WO2014190872A1

WO2014190872A1 - Selenium-containing compounds and pharmaceutical use thereof

Info

Publication number: WO2014190872A1
Application number: PCT/CN2014/078202
Authority: WO
Inventors: 黄英武
Original assignee: Huang Yingwu
Priority date: 2013-05-27
Filing date: 2014-05-23
Publication date: 2014-12-04
Also published as: CN104177312A; CN104177312B

Abstract

The present invention relates to selenium-containing derivatives represented by general formula I and having the function of inhibiting Ab1 and/or Src kinase, each substituted group being defined as described in the description; pharmaceutical compositions comprising said compounds; and use thereof for the preparation of medicine for preventing and/or treating the disease related to Ab1 and/or Src kinase.

Description

Selenium-containing compound and its medical use

Technical field

The present invention relates to a novel selenium-containing compound capable of efficiently inhibiting tyrosine protein kinases such as Abl, Src, a preparation method of the compound, a pharmaceutical composition comprising the same, and a compound for preventing and/or treating Abl And/or use in drugs for Src kinase-associated diseases.

Background technique

Malignant tumors, also known as cancer, have become the number one killer of human health, and the treatment of cancer is also of concern to people all over the world. Chemotherapy of cancer has become a major medical development in the past few decades. However, the drugs used in this therapy have only a very narrow therapeutic index, and the reactions caused by these drugs are conservative and unpredictable. Compared with these drugs, the targeted drugs introduced in recent years directly counteract small cancer molecules and impede the information pathway caused by diseases, so there is only limited non-specific toxicity. The mechanisms of tumor formation and development are complex, involving multiple receptors and signal transduction pathways, and single target inhibitors are difficult to achieve clinically. Multiple studies have shown that multi-target inhibitors are superior to single-target inhibitors, and multi-target blockade of tumor signaling is a new direction for cancer prevention and drug discovery. Among various molecular targets, tyrosine protein kinases (PTKs) are the hottest and clinically effective anti-tumor drug targets.

Tyrosine protein kinases are a large, multi-gene family of proteins that only appear in multicellular animals. Its primary function involves the regulation of multicellular organism signaling, such as cell-to-cell growth, differentiation, apoptosis, movement, and death. Tyrosine kinases play an important role in the development of many human diseases, including diabetes, cancer and the like. Tyrosine kinases are defined as typical carcinogenic factors and are involved in most types of malignancies.

Tyrosine kinase is a particularly important therapeutic target for malignant tumors because it plays an important role in the regulation of growth factors. Overactivation of tyrosine kinases leads to activation of downstream signals, which play an important role in tumorigenesis, development, metastasis, treatment and outcome. Therefore, it is important to find new anti-tumor drugs for their signal transduction pathways. Small molecule tyrosine kinase inhibitors, whose mechanism of action is mainly to block the binding of ATP to tyrosine kinase active regions in different ways. These oral inhibitors have significant effectiveness and safety. There are currently 8 tyrosine kinase inhibitors that have been marketed. Gleevec (STI-571), marketed in 2001, is a specific selective inhibitor of the inactive conformation of Bcr_Abl kinase and the first approved Bcr-Abl tyrosine kinase selective inhibitor. It represents a major advance in the field of CML treatment in the most recent years. At present, STI571 for Bcr-Abl and ZD1839 for EGFR have been approved by the US FDA for clinical application in the treatment of chronic myelogenous leukemia and non-small cell lung cancer. As a result, scientists are more confident in studying drug research for tumor-specific oncogenes, and many drugs have been in clinical trials, such as SU666 for VEGFR, PTK787, and so on. From the current experimental results, these inhibitors may not be able to cure the tumor, but the combination of these inhibitors with conventional chemotherapy will significantly improve the therapeutic effect of the tumor. The clinical development of small molecule inhibitors targeting tyrosine kinases is not only a breakthrough in understanding the molecular mechanisms of disease, but also a challenge in reassessing existing interventions. Tumors are a multi-factor, multi-step, multi-gene diseased disease. These inhibitors target only one or two target molecules. Therefore, combining multiple inhibitors (such as cocktails) may have a better effect. .

Since tyrosine kinase inhibitors have shown good therapeutic effects in the treatment of various malignant tumors, and the correct and reasonable combination will further improve the therapeutic effect. Therefore, the development of novel tyrosine kinase inhibitors to achieve single target or multi-target inhibition is of great significance for the effective treatment of malignant tumors and other diseases caused by protein kinase dysfunction.

Summary of the invention

The object of the present invention is to find and develop a small molecule inhibitor of tyrosine kinase for the preparation of a preventive and/or therapeutic drug for diseases caused by abnormal tyrosine kinases.

The present inventors have found that Formula I has significant tyrosine kinase inhibitory activity such as Abl, Src and the like.

Thus, in a first aspect of the invention, a compound of formula I is provided:

towel:

1 is a 5- to 9-membered unsubstituted or saturated hydrocarbon-substituted aromatic ring, an aromatic fused ring, an aromatic heterocyclic ring containing at least one hetero atom or an aromatic fused heterocyclic ring;

n is 0, 1, 2;

2, R3 is optionally hydrogen, C1 - C4 linear or branched saturated hydrocarbon group, halogen, electron withdrawing group;

The aromatic ring, aromatic fused ring, aromatic heterocyclic ring or aromatic fused heterocyclic ring containing at least one hetero atom in the formula I is selected from the group consisting of a benzene ring, an anthracene ring, a piperidine ring; the saturated hydrocarbon group is selected from the group consisting of The C1 to C4 linear or branched saturated anthracene of R2, R3 is selected from the group consisting of methyl and t-butyl; the halogen is selected from the group consisting of fluorine, chlorine and bromine; and the electron withdrawing group is selected from the group consisting of nitro and An oxy group; or a pharmaceutically acceptable salt or solvate thereof. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, of any one selected from the group consisting of:

2-(benzoylamino)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(4-methyl-3-nitrophenyl)-1,3-selenazole-5-carboxamide;

2-(Indolyl-3-acetamido)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(Indole-3-acetylamino)-N-(4-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(4-methylphenylacetamido)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide;

2-(4-methylphenylacetamido)-N-(4-tert-butylphenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(2,4-dimethylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-吲哚propionylamino)-N-(2-chloro-6-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indoleylamino)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(3-吲哚propionylamino)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide;

2-(4-methylphenylacetamido)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(4-methylphenylacetamido)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide;

2-(4-methylphenylacetamido)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(4-Methylphenylacetamido)-N-(4-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(2,4-dimethylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(4-tert-butylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indoleacetamido)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(2-chloro-6-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(2-pyrroleylamino)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide;

2-(2-pyrroleylamino)-N-(4-tert-butylphenyl)-1,3-selenazole-5-carboxamide;

In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable Carrier, diluent or excipient. In a third aspect of the invention, a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, according to any one of the invention, is provided for the preparation of a prophylactic and/or therapeutic tyrosine such as Abl and/or Src Use in drugs for kinase-related diseases.

In a fourth aspect of the invention, there is provided a medicament for preventing and/or treating a tyrosine kinase-related disease such as Abl and/or Src, which comprises a formula for administering a therapeutically or prophylactically effective amount of any one of the subjects in need thereof A compound, or a pharmaceutically acceptable salt or solvate thereof.

The term "hydrocarbyl" as used herein refers to a saturated straight or branched monovalent hydrocarbon radical having from 1 to 20 carbon atoms (i.e., C1-20 mercapto). In some embodiments, an alkyl group has from 1 to 10 carbon atoms (ie, C1-10 alkyl), preferably from 1 to 6 carbon atoms (ie, C1-6 alkyl), from 1 to 4 carbon atoms (ie, C1-4) Sulfhydryl) or 1-3 carbon atoms (ie C1-3 fluorenyl). Examples of "mercapto" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and the like.

The term "aromatic ring" as used herein refers to an aromatic carbocyclic group of 5 to 18 carbon atoms having one single ring or a plurality of fused rings. The aryl group preferably has 5 to 10, 5 to 8 or 5 to 6 or 6 carbon atoms. Examples of "aromatic rings" include, but are not limited to, phenyl and the like, which may be optionally substituted a single or multiple times.

The term "aromatic fused ring" as used herein refers to an aromatic carbon ring group of 5 to 18 carbon atoms having two or more fused rings. The aryl group preferably has 5 to 12, 5 to 10 or 5 to 9 carbon atoms. Examples of "aromatic fused rings" include, but are not limited to, naphthyl, anthracenyl, phenanthryl, anthracenyl, fluorenyl and fluorenyl, and the like, which may be optionally substituted by a single or multiple.

The term "aromatic heterocyclic ring" as used herein refers to a heteroaromatic ring group having 5 to 18, preferably 5 to 14, more preferably 5 to 10 members, the aromatic heterocyclic ring having one or more independently selected from N , 0 and S ring heteroatoms. Also included within the scope of the term "aromatic heterocyclic ring" as used herein are those wherein the aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic) wherein the linking group or point is in the aromatic group. On the ring. Examples of "aromatic heterocyclic rings" include, but are not limited to, pyridyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, benzofuranyl, carbazole A group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a quinolyl group, an isoquinolyl group, a fluorenyl group, a phenothiazine group, a phenoxazole group or the like, which may be optionally substituted a single or multiple times.

The term "aromatic fused heterocyclic ring" as used herein refers to a heteroaromatic ring group of 5 to 18 carbon atoms having two or more fused rings. The aromatic fused heterocyclic ring has one or more ring heteroatoms independently selected from N, 0 and S. Examples of "aromatic fused heterocycles" include, but are not limited to, fluorenyl, benzimidazolyl, and the like, which may be optionally substituted by a single or multiple.

As used herein, the term "fused aryl" has its ordinary meaning as is well known in the art, which forms a moiety in a compound of formula I, and which typically includes, but is not limited to, the fused aryl groups recited herein. Example.

As used herein, the term "fused heteroaryl" has its ordinary meaning as known in the art, which forms a moiety in a compound of formula I, and which typically includes, but is not limited to, the fused heteroaryls recited herein. An example of a base. The term "halogen" as used herein means fluoro, chloro, bromo or iodo. The term "halogen" as used herein may also include their isotopic forms.

As used herein, the following terms refer to the general meanings well-known in the art: nitrile, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, carboxyalkyl, alkoxycarbonyl, alkoxy Carbonyl fluorenyl, carboxy acyl, carboxamidoguanyl, fluorenyl, cyclodecyl, thiol, alkylsulfinyl, alkylsulfonyl, sulfamoyl, decyl, cyano, amino, amide, Amino, di-burned amino, burned amino yards.

The term "electron withdrawing group" as used herein has its ordinary meaning as is known in the art, and it generally includes, but is not limited to, the examples listed herein.

As used herein, the term "pharmaceutically acceptable" generally means that it can be used pharmaceutically or medically, or, although not directly used in pharmacy or medicine, it can be used as a pharmaceutical or medical product intermediate. It can be utilized and removed by a suitable method before it is finally used in pharmacy or medicine. For example, pharmaceutically acceptable salts include not only pharmaceutically acceptable salts which are useful in clinical use, but also salts which are not directly usable in the clinical use but which can be used in the preparation of the compounds of the present invention and which are removed in the subsequent processes.

As used herein, the term "pharmaceutically acceptable carrier, diluent or excipient" refers to pharmaceutical excipients commonly used in the pharmaceutical industry, for example, in Luo Mingsheng et al., "Pharmaceutical Excipients", Sichuan Science and Technology Press , listed in 1995.

The compounds of the present invention may exist in the form of unsolvates and solvates, including hydrated forms such as hemihydrates. In general, for the purposes of the present invention, solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms.

The "tyrosine kinase-related diseases such as Abl and/or Src" of the present invention have a general meaning as known in the art, and mainly refer to diseases caused by dysfunction of tyrosine kinases such as Abl and/or Src, mainly including Not limited to cancer such as leukemia, non-small cell lung cancer, prostate cancer, gastrointestinal stromal tumor, colon cancer, melanoma, advanced renal cell carcinoma, etc., as well as autoimmune diseases such as rheumatoid arthritis, rheumatoid arthritis, allergies Sexual inflammation, etc. The cause of dysfunction of tyrosine kinases such as Abl and/or Src has its general meanings well known in the art, including, but not limited to, regulatory disorders, gene mutations, gene recombination, and the like.

The compound of the invention of formula I can be prepared by the following method:

Figure 1

Taking the synthesis of compound 4 as an example (Fig. 1), the compound of the present invention is prepared by using methyl chloroacetate as a starting material, and sodium methoxide and methyl formate in the presence of toluene as a solvent, first reacted at room temperature after ice bath to form an intermediate. I, thiourea and methyl iodide in anhydrous ethanol as the intermediate II, and then with sodium borohydride and selenium powder made of selenium III, I and III heated to 50 in aqueous solution After reacting for 2h at °C, IV is obtained. After B0C protection, the saponification reaction is followed by adding concentrated hydrochloric acid precipitate to V, and then homo-methylaniline is subjected to condensation reaction to obtain VI, followed by deprotection of B0C with trifluoroacetic acid to obtain VI I. Indole-3-acetic acid undergoes another condensation reaction to give the final compound 4.

The terms "protecting group" and "protecting group", as used herein, are used interchangeable and mean an agent that is used to temporarily block one or more desired functional groups on a compound having multiple reactive sites. In some embodiments, the protecting group has one or more or preferably all of the following features: a) is selectively added to the functional group in good yield to give a protected substrate; said protected substrate b) is in one The reaction occurring at or at a plurality of other reaction sites is stable; and c) is selectively removed in a good yield by a reagent that does not attack the regenerated deprotected functional group. As will be appreciated by those skilled in the art, in some cases, the agent does not attack other reactive groups on the compound. In other cases, the reagent may also react with other reactive groups on the compound. Examples of protecting groups are described in detail in Greene, TW, Wilts, PG, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, New York: 1999 (other versions of the book). The entire contents of the literature are incorporated herein by reference. The term "nitrogen protecting group" as used herein is intended to mean An agent that temporarily blocks one or more desired nitrogen reaction sites on a polyfunctional compound. Preferred nitrogen protecting groups also have the typical character of the above protecting groups and some typical nitrogen protecting groups are also described in detail in Greene, TW, Wuts, PG, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, New York: Chapter 7 of 1999, the entire contents of which is incorporated herein by reference.

Those skilled in the art will appreciate that the compounds of formula I of the present invention may also be used in the form of their pharmaceutically acceptable salts or solvates. The pharmaceutically acceptable salts of the compounds of formula I include the conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and the acid addition salts of quaternary ammonium. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid. , citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene a salt of sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, stearic acid, citric acid or the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, cesium, Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, guanidine-methylglucamine and procaine salts.

The present invention also encompasses prodrugs of a compound of formula I which, upon administration, are chemically converted by metabolic processes and then become active agents. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula I. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design Of Prodrugs", H Bund Saard, El Sevier, 1985, the entire disclosure of which is hereby incorporated by reference.

The invention also includes active metabolites of the compounds of formula I.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula I, a racemate thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable A carrier that can be used for in vivo treatment and is biocompatible. The pharmaceutical composition can be prepared in various forms depending on the route of administration. The compounds of the present invention may also be prepared as various pharmaceutically acceptable salts.

The pharmaceutical composition of the present invention comprises an effective amount of a compound of the formula I of the present invention, a racemate thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof such as a hydrate and one or more A suitable pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate. , a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, poly Vinylpyrrolidone, Cellulose, Polyethylene Glycol, Sodium Carboxymethyl Cellulose, Poly Acrylate, beeswax, lanolin.

The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Internal, intraventricular, intrasternal and intracranial injection or input, or with an explant reservoir. Among them, oral administration, intraperitoneal or intravenous administration is preferred.

When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally comprises lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsule formulation generally comprises lactose and dried cornstarch. Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier or suspension. If desired, some sweeteners, fragrances or colorants may be added to the above oral formulations.

In the case of topical administration, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs. The form is as follows:

When applied topically to the eye, the compound of the present invention may be formulated in the form of a micronized suspension or solution in which the carrier is isotonic, a certain pH of sterile saline, with or without a preservative such as benzyl chloride. Base alkoxide. For ophthalmic use, the compound can also be formulated in the form of a cream such as a Vaseline cream.

When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers for ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used, including but not limited to: minerals Oil, sorbitan monostearate, Tween 60, hexadecane ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the present invention can also be administered in the form of a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injection solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterile non-volatile oils can be employed as a solvent or suspending medium, such as a monoglyceride or a diglyceride.

It should also be noted that the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor. The preferred dose is between 0.001 to 100m _g / kg body weight / day, more preferably at a dose of 0. Olmg / kg to 50mg / kg body weight / day, even more preferably at a dose of 0. lmg / kg to 25mg / kg body weight / day, the optimal dose is 1 mg / kg to 10 mg / kg body weight / day. If desired, a effective daily dose can be divided into multiple doses for administration purposes; therefore, a single dose composition can contain such amounts or sub-doses thereof to constitute a daily dose. Frequency of administration of the above compound of formula I The rate can be determined according to the clinician's experience and factors such as the patient's age, weight, gender, general health status, and the type and severity of the disease, such as 1 time, 2 times, 3 times, 4 times, 5 times, etc. Or once every 2 days, once every 3 days, once every 1 week, once every 2 weeks, etc.

The patents, patent applications, publications, etc. referred to herein are hereby incorporated by reference in their entirety in their entirety in their entirety.

detailed description

The invention is further illustrated by the following specific examples and examples, but it should be understood that these intermediates and examples are merely used in more detail and are not to be construed as limiting in any way. this invention.

The present invention provides a general and/or specific description of the materials and test methods used in the tests. While many of the materials and methods of operation used to accomplish the objectives of the present invention are well known in the art, the present invention is still described in detail herein. It will be apparent to those skilled in the art that, hereinafter, the materials and methods of operation of the present invention are well known in the art unless otherwise specified.

The melting point of the compound was determined by a RY-1 melting point apparatus and the thermometer was not corrected. Mass spectra were determined by a Micromass ZabSpec high resolution mass spectrometer (resolution 1000). 3⁄4 NMR is measured by JNM-ECA-400 superconducting R-meter, operating frequency 3⁄4 NMR 400MHz, ¹³ C Li R ΙΟΟΜΗζ ο

Example

Example 1 2-(Benzoylamino)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide

Mixing 44.4 g of methyl chloroacetate and 110 ml of dry toluene, cooling, and adding 31.6 g of methyl formate when the temperature is lowered to 0 ° C, when the internal temperature drops to -10 ° C to - 5 ° C Further, 28.2 g of 97% sodium methoxide was reacted at 5 ° C for 4 h, and then further reacted at room temperature for 3 h to finally obtain 28.15 g of a yellow oil, which was a crude methyl α-chloroformylacetate. Take 76g (lmol) of thiourea dissolved in 400ml of absolute ethanol, slowly add 141. 90 (lmol) of methyl iodide, the addition is completed, the temperature control is about 40 °C, the reaction is clarified to stop the reaction, and the reaction is cooled. , crystallization, filtration, to obtain a white crystal 89. 01g, that is, methyl isothiourea. In a 1000 ml three-necked flask, it was cooled with nitrogen, and 7.27 g of sodium borohydride and 13.63 g of selenium powder were added under an ice bath, and the mixture was stirred well. Then slowly add 250 ml of absolute ethanol. 5小时。 After adding ice bath reaction 0. 5h, then added 170ml of anhydrous ethanol to dissolve methyl isothiourea 30. 22g solution, then added 14.77 anhydrous sodium carbonate, reflux 2h, room temperature reaction for 20h. At the end of the reaction, 31⁄21 glacial acetic acid was added to the reaction solution, and hydrogen sulfide and methyl isothiourea gas generated by nitrogen gas purge were added. Exhaust gas absorption device, 5% lead acetate solution 900ml, time 2-3 hours, then filtered, the filtrate is evaporated under reduced pressure, evaporated to about 80ml - 100ml, and the filter cake is the product selenium urea, crude product 30. 10g . The freshly prepared selenium urea 23. 6g and 27.7g of methyl a-chloroformylformate are dissolved in 500ml of water, heated, reacted at 50 °C for 2h, the reaction is stopped, and the pH is adjusted to 9 with ammonia water. ester extraction, dried over anhydrous magnesium sulfate, left to stand, filtered and concentrated, the residue was purified by silica gel column (methanol: of dichloromethane = 1: 300) to give a tan solid 6. 8 _g, was Methyl 2-amino-1,3-selenazole-5-carboxylate. 4.99g2_t-butyloxyformamido-1,3-selenazole-5-carboxylic acid was dissolved in 100 ml of l 4 -dioxane solution, stirred, and then 10 ml of 1, 4-dioxane was added dropwise. Dissolved 9. 57 gt-Boc anhydride, adding 0. 025 g of DMAP, the reaction was allowed to proceed, and the reaction was started to start dropwise dropwise 6 ml of 5 mol/l sodium hydroxide. After saponification, it was concentrated to dryness, and the residue was dissolved in water and then made with hydrochloric acid. It was precipitated and filtered to give a brown solid. After drying, weighed 6.08 g, which was 2-t-butyloxycarbamoyl-1,3-selenazole-5-carboxylic acid. 6. 0 _{g of} 2-t-butyloxyformamido-1,3-selenazole-5-carboxylic acid was added to a 250 ml three-necked flask, and about 30 ml of anhydrous dichloromethane was added, most of which was insoluble, after 5 minutes. </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Stir at room temperature for about 6 hours and finish. After the completion of the reaction, the reaction mixture was washed with EtOAc EtOAc m. After that, the organic layer was evaporated to dryness, and the mixture was applied to a column, and the column was passed through a column of methanol:dichloromethane = 1:300, and finally, 4.92 g of a pale yellow solid, which was 2-t-butoxy Carbamido-5-(4-bromophenyl)-1,3-selenazole-carboxamide. 4. 89g of 2_t-butoxyformamido-5-(4-bromophenyl)-1,3-selenazole-carboxamide was added to a 100 ml eggplant-shaped bottle, and about 15 ml of anhydrous dichloromethane was added. Insoluble, 12.54 g of trifluoroacetic acid was added dropwise at room temperature, and the yellow turbid liquid was immediately clarified to be a brown-red liquid, and the reaction was about 6 hours. After the completion of the reaction, the reaction mixture was washed with saturated sodium hydrogen sulfate, water and saturated sodium chloride. After that, the organic layer is evaporated to dryness, and the mixture is applied to a column, and the column is passed through a column of methanol: chloroform: 1 : 300 (with 1% aqueous ammonia). Is 2-amino-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide. 0. 66 g benzoic acid was added to a 250 ml eggplant-shaped flask, 5 ml of anhydrous purified tetrahydrofuran was added, and it was completely dissolved. After 5 minutes, 1.24 g of phenyl dichloride dichloride was added, and after stirring for about 15 minutes, 1.5 _{g was} added. 2_Amino-N-(4-bromophenyl) _1,3-selenoazole_5_carboxamide, after 1.h, 1.79 g of triethylamine was added and stirred at room temperature for about 6 h. After the completion of the reaction, the reaction mixture was washed with EtOAc EtOAc m. 5克浅白色固体。 The organic layer was evaporated to dryness, the mixture was taken, and the column was passed through a column of EtOAc:

3⁄4-NMR (400MHz, M O-d δ 7. 53-7. 59 (m, 4Η); δ 7. 70-7. 72 (m, 3H); δ

8. 15-8. 17 (d, 2Η); δ 8. 44 (s, 1H); δ 10. 31 (s, 1H); δ 1D13. 22 (s, 1H). MS (TOF) 448. 2 (M- ).

Example 2 2-(Benzoylamino)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to 3-fluoroaniline to give a pale yellow solid (0.25 g). 3⁄4-丽1? (400 /[13⁄4, DMS0- )

δ 6. 93-6. 96 (t, 1H); δ 7. 73-7· 43 (m, IH); δ 7. 49-7. 51 (d, IH); δ 7. 56-7. 60 (t, 2H); δ 7. 66- δ 7. 72 (m, 2Η); δ 8. 15—8· 17 (d, 2Η); δ 8. 45 (s, IH); δ 10. 37 ( s, IH); δ 13. 17 (s, IH). MS (TOF) 390. 2 (M+;).

Example 3 2-(Benzoylamino)-N-(4-methyl-3-nitrophenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to 4-methyl-3-nitroamine to give a pale yellow solid (0.33 g).

H-NMR (400MHz, DMSO-oO δ 2. 55 (S, 3H); δ 7· 49- 7· 51 (d, IH); δ 7. 56-7. 60 ( t, 2Η) ; δ 7. 66-7. 69 ( t, IH); δ 7. 94-7· 97 (m, 1Η); δ 8. 15-8· 17 (d, 2Η); δ 8. 46 (d, IH); δ 8. 48 (d, IH); δ 10. 53 (s, IH) ; δ 13· 18 (s, IH) MS (TOF) 431. 3 (M+)

Example 4 2-(Indolyl-3-acetylamino)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to o-methylaniline, and the benzoic acid was changed to 3-indoleacetic acid. 3⁄4-丽 R (400MHz, DMSO- ) δ 2. 22-2. 26 (s, 3H); δ 3. 93 (s, 2Η); δ

6. 98-7. 02 (t, IH); δ 7. 07 -7. 11 (t, 1 H); δ 7. 12-7. 15 (d, 2H); δ 7. 30-7. 31 (s, 1Η); δ

7. 36-7. 38 (d, 1Η); δ 7. 55-7· 59 (t, 3Η) ; δ 8. 13 (s, IH); δ 10. 05 (s, IH) ; δ 11. 00 (s, IH); δ 12. 86 (s, lH). MS (TOF) 439. 3 (M+)„

Example 5 2-(Indol-3-Acetylamino)-N-(4-methylphenyl)-1,3-selenazole-5-carboxamide

The method of Example 1 was used to convert the p-bromoaniline to p-methylaniline, and the benzoic acid was changed to indole-3-acetic acid to give a pale yellow solid (0.33 g). 3⁄4-NMR (400MHz, DMSO-) δ 2. 27 (s, 3Η); δ 3. 93 (s, 2H); δ

7. 42-7. 45 (m, 3Η); δ 7. 55—7. 67 (m, 5H); δ 7. 89—7. 91 (dd, 1Η); δ 8. 06—8. 07 ( Dd, 1Η); δ

8. 67 (s, 1Η); δ 8. 83—8· 85 (d, 1Η); δ 9. 00—9· 02 (d, 1Η); δ 11. 04 (s, IH). MS (TOF) 439. 3 (M+).

Example 6 2-(4-Methylphenylacetamido)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to 4-methoxyaniline and the benzoic acid was changed to p-methylphenylacetic acid to give a pale yellow solid (0.33 g). 3⁄4-NMR (400MHz, DMSO-cQ

δ 2. 28 (s, 3Η); δ 3. 73 (s, 3H); δ 3. 78 (s, 2Η); δ 6. 90—6. 92 (d, 2H); δ 7. 14-7 16 (d, 2Η); δ 7. 21 -7. 23 (d, 2H); δ 7. 57 -7. 60 (d, 2Η); δ 8. 29 (s, IH); δ 10. 03 (s, IH); δ 12. 86 (s, IH;). MS (TOF) 430. 2 (M+).

Example 7 2-(4-Methylphenylacetamido)-N-(4-tert-butylphenyl)-1,3-selenazole-5-carboxamide

釆 Using the method of Example 1, the p-bromoaniline was changed to p-tert-butylaniline, and the benzoic acid was changed to p-methylphenylacetic acid to give a pale yellow solid. 0. 47 g „ ¹ H-NMR (400 MHz, DMS0 - ύ θ δ 1. 27 (s, 9H) ; δ 2. 28 (s, 3H) ; δ 3. 78 (s, 2H); δ 7. 14-7. 16 (d, 2Η); δ 7. 21-7 · 23 (d, 2H); δ 7. 34—7· 36 (d, 2Η); δ 7. 59—7. 61 (d, 2H); δ 8. 33 (s, 1Η); δ 10. 08 (s, 1Η); δ 12. 87 (s, IH) MS (TOF) 456. 2 (M+).

Example 8 2-(Benzoylamino)-N-(2,4-dimethylphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to 2,4-dimethylaniline to give a pale yellow solid (0.31 g).

H-NMR (400MHz, DMSO-) δ 2. 49 (s, 3Η); δ 2. 50 (s, 3H); δ 7. 09 (s, 2Η); δ 7. 18-7. 20 (d, IH); δ 7. 54-7. 59 (t, 2H); δ 7. 65- 7. 69 (t, IH); δ 8. 14-8· 16 ( d, 2H); δ 8. 37 (s, IH) ; δ 9. 78 (s, lH). MS (TOF) 400. 2 (M+).

Example 9 2-(3-Protonylamino)-N-(2-chloro-6-methylphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to 2-chloro-6-methylaniline and the benzoic acid was changed to 3-propionic acid to give a pale yellow solid (0.25 g). 3⁄4-匪R (400MHz, DMS0- 00 δ 2· 23 (s, 3H); δ 2. 85-2. 89 (t, 2Η); δ 3. 05-3. 07 (t, 2H); δ 6 98—7· 00 (t, 1Η); δ 7. 05—7· 07 (t, 1Η); δ 7. 11-7. 12 (d, 1 Η); δ 7. 26 -7. 34 ( m, 3Η); δ 7. 39 (m, IH); δ 7. 56—7· 58 (d, IH); δ 8. 31 (s, IH); δ 9. 95 (s, IH); δ 10. 80 (s, IH); δ 12. 70 (s, IH) MS (TOF) 487. 3 (M+).

Example 10 2-(3-吲哚-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide

Using the method of Example 1, the benzoic acid was changed to 3-indolecarboxylic acid to give a pale yellow solid of 10 mg. H-Li R (400MHz, DMSO_c0

δ 7. 15-7. 18 (m, 2H); δ 7. 46—7· 52 (m, 3Η); δ 7. 75 -Ί. 78 (m, 2 Η); δ 8. 29-8· 30 (d, 2 Η) δ 9. 84 (s, 1Η); δ 11. 78 (s, IH). MS (TOF) 490. 2 (M+).

Example 11 2-(3-吲哚-N-(3-Fluorophenyl)-1,3-selenazole-5-carboxamide

Using the method of Example 1, the p-bromoaniline was changed to 3-fluoroaniline, and the benzoic acid was changed to 3-propionic acid to obtain a pale yellow solid. 0·28 g „3⁄4-NMR (400 MHz, DMSO-oQ)

δ 2. 86-2. 89 (t, 2H); δ 3. 05-3. 09 (t, 2Η); δ 6. 90-7. 00 (m, 2H); δ 7. 05—7· 12 (m, 2Η); δ 7. 32-7. 41 (m, 2H); δ 7. 47-7. 49 (d, 1Η); δ 7. 56-7. 58 (d, 1Η); δ 7 66—7· 70 (m, 1Η); δ 8. 33 (s, 1H); δ 10. 30 (s, 1H); δ 10. 80 (s, 1H); δ 12. 73 (s, 1H); MS (TOF) 457. 2 (M+).

Example 12 2-(4-Methylphenylacetamido)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide

The benzoic acid was changed to p-methylphenylacetic acid to give a pale yellow solid: 0.226 g. 3⁄4-丽 R (400MHz, MSO-d)

δ 2. 28 (s, 3H); δ 3. 78 (s, 2Η); δ 7. 14-7. 16 (d, 2H); δ 7. 21-7. 23 (d, 2Η); δ 7 51-7. 53 (d, 2H); δ 7. 67-7. 69 (d, 2Η); δ 8. 34 (s, 1H); δ 10. 25 (s, 1H); δ 12· 91 (s, 1H;). MS (TOF) 478. 0 (M+).

Example 13 2-(4-Methylphenylacetamido)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide

Using the method of Example 1, the p-bromoaniline was changed to 3-fluoroaniline, and the benzoic acid was changed to p-methylphenylacetic acid to give a pale yellow solid. 0. 15g o 3⁄4-NMR (400 MHz, DMSO-G0 δ 2. 28 (s, 3H); δ 3. 79 (s, 2H); δ 6. 91-6· 92 (m, 1Η); δ 7. 14-7. 23 (m, 4Η); δ 7. 37— 7· 48 (m, 2H); δ 7. 65-7. 68 (d, 1Η); δ 8. 35 (s, 1Η); δ 10. 31 (s, 1Η); δ 12. 93 (s, 1Η). MS (TOF) 418. 5 (M+).

Example 14 2-(4-Methylphenylacetamido)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to 2-methylaniline, and the benzoic acid was changed to p-methylphenylacetic acid. 3⁄4-NMR (400MHz, DMSO-o

δ 2. 22 (s, 3H) ; δ 2. 28 (s, 3Η) ; δ 3. 78 (s, 2H); δ 7. 14—7. 23 (m, 8Η) ; δ 8. 29 (s , 1H); δ 9. 79 (s, 1H) ; δ 12. 87 (s, 1H). MS (TOF) 414. 4 (M+).

Example 15 2-(4-Methylphenylacetamido)-N-(4-methylphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to p-methylaniline, and the benzoic acid was changed to p-methylphenylacetic acid to give a pale yellow solid: 0.54 g. 3⁄4-丽R (400MHz, DMS0- 00 δ 2. 28 (s, 6H); δ 3. 78 (s, 2H); δ 7. 13-7. 16 (m, 4Η); δ 7. 21-7 23 (d, 2H); δ 7. 56-7· 58 (d, 2Η) ; δ 8. 32 (s, IH); δ 10. 07 ( s, IH); δ 12. 88 ( s, 1H MS (T0F) 414. 4 (M+;).

Embodiment 16 2-(3-Indolylamino)-N-(2,4-dimethylphenyl)-1,3-selenoazole _5-carboxamide

The bromoaniline was changed to 2,4-dimethylaniline and the benzoic acid was changed to 3-indoleacetic acid to give a pale yellow solid (0.33 g). 3⁄4-匪R (400MHz, DMS0-cQ δ 2. 17 (s, 3H); δ 2. 27 (s, 3H); δ 3. 93 (s, 2Η) δ 6. 98-7. 02 (t, 2Η); δ 7. 07-7. 09 (d , IH) ; δ 7· 10-7, 11 (s, 1Η); δ 7. 15-7. 17 (d , 1Η); δ 7. 30- 7. 31 (d, 1Η); δ 7. 36-7. 38 (d, 1Η); δ 7. 57-7. 59 (d, 1Η); δ 8. 27 (s, 1Η); δ 9. 70 (s, IH) δ 11. 00 (s, IH) ; δ 12. 83 (s, IH) MS (TOF) 453. 2 (M+).

Example 17 2-(3-吲-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to p-methoxyaniline, and the benzoic acid was changed to 3-indoleacetic acid to give a pale-yellow solid. 3⁄4-NMR (400MHz, DMS0_)

δ 3. 36 (s, 3H); δ 3. 93 (s, 2Η); δ 6. 90-7. 10 (m, 4H); δ 7. 30-7. 38 (m, 2Η); δ 7 57-7. 59 (d, 3H); δ 8. 29 (s, 1Η); δ 10. 02 (s, 1Η); δ 11. 00 (s, 1Η); δ 12. 84 (s, IH ). MS (TOF) 455. 2 (M+).

Example 18 2-(3-Indolylamino)-N-(4-tert-butylphenyl)-1,3-selenazole-5-carboxamide

Using the method of Example 1, the p-bromoaniline was changed to p-tert-butylaniline, and the benzoic acid was changed to 3-indoleacetic acid to give a pale-yellow solid. 0. 32g ₀ 3⁄4-NMR (400MHz, DMSO- )

δ 1, 24-1. 27 (s, 9H); δ 3. 93 (s, 2Η); δ 6. 98—7· 02 (t, 1H); δ 7. 07—7. 10 (t, 1H δ 7. 30-7. 38 (m, 4H); δ 7. 57-7. 61 (t, 3Η) δ 8. 32 (s, 1Η); δ 10. 07 (s, 1Η); δ 11. 00 (s, 1Η); δ 12. 86 (s, lH;). MS (TOF) 481· 1 (Μ +).

Example 19 2-(3-吲-Ν-(4-bromophenyl)-1,3-selenazole-5-carboxamide

The benzoic acid was changed to 3-indoleacetic acid to give a pale-yellow solid: 0.227 g. 3⁄4-NMR (400 丽 z, DMS0-c0

δ 3. 94 (s, 2H); δ 6. 98-7. 02 (t, 1Η) ; δ 7. 07-7. 10 (t, 1Η); δ 7. 30-7. 31 (d, 1Η) δ 7. 36-7. 38 (d, 1Η); δ 7. 51-7. 69 (m, 5Η); δ 8. 34 (s, 1H); δ 10. 24 (s, 1H); δ 11. 00 (s, 1H); δ 12. 91 (s, 1H). MS (T0F) 503. 1 (M+).

Example 20 2-(3-吲哚-N-(3-Fluorophenyl)-1,3-selenazole-5-carboxamide

By the method of Example 1, the p-bromoaniline was changed to 3-fluoroaniline, and the benzoic acid was changed to 3-indoleacetic acid to obtain a pale yellow solid. 0·19 g „3⁄4-NMR (400 MHz, DMSO-ii)

δ 3. 94 (s, 2H); δ 6. 91-6. 94 (t, 1Η); δ 6. 98—7. 02 (t, 1Η); δ 7. 07—7· 11 (t, 1Η) δ 7. 31 (d, 1Η); δ 7. 34-7. 40 (m, 2Η); δ 7. 46—7· 48 (d, 1H); δ 7. 57—7· 59 (d , 1H); δ 7. 65—7· 68 (d, 1H); δ 8. 35 (s, 1H); δ 10, 30 (s, 1H); δ 11. 01 (s, 1H); δ 12 . 92 (s, 1H);. MS (TOF) 443. 3 (M+).

Example 21 2-(Benzoylamino)-N-(2-chloro-6-methylphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to 2-chloro-6-methylaniline to give a white solid (0.33 g). Ή-NMR (400MHz, DMSO-4)

δ 2. 25 (s, 3Η); δ 7. 25-7. .31 (m, 2H); δ 7. 40-7. 42 (d, 1Η) ; δ 7. 56- 7. 59 (t, 2Η) ; δ 7. 65-7. 69 (t, 1H); δ 8. 15—8. 17 (d, 2H); δ 8. 42 (s, 1Η); δ 10. 01 (s, 1Η) ; δ 13. 24 (s, 1Η); MS (TOF) 420. 2 (M+) ₀

Example 22 2-(Benzoylamino-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide

。 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 H-NMR (400MHz, DMSO-oO

δ 2. 25 (s, 3Η); δ 7. 17—7· 23 (m, 2H); δ 7. 27-7. 29 (d, 1H); δ 7. 33-7. 35 (d, 1Η) δ 7. 55-7. 59 (t, 2Η); δ 7. 65-7. 67 (t, 1H); δ 8. 15-8. 17 (d, 2H); δ 8. 39 (s , 1Η); δ 9. 85 (s, 1Η); δ 13. 17 (s, 1Η). MS (TOF) 386. 2 (M+).

Example 23 2-(Benzoylamino)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide

The p-bromoaniline was changed to p-methylaniline to give a pale yellow solid (0.33 g).

[H-NMR (400MHz, DMS0-i ₆ )

δ 2. 28 (s, 3H); δ 7. 15-7. 17 (d, 2Η); δ 7. 55-7. 69 (m, 5H); δ 8. 15—8· 16 (d, 2Η δ 8. 42 (s, 1H); δ 10. 12 (s, 1H) ; δ 13. 20 (s, 1H); „ MS (TOF) 386. 2 (M+) „

Example 24 2-(2-Pyroroylamino)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide

Using the method of Example 1, the p-bromoaniline was changed to p-methoxyaniline, and the benzoic acid was changed to 2-pyrrolecarboxylic acid to give a pale yellow solid (0.33 g). 3⁄4-丽R (400MHz, Li SO-oQ

δ 3. 75 (s, 3H); δ 6. 23—6· 24 (s, 1H); δ 6. 92-6. 95 (d, 2H) ; δ 7. 13 (s, 1Η); δ 7 38 (s, 1Η); δ 7. 60-7. 62 (d, 2Η); δ 8. 35 (s, 1H); δ 10. 03 (s, 1H); δ 12. 04 (s, 1H ); δ 12. 73 (s, 1H). MS (T0F) 391. 2 (M+) ₀

Example 25 2-(2-N-(4-tert-Butylphenyl)-1,3-selenazole-5-carboxamide

The bromoaniline was changed to p-tert-butylaniline, and the benzoic acid was changed to 2-pyrrolic acid to give a pale yellow solid (0.4 g). 3⁄4_NMR (40( Hz, Li SO-G0)

δ 1. 28 (s, 9H); δ 6. 23-6· 24 (s, 1Η); δ 7. 12—7· 13 (s, 1Η); δ 7. 35—7· 38 (d, 3Η) δ 7. 62-7. 64 (d, 2H); δ 8. 38 (s, 1Η); δ 10. 08 (s, 1Η); δ 12. 05 (s, 1Η). MS (TOF) 417. 3 (M+).

Example 26 Evaluation of tyrosine kinase inhibitory activity

The present invention employs a kinase phosphorylation inhibition model to evaluate the inhibitory effects of compounds on different tyrosine kinases. The specific plan is as follows:

The buffer solution of Ra was 7.5. The buffer solution was prepared by mixing 50 mM HEPES, 0.0015% Brij_35, 10 mM MgCl _{2 and} B 2 mM DTT.

2. Preparation of the stop solution: 50 mM HEPES, 0.0015% Bri j_35, 0.2% blocking agent, 50 mM EDTA were mixed to form a stop solution with ra of 7.5.

3. Preparation of the compound: 5 μl of the initial concentration of 10 mM compound was diluted with 95 μl of 100% Li SO to obtain a 500 μΜ stock solution, and the ΙΟμΙ stock solution was added to the well of a 96-well plate, and 90 μl of the buffer was added to obtain a final concentration of 50 μM. Sample intermediate. The sample intermediate solution is diluted with the sample to a different concentration of the sample to be tested.

4. Determination of the compound: The tyrosine kinases ALK, FLT3, ABL, and SRC were separately added to the buffer solution to prepare a enzyme stock solution. A 20 μl sample test solution, 20 μl enzyme stock solution, 10 mM buffer with FAM-labeled polypeptide substrate and 10 mM ATP was added, and the mixture was incubated at room temperature for 300 minutes, and the reaction was terminated by adding a stop solution. Read the collected data and calculate the activity data as follows: % inhibition = (sample hole reading - blank hole reading) I (enzyme reading a blank hole reading) xlOO and calculate the IC50 of the active compound according to the following equation

Y=background + (maximum-background) / (1+10~ ((Lo _g IC50-X) x slope)) Evaluation results: The compounds of the present invention have significant inhibitory effects on tyrosine kinases such as ALK, FLT3, Abl and Src. Percent inhibition of compounds against different tyrosine kinases at a concentration of 10% (%)

IC50 (nM) of some compounds

Claims

Claim

1. Compounds of formula I:

I

among them-

R1 is a 5- to 9-membered unsubstituted or saturated hydrocarbon-substituted aromatic ring, an aromatic fused ring, an aromatic heterocyclic ring containing at least one hetero atom or an aromatic fused heterocyclic ring;

n is 0, 1, 2;

R2, R3 are optionally hydrogen, C1 to C4 linear or branched saturated anthracene, halogen, electron withdrawing group.

2. An aromatic ring, an aromatic fused ring, an aromatic heterocyclic ring containing at least one hetero atom or an aromatic fused heterocyclic ring according to R1 in claim 1, which is selected from the group consisting of a benzene ring, an anthracene ring, and a piperidine ring; From the methyl; R2, R3, the C1 to C4 linear or branched saturated anthracene is selected from the group consisting of methyl and t-butyl; the halogen is selected from the group consisting of fluorine, chlorine and bromine; and the electron withdrawing group is selected from the group consisting of nitro , methoxy.

3. A compound of formula I according to any one of claims 1 and 2, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: 2-(benzoylamino)-N-(4-bromophenyl) -1, 3-selenoazol-5-carboxamide;

2-(benzoylamino)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(4-methyl-3-nitrophenyl)-1,3-selenazole-5-carboxamide;

2-(Indolyl-3-acetamido)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(Indole-3-acetylamino)-N-(4-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(4-Methylphenylacetamido)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(2,4-dimethylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(2-chloro-6-methylphenyl)-1,3-selenazole-5-carboxamide;

2-( 3-decanoylamino)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide;

2-(4-Methylphenylacetamido)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(4-Methylphenylacetamido)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide; 2-(4-methylphenylacetamido)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(4-Methylphenylacetamido)-N-(4-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(2,4-dimethylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(4-tert-butylphenyl)-1,3-selenazole-5-carboxamide;

2-(3-indoleacetamido)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(3-indolylamino)-N-(3-fluorophenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(2-chloro-6-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(2-methylphenyl)-1,3-selenazole-5-carboxamide;

2-(benzoylamino)-N-(4-bromophenyl)-1,3-selenazole-5-carboxamide;

2-(2-pyrroleylamino)-N-(4-methoxyphenyl)-1,3-selenazole-5-carboxamide;

2-(2-pyrroleylamino)-N-(4-tert-butylphenyl)-1,3-selenazole-5-carboxamide;

4. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, Diluent or excipient.

5. A compound of the formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the prevention and/or treatment of Abl and/or Src kinase-associated diseases the use of.

A medicament for preventing and/or treating Abl and/or Src kinase-associated diseases, which comprises administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of the formula I according to any one of claims 1 to 4, or a compound thereof A pharmaceutically acceptable salt or solvate.