CN104974104B - Propine amide derivatives and its preparation method and pharmaceutical composition and purposes containing oxazole - Google Patents

Abstract

The present invention relates to propynamide derivatives represented by formula I, their pharmaceutically acceptable salts, their preparation methods, compositions containing one or more of these compounds, and the use of these compounds in treating tumor diseases.

Description

Oxazole-containing propynylamide derivatives and its preparation method, pharmaceutical composition and application

field of invention

The present invention relates to propynamide derivatives represented by formula I, its pharmaceutically acceptable salts, its hydrates and solvates, its polycrystals and co-crystals, its precursors or derivatives with the same biological function, and its preparation method , a composition containing one or more of the compounds, and the use of the compounds in the treatment of tumor diseases.

Background of the invention

In recent years, due to the improved understanding of enzymes and other disease-related biomolecules, the discovery or development of new drugs for the treatment of diseases has been greatly promoted. Protein kinases are an important class that has been extensively studied. It is a A large family involved in the control of various signal transduction processes in cells. Due to the conservation of their structure and catalytic function they are thought to have evolved from a common ancestral gene. Almost all kinases contain a similar 250-300 amino acid catalytic domain. These protein kinases are divided into several families according to the different phosphorylation substrates, such as protein tyrosine kinases, protein serine/threonine kinases, lipids and so on. In general, protein kinases mediate intracellular signal transduction by affecting the transfer of a phosphoryl group from a nucleoside triphosphate to a protein receptor associated with a signal transduction pathway. These phosphorylation events act as molecular switches that regulate the biological functions of target proteins and are ultimately triggered in response to various extracellular and other stimuli. Kinases exist in multilayer signal transduction pathways, and receptor tyrosine kinases are located upstream of tumor angiogenesis signal transduction pathways and upstream of tumor cell signal transduction pathways. Serine/threonine protein kinases are located downstream of signal transduction pathways in tumor and tumor angiogenesis cells. Studies have shown that blocking VEGFR and PDGF receptors upstream and Raf/MEK/ERK downstream can simultaneously reduce tumor angiogenesis and inhibit tumor cell replication, thereby hindering tumor growth.

In addition, stem cells (stem cells, SC) are a type of cells with self-renewal and differentiation potential, which are divided into embryonic stem cells and adult stem cells (ASC). Cancers may arise from malignant transformation of normal ASCs. When normal ASC is mutated due to genetic or external factors, the regulation of its self-renewal pathway will be abnormal, and its differentiation and maturation will be impaired or dedifferentiated, transforming into sc-like cancer cells. Therefore, scientists have put forward a hypothesis that there is a small group of stem cell-like cells in cancer tissue, called sc-like cancer cells, that is, cancer stem cells (CSC) or tumor stem cells. Studies suggest that abnormal signal regulation during Sc self-renewal, leading to its unrestricted growth and generation of CSCs, is likely to be a crucial early event in tumorigenesis. The signal transduction pathways that regulate the self-renewal process of SC mainly include Hh (Hedgehog), wnL/beta-catenin and Notch, etc. These pathways are involved in the self-renewal process of hematopoietic SC, neural SC and breast Sc. In rodent models, dysregulation of these signal transduction pathways leads to tumorigenesis; experiments have shown that dysregulation of these pathways also plays an important role in the development of some human tumors.

Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include, but are not limited to, tumors, inflammatory diseases, immune diseases, bone diseases, metabolic diseases, neurological diseases, cardiovascular and cerebrovascular diseases, hormone-related diseases, etc. Therefore, it is very necessary to discover and search for protein kinase inhibitors as therapeutic drugs. In addition, the regulation of signal transduction pathways that control the self-renewal process of CSCs is also very important for the inhibition of tumor metastasis. Although many inventions have made great contributions to the field, research continues in this field to improve the therapeutic effects of drugs.

Contents of the invention

The object of the present invention is to provide propynamide derivatives represented by general formula I, its pharmaceutically acceptable salt, its solvate, its prodrug, its polycrystal or cocrystal.

Another object of the present invention is to provide a method for preparing propynamide derivatives represented by general formula I.

Another object of the present invention is to provide a pharmaceutical composition containing propynamide derivatives represented by general formula I.

Another object of the present invention is to provide the use of this compound in anticancer drugs.

In order to accomplish the purpose of the present invention, can adopt following technical scheme:

The present invention relates to having the following structure propyne amide derivatives shown in general formula I:

Or its pharmaceutically acceptable salts, its hydrates and solvates, its polycrystals and co-crystals, its precursors or derivatives with the same biological function.

The present invention also discloses a method for preparing the compound of the present invention, comprising the following route steps:

The method for preparing the described compound of claim 1, comprises the steps:

Route 1

This route is characterized in that the R2 group is connected first, then the benzoxazole ring is formed, and finally the alkyne is acylated.

In step (a), p-R2 m-nitrobenzoic acid 1 is used as a raw material, converted into an acid chloride with common reagents and methods, and then reacted with o-hydroxyaniline to form an amide, which is heated and ring-closed in an acidic environment to form benzoxazole 2 ; Or directly condense acid 1 and o-hydroxyaniline through dehydrating agent or condensing agent to generate amide and heat ring closure to generate benzoxazole 2.

In step (b), the nitro group in compound 2 is reduced to an amine group by a common method to generate compound 3.

In step (c), the alkynoic acid and compound 3 are dehydrated by a condensing agent, or the alkynoyl chloride is reacted with 3 to generate the alkyne amide target compound I.

route 2

This route is characterized in that the benzoxazole ring is formed first, and then the R2 group is connected.

In step (a), the carboxyl compound 4 is used as a raw material to directly heat and condense with o-hydroxyaniline in the presence of a dehydrating agent to form a benzoxazole ring compound 7.

In step (b), the aldehyde compound 5 is used as a raw material to directly condense with o-hydroxyaniline in the presence of a catalyst such as zinc dibromide or palladium acetate to form a benzoxazole ring compound 7.

In step (c), the acid chloride compound 6 is used as a raw material, first reacted with o-hydroxyaniline to form an amide, and then heated and closed in an acidic environment to form a benzoxazole ring compound 7.

In step (d), compound 7 is reacted with R ₂ H in a basic (such as potassium carbonate) environment to generate compound 2.

In step (e), the nitro group in compound 2 is reduced to an amine group by conventional methods to generate compound 3.

In step (f), the alkynoic acid and compound 3 are dehydrated by a condensing agent, or the alkynoyl chloride is reacted with 3 to generate the alkyne amide target compound I.

Route 3

This route is characterized in that the R2 group is first connected, then an alkyne amide is formed, and finally a benzoxazole ring is formed.

In step (a), compound 8 is used as a raw material, and its nitro group is reduced to an amine group by a common method to generate compound 9. In step (b), alkynoic acid and compound 9 are dehydrated by a condensing agent, or alkynoyl chloride is reacted with 9 to generate alkyne amide compound 10. In step (c), 10 is hydrolyzed under alkaline or enzymatic conditions to obtain carboxylic acid compound 12.

In step (d), 12 is converted into an acid chloride with common reagents and methods, and then reacted with o-hydroxyaniline to form an amide, which is heated and ring-closed in an acidic environment to form the target compound I of benzoxazole; or the acid 12 and o-hydroxyl Aniline is directly condensed by a dehydrating agent or a condensing agent to generate an amide, and the ring is closed by heating to generate the target compound I of benzoxazole.

In step (e), compound 10 was directly reduced to aldehyde 11 with a reducing agent.

In step (f), compound 11 is directly condensed with o-hydroxyaniline in the presence of a catalyst such as zinc dibromide or palladium acetate to obtain the target compound I of benzoxazole.

In addition, the starting materials and intermediates in the above reactions are easy to obtain, or can be easily synthesized by conventional methods in organic synthesis for those skilled in the art.

The propyne amide derivatives described in formula I can exist in the form of solvates or non-solvates, and different solvates may be obtained by using different solvents for crystallization. The pharmaceutically acceptable salts described in formula I include different acid addition salts, such as the acid addition salts of the following inorganic acids or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, three Fluoroacetic Acid, Lycic Acid, Maleic Acid, Tartaric Acid, Fumaric Acid, Citric Acid, Lactic Acid. All such salts within the scope of this invention may be prepared by conventional methods. During the preparation process of the propynamide derivatives, solvates and salts thereof, polycrystals or co-crystals may appear under different crystallization conditions.

The present invention also relates to pharmaceutical compositions containing the compound of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.

The compound of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage form can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and double emulsion), suspension, injection (including water injection, powder injection and infusion), eye drops formulations, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) mist, sprays, etc.; semi-solid dosage forms can be ointment, Gels, pastes, etc.

The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

To form the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, iso Propanol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecylsulfonate, etc.; lubricant and flow aid The agent can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

In order to make the administration unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and glidants used in the preparation of tablets of the compound of the present invention can also be used in the preparation of capsules of the compound of the present invention.

In order to make the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators and osmotic pressure regulators in this field can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc. For preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.

In addition, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations, if necessary.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc. Generally, the suitable daily dosage range of the compound of the present invention is 0.001-150 mg/Kg body weight, preferably 0.01-100 mg/Kg body weight. The above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.

The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.

The compounds of the present invention are multi-target protein kinase inhibitors or their precursors. These protein kinases are divided into multiple families according to different phosphorylation substrates, such as protein tyrosine kinases, protein serine/threonine kinases, lipids, etc. . In general, protein kinases mediate intracellular signal transduction by affecting the transfer of a phosphoryl group from a nucleoside triphosphate to a protein receptor associated with a signal transduction pathway. These phosphorylation events act as molecular switches that regulate the biological functions of target proteins and are ultimately triggered in response to various extracellular and other stimuli. Kinases exist in multilayer signal transduction pathways, and receptor tyrosine kinases are located upstream of tumor angiogenesis signal transduction pathways and upstream of tumor cell signal transduction pathways. Serine/threonine protein kinases are located downstream of signal transduction pathways in tumor and tumor angiogenesis cells. Studies have shown that blocking VEGFR and PDGF receptors upstream and Raf/MEK/ERK downstream can simultaneously reduce tumor angiogenesis and inhibit tumor cell replication, thereby hindering tumor growth. The compound of the present invention has high bioavailability and can be used for the treatment of various human malignant tumors, including liver cancer, gastric cancer, kidney cancer, lung cancer, pancreatic cancer, colorectal cancer, bladder cancer and breast cancer, Ovarian cancer, squamous cell carcinoma, glioma, leukemia, head and neck cancer.

Detailed ways

The invention will be further described below in conjunction with the examples, but the scope of the invention is not limited.

Measuring instrument: Vaariaan Mercury 300 or 400 nuclear magnetic resonance instrument for nuclear magnetic resonance spectroscopy. Mass spectrometry uses ZAD-2F and VG300 mass spectrometers.

Example 1.2-(3-(butyne-2-amido)-4-methoxyphenyl)-5-bromobenzoxazole

Synthesis of 2-(4-fluoro-3-nitrophenyl)-5-bromobenzoxazole:

Under stirring, 2-amino-4-bromophenol (935mg, 5.0mmol) was added to a solution of 4-fluoro-3-nitrobenzoyl chloride (5.0mmol) in 1,4-dioxane, and methyl Sulfonic acid (1ml, 15.0mmol) was heated to 100°C for 3h, and 1,4-dioxane was evaporated under reduced pressure. The residue was extracted with ethyl acetate/saturated NaHCO ₃ , the organic phase was washed successively with saturated NaHCO ₃ and NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and column chromatographed to obtain 1.03 g of off-white solid.

Synthesis of 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole:

Compound 2-(4-fluoro-3-nitrophenyl)-5-bromobenzoxazole (403mg, 1.2mmol) was dissolved in 70ml of DMF, methanol (192mg, 6.0mmol), cesium carbonate (1.95g, 6.0 mmol), react at room temperature for 12h. After concentration, it was extracted with ethyl acetate/water, the organic phase was washed with water and saturated NaCl solution successively, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain 489 mg of yellow powder. .

Synthesis of 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole:

Compound 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (489mg, 1.4mmol) was dissolved in 10ml of methanol, 1ml of water was added, NH ₄ Cl (752mg, 14.0mmol) , Zn (912mg, 14.0mmol), reflux reaction for 2h, filter to remove Zn, concentrate and extract with ethyl acetate/water, wash the organic phase with water and saturated NaCl solution successively, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate to obtain Yellow solid 280mg.

Synthesis of 2-(3-(butyne-2-amido)-4-methoxyphenyl)-5-bromobenzoxazole:

Dissolve butynoic acid (102mg, 1.2mmol) in 10ml of benzene, add oxalyl chloride (228mg, 1.8mmol), react at 50°C for 3h, and distill off benzene and oxalyl chloride. Butynoyl chloride was dissolved in anhydrous THF, and added dropwise to a solution of 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole (84mg, 0.24mmol) in THF and pyridine at 0°C , After the dropwise addition, it was raised to room temperature and reacted for 4h. The reaction solution was extracted with ethyl acetate/saturated NaHCO ₃ , the organic phase was washed with saturated NaHCO ₃ and NaCl solution in sequence, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated and then column chromatography , recrystallized from ethyl acetate to obtain 70 mg of light yellow solid. ¹ H NMR(DMSO-d ₆ ,400MHz)δ:9.83(s,1H,-CONH-),8.62(s,1H,ArH),7.99～7.96(m,2H,ArH),7.75～7.73(d, 1H,ArH),7.54～7.52(dd,1H,ArH),7.28～7.26(d,1H,ArH),3.92(s,3H,-OCH ₃ ),2.04(s,3H,-CH ₃ ).MS (FAB) (M ⁺⁺ 1=386)

Example 2.2-(3-(butyne-2-amido)-4-ethoxyphenyl)-5-bromobenzoxazole

Replace 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole with 2-(3-amino-4-ethoxyphenyl)-5-bromobenzoxazole, refer to According to the operation process of Example 1, 2-(3-(butyne-2-amido)-4-ethoxyphenyl)-5-bromobenzoxazole was obtained as light yellow solid. ¹ H NMR (400MHz,DMSO-d ₆ )δ:9.73(s,1H,-CONH-),8.63(s,1H,ArH),7.98～7.93(m,2H,ArH),7.75～7.73(d, 1H,ArH),7.54～7.52(d,1H,ArH),7.26～7.24(d,1H,ArH),4.22～4.17(q,2H,-OCH ₂ -),2.05(s,3H,-CH ₃ ),1.41～1.38(t,3H,-CH ₂ CH ₃ ).MS(FAB)(M ⁺ +1=400)

Example 3.2-(3-(butyne-2-amido)-4-propoxyphenyl)-5-bromobenzoxazole

Replace 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole with 2-(3-amino-4-propoxyphenyl)-5-bromobenzoxazole, refer to According to the operation process of Example 1, 2-(3-(butyne-2-amido)-4-propoxyphenyl)-5-bromobenzoxazole was obtained as light yellow solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.75(s,1H,-CONH-),8.60(s,1H,ArH),8.00～7.95(m,2H,ArH),7.78～7.72(m, 1H,ArH),7.56～7.54(m,1H,ArH),7.29～7.24(m,1H,ArH),4.11～4.05(m,2H,-OCH ₂ -),2.06(s,3H,-CH ₃ ),1.83～1.78(m,2H,-CH ₂ -),1.05～0.97(t,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=414)

Example 4.2-(3-(butyne-2-amido)-4-methoxyethoxyphenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-methoxyethoxyphenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole , with reference to the operation process of Example 1, 2-(3-(butyne-2-amido)-4-methoxyethoxyphenyl)-5-bromobenzoxazole white solid was obtained. ¹ H NMR (400MHz,DMSO-d ₆ )δ:9.68(s,1H,-CONH-),8.66(s,1H,ArH),8.00～7.93(m,2H,ArH),7.76～7.74(d, 1H,ArH),7.55～7.52(dd,1H,ArH),7.32～7.30(d,1H,ArH),4.28～4.26(t,2H,-OCH ₂ -),3.75～3.72(t,2H,- OCH ₂ -),3.33(s,3H,-OCH ₃ ),2.05(s,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=430)

Example 5.2-(3-(butyne-2-amido)-4-ethoxyethoxyphenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-ethoxyethoxyphenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole , with reference to the operation process of Example 1, 2-(3-(butyne-2-amido)-4-ethoxyethoxyphenyl)-5-bromobenzoxazole was obtained as a white solid. ¹ H NMR (400MHz,DMSO-d ₆ )δ:9.63(s,1H,-CONH-),8.66(s,1H,ArH),7.99～7.93(m,2H,ArH),7.76～7.74(d, 1H,ArH),7.55～7.53(d,1H,ArH),7.33～7.31(d,1H,ArH),4.28～4.26(t,2H,-OCH ₂ -),3.76～3.75(t,2H,- OCH ₂ -),3.53～3.51(t,2H,-OCH ₂ -),2.05(s,3H,-CH ₃ ),1.15～1.11(t,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=444)

Example 6.2-(3-(butyne-2-amido)-4-ethoxyethoxyethoxyphenyl)-5-bromobenzoxazole

Replace 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole with 2-(3-amino-4-ethoxyethoxyethoxyphenyl)-5-bromobenzoxazole Oxazole, refer to the operation process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-ethoxyethoxyethoxyphenyl)-5-bromobenzoxazole as a white solid. ¹ H NMR (400MHz,DMSO-d ₆ )δ:9.63(s,1H,-CONH-),8.63(s,1H,ArH),7.99～7.92(m,2H,ArH),7.75～7.73(d, 1H,ArH),7.54～7.52(d,1H,ArH),7.32～7.30(d,1H,ArH),4.28～4.26(t,2H,-OCH ₂ -),3.83～3.81(t,2H,- OCH ₂ -),3.62～3.60(t,2H,-OCH ₂ -),3.50～3.48(t,2H,-OCH ₂ -),3.43～3.41(t,2H,-OCH ₂ -),2.05(s ,3H,-CH3),1.09～1.06(t,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=488)

Example 7.2-(3-(butyne-2-amido)-4-cyclopropylmethoxyphenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-cyclopropylmethoxyphenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole , with reference to the operation process of Example 1, 2-(3-(butyne-2-amido)-4-cyclopropylmethoxyphenyl)-5-bromobenzoxazole was obtained as a white solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.68(s,1H,-CONH-),8.60(s,1H,ArH),7.98～7.91(m,2H,ArH),7.75～7.72(d, 1H,ArH),7.54～7.51(d,1H,ArH),7.26～7.23(d,1H,ArH),4.01～3.98(d,2H,-OCH ₂ -),2.05(s,3H,-CH ₃ ),1.41～1.29(m,1H,-CH-),0.61～0.56(m,2H,-CH ₂ -),0.40～0.36(m,2H,-CH ₂ -).MS(FAB)(M ⁺ +1=426)

Example 8.2-(3-(butyne-2-amido)-4-dimethylaminoethoxyphenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-dimethylaminoethoxyphenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole oxazole, refer to the operation process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-dimethylaminoethoxyphenyl)-5-bromobenzoxazole as a white solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:10.42(s,1H,-CONH-),8.75(s,1H,ArH),8.02～7.92(m,2H,ArH),7.79～7.73(m, 1H,ArH),7.57～7.54(dd,1H,ArH),7.39～7.33(m,1H,ArH),4.25～4.22(t,2H,-OCH _2- ),2.63～2.61(t,2H,- NCH ₂ -),2.26(s,6H,-NCH ₃ ),2.05(s,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=443)

Example 9.2-(3-(butyne-2-amido)-4-(thiophene-2-methoxy)phenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-(thiophene-2-methoxy)phenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromo Benzoxazole, refer to the operating process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-(thiophene-2-methoxy)phenyl)-5-bromobenzoxazole Azole white solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.80(s,1H,-CONH-),8.59(s,1H,ArH),8.02～7.96(m,2H,ArH),7.78～7.76(d, 1H,ArH),7.60～7.55(m,2H,ArH),7.46～7.43(d,1H,ArH),7.32(s,1H,ArH),7.08～7.06(d,1H,ArH),5.51(s ,2H,-OCH ₂ -),2.06(s,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=467)

Example 10.2-(3-(butyne-2-amido)-4-(pyridine-2-methoxy)phenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-(pyridine-2-methoxy)phenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromo Benzoxazole, refer to the operating process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-(pyridine-2-methoxy)phenyl)-5-bromobenzoxazole Azole light yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ: 10.15(s, 1H, -CONH-), 8.60～8.58(d, 2H, ArH), 7.99(s, 1H, ArH), 7.93 ~7.91(d,1H,ArH),7.85~7.82(m,1H,ArH),7.75~7.73(d,1H,ArH),7.61~7.59(d,1H,ArH),7.54(s,1H,ArH) ),7.37-7.34(m,1H,ArH),7.30～7.28(d,1H,ArH),5.37(s,2H,-OCH ₂ -),2.06(s,3H,-CH ₃ ).MS(FAB ) (M ⁺ +1=463)

Example 11.2-(3-(butyne-2-amido)-4-(pyridine-3-methoxy)phenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-(pyridine-3-methoxy)phenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromo Benzoxazole, refer to the operating process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-(pyridine-3-methoxy)phenyl)-5-bromobenzoxazole Azole pale yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ:9.99(s,1H,-CONH-),8.77～8.54(m,1H,ArH),8.00～7.95(m,2H,ArH) ,7.76-7.73(m,1H,ArH),7.55～7.53(d,1H,ArH),7.45～7.42(m,1H,ArH),7.37～7.35(d,2H,ArH),7.31～7.11(m ,2H,ArH),5.35(s,2H,-OCH ₂ -),2.04(s,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=463)

Example 12.2-(3-(butyne-2-amido)-4-(4-methylpiperazinyl)phenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-(4-methylpiperazinyl)phenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromo Benzoxazole, refer to the operating process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-(4-methylpiperazinyl)phenyl)-5-bromobenzoxazole Azole pale yellow solid. ¹ H NMR (300MHz, DMSO-d ₆ )δ: 9.48(s, 1H, -CONH-), 8.48(s, 1H, ArH), 8.02～8.00(d, 2H, ArH), 7.78 ~7.76(d,1H,ArH),7.58~7.56(d,1H,ArH),7.32~7.30(d,1H,ArH),2.97(s,4H,-2NCH ₂ -),2.54(s,4H, -2NCH ₂ -),2.27(s,3H,-NCH ₃ ),2.08(s,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=454)

Example 13.2-(3-(butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-(2-morpholinoethoxy)phenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromo Benzoxazole, refer to the operating process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole Azole pale yellow solid. ¹ H NMR (300MHz, DMSO-d ₆ )δ: 9.78(s, 1H, -CONH-), 8.65(s, 1H, ArH), 8.00～7.94(m, 2H, ArH), 7.77 ～7.74(d, 1H, ArH), 7.56～7.53(d, 1H, ArH), 7.36～7.33(d, 1H, ArH), 4.31～4.28(t, 2H, -OCH ₂ -), 3.68～3.58( t,4H,2-OCH ₂ -),2.82～2.75(m,6H,3-NCH ₂ -),2.05(s,3H,-CH ₃ ).MS(FAB)(M ⁺ +1=485)

Example 14.2-(3-(butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-6-bromobenzoxazole

Substitute 2-(3-amino-4-(2-morpholinoethoxy)phenyl)-6-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromo Benzoxazole, refer to the operating process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-6-bromobenzoxazole Azole light yellow solid. ¹ HNMR(300MHz,DMSO-d6):δ(ppm):9.73(s,1H,-NHCO-),8.63(s,1H,ArH),8.10(s,1H,ArH),7.97～7.94(d, 1H, ArH),7.74～7.71(d,1H,ArH),7.56～7.54(d,1H,ArH),7.37～7.33(d,1H,ArH),4.29～4.26(t,2H,-OCH2-) ,3.64～3.59(t,4H,-OCH ₂ -),2.75～2.71(t,2H,-NCH ₂ -),2.50～2.48(t,4H,-NCH ₂ -),2.06(s,3H,- CH ₃ ).MS(FAB) (M ⁺ +1=485)

Example 15.2-(3-(butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-7-bromobenzoxazole

Substitute 2-(3-amino-4-(2-morpholinoethoxy)phenyl)-7-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromo Benzoxazole, refer to the operating process of Example 1 to obtain 2-(3-(butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-7-bromobenzoxazole Azole light yellow solid. ¹ H-NMR(300MHz,DMSO-d6):δ(ppm):9.75(s,1H,-NHCO-),8.63(s,1H,ArH),7.98～7.95(m,1H,ArH),7.78～ 7.76(d,1H,ArH),7.62～7.60(d,1H,ArH),7.37～7.31(m,2H,ArH),4.30～4.26(t,2H,-OCH ₂ -),3.62～3.60(t ,4H,-OCH2-),2.76～2.72(t,2H,-NCH ₂ -),2.50～2.48(t,4H,-NCH ₂ -),2.06(s,3H,-CH ₃ ).MS(FAB ) (M ⁺ +1=485)

Example 16.2-(3-(butyne-2-amido)-4-(3-morpholinepropylamino)phenyl)-5-bromobenzoxazole

Substitute 2-(3-amino-4-(3-morpholinopropylamino)phenyl)-5-bromobenzoxazole for 2-(3-amino-4-methoxyphenyl)-5-bromobenzene Oxazole, the operating process of reference example 1, obtains 2-(3-(butyne-2-acylamino)-4-(3-morpholine propylamino) phenyl)-5-bromobenzoxazolin Yellow solid. ¹ H NMR(300MHz,DMSO-d ₆ )δ:8.17(s,1H,-CONH-),8.05～7.99(m,1H,ArH),7.80(s,1H,ArH),7.38(s ,3H,ArH),6.77～6.74(d,1H,ArH),3.89～3.86(m,4H,-2OCH ₂ -),3.79(s,1H,-NH-),3.37～3.33(t,2H, -NCH ₂ -),2.69～2.55(m,6H,-3NCH ₂ -),2.02(s,3H,-CH ₃ ),1.98～1.94(m,2H,-CH ₂ -).MS(FAB)( M ⁺ +1 = 498)

Example 17.2-(3-(butyne-2-amido)-4-(3-morpholinepropoxy)phenyl)-benzoxazole

Synthesis of N-(2-hydroxy-5-bromophenyl)-3-nitro-4-(3-morpholinopropoxy)benzamide

The compound 3-nitro-4-(3-morpholine propoxy)benzoic acid (1.0g, 2.88mmol) was dissolved in 20mlTHF, and HATU (1.7g, 4.32mmol), TEA (1.2g, 11.52 mmol) and o-aminophenol (629mg, 5.76mmol), reacted at room temperature for 12h, the reaction solution was extracted with ethyl acetate/saturated NaHCO ₃ , the organic phase was washed successively with saturated NaHCO ₃ and NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered , concentrated and column chromatography gave gray solid 0.780g.

Synthesis of 2-(3-nitro-4-(3-morpholinopropoxy)phenyl)benzoxazole

The compound N-(2-hydroxyl-5-bromophenyl)-3-nitro-4-(3-morpholine propoxy)benzamide (200mg, 0.50mmol) was dissolved in 10ml of xylene, and p- Toluenesulfonic acid (210mg, 1.10mmol), reflux reaction for 4h, the reaction solution was extracted with ethyl acetate/water, the organic phase was washed with water and saturated NaCl solution successively, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain 0.190g of solid .

Synthesis of 2-(3-amino-4-(3-morpholinopropoxy)phenyl)benzoxazole

Compound 2-(3-nitro-4-(3-morpholinopropoxy)phenyl)benzoxazole (190mg, 0.50mmol) was dissolved in 10ml of methanol, 1ml of water was added, NH ₄ Cl (267mg, 5.00mmol) and Zn (325mg, 5.00mmol), reflux for 2h, filter to remove Zn, concentrate and extract with ethyl acetate/water, wash the organic phase with water and saturated NaCl solution successively, dry over anhydrous Na ₂ SO ₄ , filter, After concentration, 0.170 g of light gray solid was obtained.

Synthesis of 2-(3-(2-butynylamino)-4-(3-morpholinopropoxy)phenyl)benzoxazole

Dissolve butynoic acid (81mg, 0.96mmol) in 10ml of benzene, add oxalyl chloride (183mg, 1.44mmol), react at 50°C for 3h, and distill off benzene and oxalyl chloride. Butynoyl chloride was dissolved in anhydrous THF, and added dropwise to 2-(3-amino-4-(3-morpholinepropoxy)phenyl)benzoxazole (170mg, 0.48mmol) in THF and pyridine at 0°C solution, after the dropwise addition was completed, it was moved to room temperature to react for 4h, the reaction solution was extracted with ethyl acetate/saturated NaHCO ₃ , the organic phase was washed with saturated NaHCO ₃ and NaCl solution in sequence, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated and column Chromatography and recrystallization from ethyl acetate gave 0.070 g of a white solid. ¹ H NMR(DMSO-d ₆ ,300MHz)δ:9.75(s,1H,-CONH-),8.59(s,1H,ArH),8.00～7.97(d,1H,ArH),7.79～7.76(m, 2H,ArH),7.41～7.38(m,2H,ArH),7.31～7.28(d,1H,ArH),4.21～4.17(t,2H,-OCH ₂ -),3.60～3.57(t,4H,2 -OCH ₂ -),2.50～2.44(t,2H,-NCH ₂ -),2.40～2.38(t,4H,2-NCH ₂ -),2.07(s,3H,-CH ₃ ),1.99～1.94( m,2H,-CH ₂ -).MS(FAB) (M ⁺ +1=420)

Example 18.2-(3-(butyne-2-amido)-4-(3-morpholinepropoxy)phenyl)-5-bromobenzoxazole

Replace 2-aminophenol with 2-amino-4-bromophenol, refer to the operation process of Example 17 to obtain 2-(3-(butyne-2-amido)-4-(3-morpholine propoxy) Phenyl)-5-bromobenzoxazole light yellow solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.77(s,1H,-CONH-),8.60(s,1H,ArH),8.01～7.96(m,2H,ArH),7.78～7.75(d, 1H,ArH),7.57～7.54(dd,1H,ArH),7.31～7.28(d,1H,ArH),4.21～4.17(t,2H,-OCH ₂ -),3.61～3.59(t,4H,2 -OCH ₂ -),2.50～2.48(t,2H,-NCH ₂ -),2.45～2.43(t,4H,2-NCH ₂ -),2.07(s,3H,-CH ₃ ),1.98～1.92( m,2H,-CH ₂ -).MS(FAB) (M ⁺ +1=499)

Example 19.2-(3-(butyne-2-amido)-4-(3-morpholinepropoxy)phenyl)-6-bromobenzoxazole

Replace 2-aminophenol with 2-amino-5-bromophenol, refer to the operation process of Example 17 to obtain 2-(3-(butyne-2-amido)-4-(3-morpholine propoxy) Phenyl)-6-bromobenzoxazole white solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.74(s,1H,-CONH-),8.56(s,1H,ArH),8.08(s,1H,ArH),7.96～7.93(d,1H, ArH),7.72～7.69(d,1H,ArH),7.55～7.53(d,1H,ArH),7.28～7.25(d,1H,ArH),4.18～4.14(t,2H,-OCH ₂ -), 3.60～3.57(t,4H,2-OCH ₂ -),2.50～2.44(t,2H,-NCH ₂ -),2.38～2.36(t,4H,2-NCH ₂ -),2.04(s,3H, -CH ₃ ),1.96～1.92(m,2H,-CH ₂ -).MS(FAB)(M ⁺ +1=499)

Example 20.2-(3-(butyne-2-amido)-4-(3-morpholinepropoxy)phenyl)-7-bromobenzoxazole

Replace 2-aminophenol with 2-amino-6-bromophenol, refer to the operation process of Example 17 to obtain 2-(3-(butyne-2-amido)-4-(3-morpholine propoxy) Phenyl)-7-bromobenzoxazole white solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.78(s,1H,-CONH-),8.57(s,1H,ArH),7.99～7.96(m,1H,ArH),7.76～7.73(d, 1H,ArH),7.61～7.59(d,1H,ArH),7.36～7.31(m,2H,ArH),4.19～4.14(t,2H,-OCH2-),3.57～3.55(t,4H,2- OCH ₂ -),2.50～2.44(t,2H,-NCH ₂ -),2.38～2.36(t,4H,2-NCH ₂ -),2.06(s,3H,-CH ₃ ),1.96～1.92(m ,2H,-CH ₂ -).MS(FAB) (M ⁺ +1=499)

Example 21.2-(3-(butyne-2-amido)-4-(3-morpholinepropoxy)phenyl)-6-fluorobenzoxazole

Replace 2-aminophenol with 2-amino-5-fluorophenol, refer to the operation process of Example 17 to obtain 2-(3-(butyne-2-amido)-4-(3-morpholine propoxy) Phenyl)-6-fluorobenzoxazole light pink solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.73(s,1H,-CONH-),8.56(s,1H,ArH),7.94～7.91(d,1H,ArH),7.79～7.75(dd, 2H, ArH), 7.28～7.21(m, 2H, ArH), 4.18～4.14(t, 2H, -OCH ₂ -), 3.58～3.55(t, 4H, 2-OCH ₂ -), 2.48～2.42(t ,2H,-NCH ₂ -),2.38～2.36(t,4H,2-NCH2-),2.04(s,3H,-CH ₃ ),1.96～1.92(m,2H,-CH ₂ -).MS( FAB) (M ⁺ +1 = 438)

Example 22.2-(3-(butyne-2-amido)-4-(3-morpholinepropoxy)phenyl)-6-chlorobenzoxazole

Replace 2-aminophenol with 2-amino-5-chlorophenol, refer to the operation process of Example 17 to obtain 2-(3-(butyne-2-amido)-4-(3-morpholine propoxy) Phenyl)-6-chlorobenzoxazole white solid. ¹ H NMR (300MHz,DMSO-d ₆ )δ:9.74(s,1H,-CONH-),8.56(s,1H,ArH),7.96～7.93(d,2H,ArH),7.77～7.75(d, 1H, ArH), 7.41～7.40(d, 1H, ArH), 7.29～7.26(d, 1H, ArH), 4.19～4.14(t, 2H, -OCH ₂ -), 3.57～3.55(t, 4H, 2 -OCH ₂ -),2.50～2.44(t,2H,-NCH ₂ -),2.38～2.36(t,4H,2-NCH ₂ -),2.04(s,3H,-CH ₃ ),1.96～1.92( m,2H,-CH ₂ -).MS(FAB) (M ⁺ +1=455)

Example 23.2-(3-(butyne-2-amido)-4-(3-morpholinepropoxy)phenyl)-7-chlorobenzoxazole

Replace 2-aminophenol with 2-amino-6-chlorophenol, and refer to the operation process of Example 17 to obtain 2-(3-(butyne-2-amido)-4-(3-morpholine propoxy) Phenyl)-7-chlorobenzoxazole white solid. ¹ H NMR(300MHz,DMSO-d6):δ(ppm):9.78(s,1H,-NHCO-),8.58(s,1H,ArH),7.99～7.97(d,1H,ArH),7.76～7.73 (d,1H,ArH),7.50～7.48(d,1H,ArH),7.42～7.37(m,1H,ArH)7.30～7.27(d,1H,ArH)4.19～4.14(t,2H,-OCH ₂ -),3.57～3.55(t,4H,-OCH ₂ -),2.50～2.44(t,2H,-NCH ₂ -),2.38～2.36(t,4H,-NCH ₂ -),2.06(s,3H ,-CH ₃ ), 1.96～1.92 (m,2H,-CH ₂ -). MS (FAB) (M ⁺ +1 = 455).

Example 24.2-(3-(4-Dimethylaminobutyne-2-amido)-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole

Dissolve 2-(3-amino-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole (136mg, 0.33mmol) in 10ml of dichloromethane, add triphosgene (148mg, 0.5 mmol) in dichloromethane solution, reacted at room temperature under N ₂ protection for 12 h, concentrated the reaction solution, added diethyl ether and filtered to obtain a white solid. Dimethylaminopropyne (60mg, 0.66mmol) was dissolved in anhydrous THF, and added dropwise to a solution of n-butyllithium in cyclohexane (0.4ml, 0.66mmol) at -40°C, and reacted for 1h. Dissolve the obtained white solid in THF and add it dropwise to the reaction solution. After completion, move it to room temperature for 12 hours. The reaction solution is extracted with ethyl acetate/water, and the organic phase is washed with 2N HCl and NaCl solution in sequence. Anhydrous Na ₂ SO ₄ Drying, filtration, column chromatography after concentration to give 2-(3-(4-dimethylaminobutyne-2-amido)-4-(2-morpholineethoxy)phenyl)-5-bromobenzene And oxazole white solid. ¹ H NMR (400MHz,DMSO-d ₆ )δ:8.84(s,1H,-CONH-),8.00(s,1H,ArH),7.84～7.81(dd,1H,ArH),7.78～7.75(d, 1H,ArH),7.56-7.54(d,2H,ArH),7.27～7.25(d,1H,ArH),4.29～4.26(t,2H,-OCH ₂ -),3.58～3.56(t,4H,2 -OCH ₂ -), 3.29(s,2H,-NCH ₂ -), 2.99(s,6H,-2NCH ₃ ), 2.79～2.77(t,2H,-NCH ₂ -), 2.50～2.48(t,4H ,2-NCH ₂ -). MS(FAB)（M ⁺⁺ 1=528）

Example 25.2-(3-(phenylpropynylamino)-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole

With phenylacetylene instead of dimethylamine propyne, refer to the operation process of Example 21 to obtain 2-(3-(phenylpropynylamino)-4-(2-morpholineethoxy)phenyl)-5- Bromobenzoxazole is a white solid. ¹ H NMR (400MHz,DMSO-d ₆ )δ:10.08(s,1H,-CONH-),8.66(s,1H,ArH),8.01～7.98(d,2H,ArH),7.77～7.75(d, 1H,ArH),7.67-7.65(d,2H,ArH),7.56～7.49(dd,4H,ArH),7.39～7.37(d,1H,ArH),4.31～4.29(t,2H,-OCH ₂ - ), 3.58～3.56(t,4H,2-OCH ₂ -), 2.76～2.74(t,2H,-NCH ₂ -), 2.50～2.48(t,4H,2-NCH ₂ -).MS(FAB) (M ⁺⁺ 1=547)

pharmacological activity

Evaluation of in vitro activity:

MTT method to determine the survival rate of tumor cells

The cells in the logarithmic growth phase were digested with trypsin and prepared into a cell solution with a concentration of 0.8-2×10 ⁴ cells/ml, inoculated in a 96-well plate at 1000 cells/well, and added 100 μl to each well. The next day, add fresh medium containing different concentrations of drugs and corresponding solvent controls, add 100 μl to each well (DMSO final concentration <0.5%), set 5 to 7 dose groups for each drug, set at least three parallel wells for each group, and set up at 37 After continuing to culture at ℃ for 120 hours, discard the supernatant, add 100 μl freshly prepared serum-free medium containing 0.5 mg/ml MTT to each well, continue to cultivate for 4 hours, discard the culture supernatant, add 200 μl DMSO to each well to dissolve the MTT formazan precipitate, and use Shake and mix with a micro-oscillator, measure the optical density (OD) with a MK3 microplate reader at a reference wavelength of 450nm and a detection wavelength of 570nm, and use the tumor cells treated with the solvent control as the control group, and use the following formula to calculate the effect of the drug on the tumor cells. Inhibition rate, and calculate IC ₅₀ according to the intermediate effect equation:

MTT Screening Results

Claims (9)

1. propynamide derivatives shown in formula I or pharmaceutically acceptable salts thereof; R is selected from methyl, ethyl, isopropyl, _t -butyl, phenyl, chlorophenyl, fluorophenyl, dimethylaminomethyl; R2 is selected from isobutoxy, isopentyloxy, isohexyloxy, 2-methylbutoxy, 3-methylpentyloxy; R2 is also selected from the following structures: Wherein, D is selected from -O-, -NH-, B and C are independently selected from single bond, -O-, -N-, -CH ₂ -, A is selected from H, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, thienyl, pyridyl, cyclopropyl, diethylamino, dimethylamino, n ₁ , n ₂ , n ₃ are independently selected from 0, 1, 2, 3; R3 is selected from fluorine, chlorine, bromine, cyano. 2. A class of propynamide derivatives or pharmaceutically acceptable salts thereof, wherein the derivatives are selected from: 2-(3-(Butyne-2-amido)-4-hydroxyphenyl)benzoxazole 2-(3-(Butyne-2-amido)-4-ethoxyphenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-propoxyphenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-methoxyethoxyphenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-ethoxyethoxyphenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-ethoxyethoxyethoxyphenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-cyclopropylmethoxyphenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-dimethylaminoethoxyphenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(thiophene-2-methoxy)phenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(pyridine-2-methoxy)phenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(pyridine-3-methoxy)phenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-6-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(2-morpholineethoxy)phenyl)-7-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropylamino)phenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropoxy)phenyl)-benzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropoxy)phenyl)-5-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropoxy)phenyl)-6-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropoxy)phenyl)-7-bromobenzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropoxy)phenyl)-6-fluorobenzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropoxy)phenyl)-6-chlorobenzoxazole 2-(3-(Butyne-2-amido)-4-(3-morpholinopropoxy)phenyl)-7-chlorobenzoxazole 2-(3-(Dimethylaminopropynylamino)-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole 2-(3-(Phenylpropynylamino)-4-(2-morpholineethoxy)phenyl)-5-bromobenzoxazole 3. according to the compound of claim 1 or 2, it is characterized in that, described pharmaceutically acceptable salt comprises: hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, Acetate, trifluoroacetate, salicylate, amino acid salt, lycate, maleate, tartrate, fumarate, citrate, lactate. 4. The method for preparing the described compound of claim 1, comprising the steps of: route 1 route 2 Route 3 5. according to the preparation method of claim 4 route 1, it is characterized in that, first connect R2 group, then form benzoxazole ring, finally alkyne acylation; In step (a), take p-R2 m-nitrobenzoic acid 1 as The raw material is converted into an acid chloride with common reagents and methods, and then reacted with o-hydroxyaniline or o-mercaptoaniline to form an amide, which is heated and ring-closed in an acidic environment to generate benzoxazole 2; or the acid 1 and o-hydroxyaniline are directly dehydrated agent or condensing agent to condense to generate amide and heat ring closure to generate benzoxazole 2; in step (b), the nitro group in compound 2 is reduced to amine group to generate compound 3 by common method; in step (c), alkynoic acid Dehydration with compound 3 by a condensing agent, or reaction of alkynoyl chloride with 3 to generate alkyne amide target compound I. 6. according to the preparation method of claim 4 route 2, it is characterized in that, first form benzoxazole ring, then connect R2 group; In step (a), take carboxyl compound 4 as raw material, in the presence of dehydrating agent and adjacent Hydroxyaniline is directly heated and condensed to form benzoxazole ring compound 7; in step (b), aldehyde compound 5 is used as raw material, and o-hydroxyaniline is directly condensed to form benzoxazole in the presence of catalyst zinc dibromide or palladium acetate Cyclic compound 7; in step (c), using acid chloride compound 6 as a raw material, first reacting with o-hydroxyaniline to form an amide, heating and ring-closing in an acidic environment to generate benzoxazole ring compound 7; in step (d), compound 7 React with R ₂ H under alkaline environment to generate compound 2; in step (e), use common methods to reduce the nitro group in compound 2 to amine to generate compound 3; in step (f), alkynoic acid and compound 3 Dehydration by a condensing agent, or the reaction of acetylenic acid chloride with 3 produces the target compound I of acetylenic amide. 7. according to the preparation method of claim 4 route 3, it is characterized in that, first connect R2 group, then form alkyne amide, finally form benzoxazole ring; In step (a), take compound 8 as raw material, use common method to Its nitro group is reduced to amine to generate compound 9; in step (b), alkynoic acid and compound 9 are dehydrated by a condensing agent, or alkynoyl chloride is reacted with 9 to generate alkyne amide compound 10; in step (c), 10 is dehydrated under alkaline conditions carboxylic acid compound 12 is obtained by ester hydrolysis under environmental or enzymatic conditions; in step (d), 12 is converted into an acid chloride with common reagents and methods, and then reacted with o-hydroxyaniline to form an amide, and heated in an acidic environment to form benzene oxazole target compound I; or directly condense acid 12 and o-hydroxyaniline through a dehydrating agent or a condensing agent to generate an amide and heat ring closure to generate benzoxazole target compound I; in step (e), compound 10 is Direct reduction to aldehyde 11; in step (f), compound 11 is directly condensed with o-hydroxyaniline in the presence of catalyst zinc dibromide or palladium acetate to obtain benzoxazole target compound I. 8. A pharmaceutical composition, characterized in that it contains the compound of claim 1 and a pharmaceutically acceptable carrier. 9. The use of the compound according to claim 1 or 2 in the preparation of drugs for the prevention and treatment of tumor diseases, characterized in that the tumor diseases are lung cancer, pancreatic cancer, colorectal cancer, and glioma.