2-Aminophenyl)-2-methyl-4-(4-(triphenylphosphonium)butanamido)benzamide I-10, N-(2-Aminophenyl)-3-fluoro-4-(4-(triphenylphosphonium)butanamido)benzamide I-11, N-(2-Aminophenyl)-3-chloro-4-(4-(triphenylphosphonium)butanamido)benzamide I-12, N-(2-Aminophenyl)-2-fluoro-4-(4-(triphenylphosphonium)butanamido)benzamide I-13, N-(2-Aminophenyl)-5-(4-(triphenylphosphonium)butanamido)picolamide I-14, N-(2-Aminophenyl)-6-(4-(triphenylphosphonium)butanamido)nicotinamide I-15, N-(2-Amino-4-fluorophenyl)-5-(4-(triphenylphosphonium)butanamido)picolamide I-16, N-Hydroxy-5-(4-(triphenylphosphonium)butanamido)picolamide I-17, N-(2-Aminophenyl)-2-fluoro-4-(5-(triphenylphosphonium)valeramido)benzamide I-18, N-(2-Aminophenyl)-2-fluoro-4-(6-(triphenylphosphonium)hexanamido)benzamide I-19, N-(2-Aminophenyl)-2-chloro-4-(4-(triphenylphosphonio)butanamido)benzamide I-20, N-(2-Aminophenyl)-2-bromo-4-(4-(triphenylphosphonio)butanamido)benzamide I-21, N-(2-Aminophenyl)-2-methoxy-4-(4-(triphenylphosphonio)butanamido)benzamide I-22, N-(2-Aminophenyl)-5-(5-(triphenylphosphonio)pentanamido)picolinamide I-23, N-(2-Aminophenyl)-5-(6-(triphenylphosphonio)hexanamido)picolinamide I-24, N-(2-Aminophenyl)-6-(4-(triphenylphosphonio)butanamido)pyridazine-3-carboxamide I-25, N-(2-Aminophenyl)-2,5-difluoro-4-(4-(triphenylphosphonio)butanamido)benzamide I-26, N-(2-Aminophenyl)-2,6-difluoro-4-(4-(triphenylphosphonio)butanamido)benzamide I-27, N-(2-Aminophenyl)-6-(4-(triphenylphosphonio)butanamido)pyrazine-3-carboxamide I-28, N 1 -(2-aminophenyl)-N 4 -(2-(triphenylphosphino)ethyl)terephthalamide I-29, N-(2-Aminophenyl)-4-(3-oxo-3-((2-(triphenylphosphonio)ethyl)amino)propyl)benzamide I-30, N-(2-Aminophenyl)-4-(((3-(triphenylphosphonio)propyl)amino)methyl)benzamide I-31, N-(2-Aminophenyl)-4-(((3-(triphenylphosphonio)butyl)amino)methyl)benzamide I-32, N-(2-Aminophenyl)-4-(((3-(triphenylphosphonio)pentyl)amino)methyl)benzamide I-33, N-(6-(2-Propylhydrazine-1-carbonyl)pyridin-3-yl)-4-(triphenylphosphonio)butanamide I-34, N-(6-(2-Butylhydrazine-1-carbonyl)pyridin-3-yl)-4-(triphenylphosphino)butanamide I-35.

6. The triphenylphosphine compound according to claim 1, wherein The pharmaceutically acceptable salt is a salt formed by the compound and any one of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.

7. A method for preparing the triphenylphosphine compound according to claim 1, characterized in that, It is selected from any one of the following methods: Method 1: (1) Perform acid amide condensation on triphenylphosphonio carboxylic acid and Q-methyl ester to obtain intermediate 2; (2) Hydrolyze intermediate 2 with a base to obtain intermediate 3; (3) React intermediate 3 with amino-G to generate the triphenylphosphine compound I; Method 2: (1) Perform acid amide condensation / coupling reaction on triphenylphosphonio amine and Q-methyl ester to obtain intermediate 6; (2) Hydrolyze intermediate 6 to obtain intermediate 7; (3) Perform acid amide condensation on intermediate 7 and NH2-G to obtain the triphenylphosphine compound I; Method 3: (1) React (3-propylcarboxy)triphenylphosphonium bromide with methyl 5-aminopyridine-2-carboxylate to obtain intermediate 10; (2) Condense intermediate 10 with hydrazine hydrate to obtain intermediate 11; (3) Reduce the imine of intermediate 11 to obtain the triphenylphosphine compound I; Wherein, the definitions of n, Q, and G are as described in claim 1; React the corresponding acid with compound I prepared by any of the above methods to form a salt, thereby obtaining the pharmaceutically acceptable salt.

8. A pharmaceutical composition, characterized in that, It comprises the triphenylphosphine compound described in claim 1 and a pharmaceutically acceptable carrier.

9. Use of the triphenylphosphine compound described in claim 1 or the pharmaceutical composition described in claim 8 in the preparation of a drug for treating and / or preventing diseases related to HDAC3 inhibition.

10. The application according to claim 9, wherein The drug is for treating and / or preventing obesity, Alzheimer's disease, acute liver injury, liver fibrosis, multiple myeloma, lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastric cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin-dependent diabetes or autoimmune diseases.

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