CN107304203A - Five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes - Google Patents

Abstract

The present invention provides a class of five-membered heterocyclic compounds and their preparation methods, pharmaceutical compositions and uses. Specifically, the present invention provides a class of compounds with the following formula (I), wherein the definitions of each group are as described in the description mentioned. The compound of formula I has the effect of inhibiting tubulin activity, and can be used to prepare medicines for treating or preventing mammalian diseases related to abnormal regulation of tubulin.

Description

Five-membered heterocyclic compound and its preparation method, pharmaceutical composition and application

technical field

The present invention relates to the field of biomedicine, in particular to a multi-substituted five-membered heterocyclic compound, its preparation method, pharmaceutical composition and use thereof.

Background technique

Microtubules are composed of tubulin, which exists in the cytoplasm of almost all eukaryotic organisms, plays an important role in the cytoskeleton in cells, maintains cell shape, assists in intracellular transport, and assembles with other proteins into spindles, grana, Centrioles, flagella, ciliated neural tube and other structures. Microtubule-associated proteins bind to microtubules and can regulate microtubule functions, including MAP1, MAP12, MAP4, tau proteins, etc. Microtubules play a key role in cell mitosis and chromosome segregation, and can affect the proliferation of tumor cells. They are the targets of anti-tumor drugs. Tubulin inhibitors can effectively prevent the mitosis of tumor cells and cause the cells to enter the apoptosis stage, thereby inhibiting the growth of tumors.

In the nervous system, the stability of the microtubule system is also the basis for maintaining nutrient transport between the cell body and processes. It has been confirmed that tubulin and microtubule-associated proteins are closely related to key proteins in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Therefore, there is an urgent need in the art to develop novel tubulin modulators.

Contents of the invention

The purpose of the present invention is to provide a novel tubulin regulator.

The first aspect of the present invention provides a compound of formula (I), or its isomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, solvate:

in:

X ₁ is selected from N or CR ₁ (when R1 is H, it is expressed as C);

X ₂ is selected from NR ₁ , O or S;

X is selected from the group consisting of NH, O, _S , C=O, C=S, C=NH, -(C=O)-NH-, -(C=O)-O-, -(C=O )-S-, -(C=S)-NH-, -(C=S)-O-, -(C=S)-S-, -(C=NH)-NH-, -(C=NH )-O- or -(C=NH)-S-;

R is selected from the group consisting _of hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano, carboxyl, C _2-6 ester, C _1-6 amido, unsubstituted or halogenated C _1-12 alkane C _{1-12 aryl} or heteroaryl, -CH _{2 -} (C _1-12 aryl or heteroaryl);

Ar ₁ group is substituted or unsubstituted C _1-18 aryl or heteroaryl, substituted or unsubstituted -CH ₂ -(C _1-12 aryl or heteroaryl), substituted or unsubstituted C _{1 -18} heterocyclyl, substituted or unsubstituted -CH ₂ -(C _1-12 heterocyclyl); wherein, Ar ₁ is a bicyclic group and has at least one C _1-12 alkyl or cycloalkane Substituents;

Ar ₂ group is substituted or unsubstituted C _1-12 alkyl or cycloalkyl, substituted or unsubstituted -CH ₂ -Y-(C _1-12 alkyl or cycloalkyl) (wherein Y is O or NH or S), substituted or unsubstituted C _1-12 aryl or heteroaryl, substituted or unsubstituted -CH ₂ -(C _1-12 aryl or heteroaryl), substituted or unsubstituted C _{1 -12} heterocyclic groups; wherein, the Ar2 group has at least one alkoxy substituent;

And when Ar ₂ is a C _1-12 aryl group, said Ar ₁ also has at least one halogen substituent;

m is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 0, 1, 2, 3, 4, 5, 6;

Wherein, the substitution is substituted by one or more substituents selected from the following group: halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, C _1-12 alkyl or cycloalkyl, C _1-12 alkoxyl group, oxygen atom (i.e. =O), C _1-12 alkylamino group unsubstituted or substituted by C _1-4 alkylamino group, C _2-6 ester group, C _2-6 acyl group, C _1-6 amido, thio C _1-12 alkyl, carboxyl, C _1-12 aryl unsubstituted or substituted by 1-5 halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl Or heteroaryl, or unsubstituted or _C1-12 heterocyclic group substituted by 1-5 halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl (containing 1-5, preferably 1-3 a heteroatom selected from N, O or S).

In another preferred example, the _X3 is selected from the following group: NH, O, S, C=O, C=S, C=NH, -(C=O)-NH-, -(C=O) -O-, -(C=O)-S-, -(C=S)-NH-, -(C=S)-O-, -(C=S)-S-;

_The R is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano, carboxyl, ester, amido, unsubstituted C _1-6 alkyl or cycloalkyl, (1- 3) Fluoro C _1-6 alkyl or cycloalkyl, (1-3) C _1-6 amino substituted C _1-6 alkyl or cycloalkyl, (1-3) C _1-6 alkoxy Substituted C _1-6 alkyl or cycloalkyl, -CH ₂ -Y-(C _1-6 alkyl), C _1-12 aryl or heteroaryl, -CH ₂ -(C _1-12 aryl or heteroaryl).

In another preferred example, in the Ar ₁ or Ar ₂ group, the C _5-12 aryl or heteroaryl is selected from the following group:

m is 0, 1, 2, 3, 4, 5;

n is 0, 1, 2, 3, 4, 5.

In another preferred example, X ₁ , X ₂ , X ₃ , R ₁ , Ar ₁ , Ar ₂ , m and n are each independently a group shown in Table 1.

In another preferred example, the Ar ₁ is selected from the following group: C _1-8 heteroaryl and C _2-10 heteroaryl, C _4-8 heteroaryl and C _2-10 heterocyclyl.

In another preferred example, the C _1-8 heteroaryl group contains 1-3 nitrogen atoms.

In another preferred example, the C _1-8 heteroaryl is a six-membered ring.

In another preferred example, the C _2-10 heteroaryl or C _2-10 heterocyclyl contains 1-3 nitrogen atoms.

In another preferred example, the C _2-10 heteroaryl or C _2-10 heterocyclyl is a six-membered ring.

In another preferred example, the heterocyclic group is a saturated or partially unsaturated heterocyclic group, and the heterocyclic group is a non-aromatic group.

In another preferred example, said Ar ₁ is substituted or unsubstituted and has the structure shown in the following formula:

Wherein, the dotted line is a chemical bond or nothing; each A ₁ , A ₂ , A ₃ , A ₄ , A ₅ , A ₆ , A ₇ , A ₈ and A ₉ are each independently O, S, N, NH, CH or CH ₂ ;

Ra is H, halogen, C _1-6 alkyl, one or more halogenated C _1-6 alkyl or cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Alkylamino.

Rb is fluorine, chlorine, C _1-6 alkyl, one or more halogenated C _1-6 alkyl or cycloalkyl or C _1-6 alkoxy or C _1-6 alkylthio or C _1-6 Alkylamino, substituted or unsubstituted C _5-12 aryl or aromatic heterocyclic group;

And when A ₈ is N, Rb is none;

Substitutions are as defined in the first aspect of the invention.

In another preferred example, when A ₈ is C (not CH or CH ₂ ) and Ar2 is alkoxyphenyl or alkoxypyridyl, Rb is Cl or F.

In another preferred example, when A ₈ is C (not CH or CH ₂ ) and Ar2 is a six-membered aromatic ring group or heteroaryl ring group substituted with alkoxy, Rb is Cl or F.

In another preferred example, when X2 is NH and Ar2 is a six-membered aromatic ring group or aromatic heterocyclic group substituted by alkoxy, Rb is Cl or F.

In another preferred example, when X2 is NH and Ar2 is a six-membered aromatic ring group or aromatic heterocyclic ring group substituted by alkoxy, N is Cl or F.

In another preferred example, the Ar ₂ is substituted or unsubstituted and has the structure shown in the following formula:

Wherein, each of B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ is independently O, S, N, NH, CH or CH ₂ ;

Rc is amino, trifluoromethyl, C _1-6 alkoxy, C _1-6 alkylamino, (1-3) halogenated C _1-6 alkyl or C _1-6 thioalkyl.

In another preferred example, Rb is located on the Y atom.

In another preferred example, the compound of general formula (I) is selected from the compounds represented by general formula (Ia):

Wherein, the dotted line is a chemical bond or nothing; Y=CH or N; R1, X1, X2, X3, Ar2, m and n are as defined in the first aspect of the present invention; Ra and Rb are as defined in the first aspect of the present invention.

In another preferred example, when X ₁ is C, and X ₂ is NH, O or S, the compound of general formula (I) is selected from the compounds shown in the following general formula (Ia) (wherein the thick horizontal line "-" indicates the connecting part ):

In another preferred example, the compound of general formula (Ia) is selected from compounds represented by general formula (Ib):

Wherein, the dotted line is a chemical bond or nothing; Y=CH or N; X2=NH, O or S; R1, X3, and Ar2 are as defined in the first aspect of the present invention; Ra and Rb are as defined in the first aspect of the present invention.

In another preferred example, when X2=NH or O, the compound represented by the general formula (Ib) is preferably selected from the following compounds (the short thick line "-" represents the linking part):

In another preference, when X2=S, the compound shown in the general formula (Ib) is selected from the compounds shown in the general formula (Ic), (Id), and (Ie):

The second aspect of the present invention provides a use of the pharmaceutical composition as described in the first aspect of the present invention, for the preparation of a pharmaceutical composition for treating or preventing diseases selected from the following group: dysregulation of microtubule-associated proteins A relevant mammalian disease; preferably a disease selected from the group consisting of: cancer, neurodegenerative diseases, malaria, AIDS, gout, diabetes.

In another preferred example, the cancer is selected from the group consisting of colon cancer, cervical cancer, breast cancer, liver cancer, gastric cancer, kidney cancer, lung cancer, fibrosarcoma, epidermal squamous cell carcinoma, prostate cancer, leukemia, pancreatic cancer , oral cancer, glioma, neuroblastoma.

In another preferred example, the tumor cells are tumor cells selected from the group consisting of colon cancer cells, cervical cancer cells, breast cancer cells, liver cancer cells, gastric cancer cells, kidney cancer cells, lung cancer cells, fibrosarcoma cells, Epidermal squamous cell carcinoma cells, prostate cancer cells, leukemia cells, pancreatic cancer cells, oral cancer cells, glioma cells, neuroblastoma cells, paclitaxel-resistant lung cancer cells, vincristine-resistant oral cancer cells, doxorubicin-resistant chronic myelogenous leukemia cells. In another preferred example, the tumor cells are selected from the group consisting of HCT116, Hela, MCF-7, LM3, NCI-N87, Caki-1, A549, HT1080, A431, PC3, HL60, Panc-1, KB , U87-MG, K562, Kasumi-1, THP-1, Jurkat, REH, Raji, RNK-16, KMS-1, P39, U118-MG, H4, SK-N-SH, SH-SY5Y, A549/Taxol , KB/VCR, K562/Adr.

In another preferred example, the mammalian disease related to abnormal regulation of microtubule-associated protein is a disease selected from the group consisting of lymphoma, lung cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, brain tumor and cervical cancer.

A third aspect of the present invention provides a method for preparing a compound represented by formula (I):

Wherein, the definitions of X ₁ , X ₂ , X ₃ , R ₁ , Ar ₁ , Ar ₂ , m and n are as described in the first aspect of the present invention;

The method comprises the steps of:

(i-a) reacting a compound of formula a with a compound of formula b in an inert solvent to obtain a compound of formula c;

(ii-a) reacting a compound of formula c with a compound of formula d in an inert solvent to obtain a compound of formula e;

And when Q=NR ₁ , the following optional steps are also included: (iii-a) in an inert solvent, use the compound of formula e to remove the protecting group to obtain the compound of formula f;

Wherein, X is halogen; U is selected from the following group: halogen, OMs, OTs, boric acid, boric acid pinacol ester; Q is O, S or NR ₁ ; P is selected from the following group: p-methoxybenzyl, benzyl , tert-butoxycarbonyl;

Or the method comprises the steps of:

(i-b) In an inert solvent, the compound of formula g is replaced by halogen to obtain the compound of formula h;

Wherein, R ₁ is halogen (fluorine, chlorine, bromine or iodine)

The definitions of the remaining groups are the same as those of the first aspect of the present invention;

Or the method comprises the steps of:

(i-c) In an inert solvent, the compound of formula a and the compound of formula b undergo a ring-closing reaction to obtain the compound of formula c;

Preferably, the ring-closing reaction is catalyzed by inorganic salts;

Wherein, V is halogen, OMs, or OTs; the definition of other groups is the same as the first aspect of the present invention, but R ₁ is a non-halogen group.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

Description of drawings

Figure 1 is a schematic diagram showing that compound 492 concentration-dependently inhibits neutrophil flow in mice with peritonitis induced by sodium urate crystals.

detailed description

After long-term and in-depth research, the inventors have found that a class of compounds with the structure shown in formula (I) have the effect of inhibiting tubulin activity, and can be used to prepare breast-feeding drugs for the treatment or prevention of abnormal regulation of tubulin. Drugs for animal diseases. Based on the above findings, the inventors have accomplished the present invention.

the term

In this paper, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, amino, hydroxyl, nitro, cyano, trifluoromethane group, C _1-12 alkyl or cycloalkyl, C _1-12 alkoxy, oxygen atom (i.e. = O), unsubstituted or C _1-4 alkylamino substituted C _1-12 alkylamino, C _2-6 ester group, C _2-6 acyl group, C _2-6 amide group, thio C _1-12 alkyl, carboxyl, C _5-12 aryl or heteroaryl, C _5-12 heterocyclic group ( containing 1-5, preferably 1-3 heteroatoms selected from N, O or S).

The term "C _1-12 alkyl" refers to a straight chain or branched chain alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, or similar groups.

The term "C _1-12 cycloalkyl" refers to a cycloalkyl group having 1-12, preferably 3-12 (ie C _3-12 ) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, Cycloheptyl, or similar groups.

The term "C _1-12 alkoxy" refers to a straight-chain or branched alkoxy group having 1-12 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.

The term "halogen" refers to F, Cl, Br and I.

The term "C _1-12 alkylamino" refers to a C _1-12 alkyl substituted by an amino group, for example having "C _1-12 alkyl-NH-" or "(alkyl) ₂ -N-(total number of carbon atoms is 1-12)", "-C _1-12 alkylene-NH ₂ ", "alkyl-N-alkylene-(the total number of carbon atoms is 1-12)", or "(alkyl) ₂ - N-alkylene-(the total number of carbon atoms is 1-12)" structure groups, such as CH ₃ NH-, C ₂ H ₅ NH-, C ₃ H ₇ NH-, (CH ₃ ) ₂ N-, - CH ₂ NH ₂ , —C ₂ H ₅ NH ₂ , —C ₃ H ₇ NH ₂ , —C ₂ H ₄ N(CH ₃ ) ₂ , or similar groups. Wherein, the definition of C _1-12 alkyl is as described above.

The term "C ₂ -C ₆ ester group" refers to a substituent having a structure of "straight chain or branched chain alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-oxy-" having 1-5 carbon atoms Groups such as ethyl, propyl, butyl, or similar groups.

The term "C ₁ -C ₆ amide group" refers to a substituent having a structure of "straight chain or branched chain alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-amino-" having 0-5 carbon atoms groups, such as acetamide, propionamide, butyramide, or similar groups.

The term "C ₁ -C ₁₂ aryl" refers to an aryl group having 1-12 (preferably 6-10, ie C _6-10 ) carbon atoms, such as phenyl, naphthyl, etc., and the aryl group can be be substituted or not.

The term "C ₁ -C ₁₂ heteroaryl" refers to a heteroaryl group having 1-12 carbon atoms and one or more (preferably 1-3) heteroatoms selected from O, S and/or N, preferably 5 -8 membered heteroaryl. The heteroaryl group can be substituted or unsubstituted.

The term "C ₁ -C ₁₂ heterocyclyl" refers to a non-aromatic cyclic group having 1-12 carbon atoms and one or more (preferably 1-3) heteroatoms selected from O, S and/or N Group, preferably 5-8 membered heterocyclic group. The heterocyclic group may be substituted or unsubstituted.

In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for human and/or animal without undue adverse side effects (such as toxicity, irritation and allergic reaction), ie, has a reasonable benefit/risk ratio.

In the present invention, the term "effective amount" refers to the amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or exhibits a detectable therapeutic or preventive effect. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the disorder, and the therapeutic agents and/or combination of therapeutic agents chosen for administration. Therefore, it is not useful to prespecify an exact effective amount. However, the effective amount can be determined by routine experimentation, within the judgment of the clinician, for a given situation.

Unless otherwise specified, in the present invention, all appearing compounds are intended to include all possible optical isomers, such as single chiral compounds, or mixtures (ie racemates) of various chiral compounds. In all compounds of the present invention, each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R and S configurations.

As used herein, the term "compound of the present invention" refers to a compound represented by formula I. The term also includes the various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.

The preparation of formula (I) compound

The invention provides a compound shown in the following formula:

Wherein, X ₁ , X ₂ , X ₃ , R ₁ , Ar ₁ , Ar ₂ , m and n are as defined above.

Preferred compounds are shown in Table 1.

Described compound can be prepared by following preparation method:

It is characterized in that the method comprises the following steps:

(i-a) reacting a compound of formula a with a compound of formula b in an inert solvent to obtain a compound of formula c;

(ii-a) reacting a compound of formula c with a compound of formula d in an inert solvent to obtain a compound of formula e;

And when Q=NR ₁ , the following optional steps are also included: (iii-a) in an inert solvent, use the compound of formula e to remove the protecting group to obtain the compound of formula f;

Wherein, X is halogen; U is selected from the following group: halogen, OMs, OTs, boric acid, boric acid pinacol ester; Q is O, S or NR ₁ ; P is selected from the following group: p-methoxybenzyl, benzyl , tert-butoxycarbonyl;

Or the method comprises the steps of:

(i-b) In an inert solvent, the compound of formula g is replaced by halogen to obtain the compound of formula h;

Wherein, R ₁ is halogen (fluorine, chlorine, bromine or iodine).

Said compound can also be prepared by the following steps:

(i-c) In an inert solvent, the compound of formula a and the compound of formula b undergo a ring-closing reaction to obtain the compound of formula c;

Preferably, the ring-closing reaction is catalyzed by inorganic salts;

Wherein, V is halogen, OMs, or OTs; the definitions of the other groups are the same as described above, but R ₁ is a non-halogen group.

In the above-mentioned synthetic reaction process, described each inert solvent is not particularly limited, can be selected from dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), di Methyl sulfoxide (DMSO), ethylene glycol dimethyl ether, 1,2-dichloroethane, dimethyl phthalate (DMP), N-methylpyrrolidone (NMP), methanol, ethanol, n-butyl Alcohol, isopropanol, petroleum ether, ethyl acetate, n-hexane or ether.

In the above preparation process, the necessary alkali can be selected such as sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, potassium phosphate, sodium methylate, sodium ethylate, sodium tert-butoxide, tert-butanol Potassium, diethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; essential The acid can be selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid or p-toluenesulfonic acid and the like.

In the above preparation process, the necessary inorganic salts can be sodium fluoride (NaF), potassium fluoride (KF), barium chloride, aluminum chloride and the like.

Each step in the above preparation process can also optionally use a catalyst, and the catalyst can be selected from tetrakistriphenylphosphopalladium (Pd(PPh ₃ ) ₄ ), palladium acetate (Pd(OAC) ₂ ), dichloro Palladium chloride (PdCl ₂ ) palladium carbon, ditriphenylphosphine palladium dichloride (PdCl ₂ (PPh) ₂ ), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (PdCl ₂ (dppf) ₂ ), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), iodine (or bromine or chlorine) cuprous, iodine (or bromine or chlorine) copper, copper powder, etc. . When it is necessary to use a catalytic ligand, the necessary catalytic ligand can be selected from triphenylphosphine, 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos) and 2-bicyclohexyl Phosphine-2',6'-dimethoxybiphenyl (Sphos) and the like.

The organometallic reagent may be n-butyllithium, sodium borohydride, lithium borohydride, or sodium triacetylborohydride. The halogenation reagent can be phosphorus tribromide, phosphorus oxychloride, bromine, iodine, nitrogen chloride (or bromine or iodine) succinimide (NCS, NBS or NIS) or phenyl trimethyl trimethyl ammonium bromide.

The oxidizing agent may be Dess-Martin oxidizing agent, Swern oxidizing agent, m-chloroperoxybenzoic acid, pyridinium chlorodichromate (PDC) or pyridinium chlorochromate (PCC).

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent inhibitory activity on tubulin, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are the main The pharmaceutical composition of active ingredients can be used for treating, preventing and alleviating diseases related to tubulin activity or expression, especially for diseases related to tubulin activity or expression. According to the prior art, the compounds of the present invention are useful in the treatment of the following diseases: cancer, neurodegenerative diseases, malaria, AIDS, gout, diabetes, etc.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 5-500 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

Compared with the prior art, the main advantages of the present invention include:

(1) A class of compounds with novel structures is provided, and the compounds have tubulin inhibitory activity.

(2) A compound with tumor suppressing activity is provided, and the compound can be used to prepare a drug for treating tumors.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

Proton NMR spectra were recorded with Bruker AMX-400, Gemini-300 or AMX-600 NMR instruments, and the unit of chemical shift δ was ppm. All solvents were of analytical grade. Use iodine, ultraviolet fluorescence and other methods to develop color. The organic solvent was evaporated under reduced pressure in a rotary evaporator. The starting reactants used in the present invention are purchased commercially without special description.

It should be noted that, in the following examples, the conventional post-treatment method is: after the reaction is completed, add an appropriate amount of organic solvent and water to the reaction solution, separate the organic phase and the aqueous phase, combine the organic phase, and use _NaSO Drying, After filtration, the crude product was obtained by rotary evaporation under reduced pressure, and the final product was obtained after separation and purification by column chromatography.

Preparation Examples:

Embodiment 1: Preparation of Compound 1 (with reference to the scheme shown in the following reaction formula)

Step (i): N-PMB-5-iodo-3-chloropyrrole (1 g, 1 eq), p-methoxyaniline (1.06 g, 3 eq) and potassium phosphate (1.22 g, 2 eq) were dissolved in 1,4-bis Add cuprous iodide (55 mg, 10%) to 30 mL of oxyhexane solution under nitrogen protection, and react at 110 degrees for 24 hours. The reaction is completed, and the solvent is directly evaporated to dryness. Column chromatography gives N-PMB-5-(4-methoxy Aniline)-3-chloropyrrole (532mg);

Step (ii): N-PMB-5-(4-methoxyaniline)-3-chloropyrrole (500 mg, 1 eq), (2-methyl-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridin-3-yl)boronic acid (393.8mg, 1.5eq) and potassium phosphate (619mg, 2eq) were dissolved in 5mL of n-butanol, nitrogen protection, adding palladium acetate (16mg, 0.05eq) and xphos ( 70mg, 0.1eq), reacted at 110 degrees for 12 hours, and the reaction was completed. Direct evaporation to dryness and column chromatography gave compound e (437mg);

Step (iii): Compound e (150 mg) was dissolved in 20 mL of trifluoroacetic acid, and stirred overnight at room temperature to complete the reaction. Saturated sodium bicarbonate adjusted the pH to weakly alkaline, extracted with ethyl acetate, dried the organic layer and evaporated to dryness to obtain compound 1 (71 mg); H NMR (400MHz, CDCl3) δ8.87 (s, 1H), 7.80 (s ,1H),7.72–7.37(m,2H),7.20–6.85(m,2H),6.10(d,J＝7.8Hz,1H),5.68(d,J＝7.9Hz,1H),3.99(s, 1H),3.79(s,3H),2.66–2.59(m,5H),2.08(dd,J＝4.9,0.8Hz,1H),1.87–1.76(m,1H).

The preparation methods of the compounds shown in Examples 2-47 are the same as those shown in Example 1 except that the compounds b or d are different.

The preparation of embodiment 50 compound 50

Step (i): 5-Bromo-3-chlorofuran (1 g, 1 eq), p-methoxyaniline (2.04 g, 3 eq) and potassium phosphate (2.34 g, 2 eq) were dissolved in N-methylpyrrolidone 15 mL, nitrogen Protection, add cuprous bromide (158mg, 20%), react at 150 degrees for 24 hours, the reaction is complete, extract with ethyl acetate, dry the organic layer and evaporate to dryness column chromatography to obtain 5-(4-methoxyaniline)-3-chloro Furan (613 mg);

Step (ii): 5-(4-methoxyaniline)-3-chlorofuran (500 mg, 1 eq), 2-methylimidazolium[1,2-a]pyrimidine-3-boronic acid (791 mg, 2 eq) and Cesium fluoride (679mg, 2eq) was dissolved in 15mL of tetrahydrofuran, under nitrogen protection, Pd2(dba)3 (205mg, 0.1eq) and tri-tert-butylphosphine (90mg, 0.2eq) were added, refluxed for 10 hours, and the reaction was complete. Direct evaporation to dryness and column chromatography gave 5-(4-methoxyanilino)-3-(2-methylimidazolium[1,2-a]pyrimidine-3-)furan (107 mg);

¹ H NMR (400MHz, CDCl3) δ9.58(dd, J=7.9, 3.0Hz, 1H), 8.77(dd, J=8.0, 3.0Hz, 1H), 7.78–7.43(m, 2H), 7.27(t ,J=8.2Hz,1H),7.03(ddd,J=8.2,6.7,3.3Hz,3H),5.93(d,J=7.0Hz,1H),3.79(s,3H),2.61(s,3H) .

Except that compound b or d is different, the preparation method of embodiment 48,49,51-202 is the same as that of embodiment 50, see the following table

Embodiment 411 Preparation of Compound 411 (with reference to the scheme shown in the following reaction formula)

Add 0.1g (1eq) of p-methoxythiourea and 0.215g (1eq) of heterocyclic compound into a 25ml three-necked flask, add 6mL of methanol and water (volume:volume=1:1) to it, and add catalytic Measure NaF (2.3mg, 0.1eq), react at room temperature for 1-5 minutes, TLC detects that the reaction is complete, wash with saturated sodium bicarbonate solution, extract with dichloromethane (10mLx3), dry the organic layer and evaporate to dryness column chromatography to obtain compound 411 .

¹ H NMR (400MHz, CDCl3) δ8.95(d, J=7.9Hz, 1H), 7.90(d, J=8.1Hz, 1H), 7.55(d, J=8.0Hz, 2H), 7.11(s, 1H), 7.02(d, J=7.8Hz, 2H), 3.79(s, 3H), 2.61(s, 3H), 2.36(s, 3H).

Except that the compound a or b is different, the preparation method shown in the table below is the same as that of Example 411, see the table below.

The preparation of embodiment 408 compound 408

Compound (100mg, 1eq) was dissolved in 2mL of acetic acid, nitrogen bromosuccinimide (54mg, 1.5eq) was added, reacted at 60°C for 12 hours, and the reaction was completed. Quenched with saturated sodium bicarbonate, extracted with ethyl acetate (10mLx3), dried the organic layer with sodium sulfate, evaporated to dryness, and obtained compound 408 (37mg) by column chromatography. ¹ H NMR (400MHz, CDCl3) δ8.55 (dd, J = 15.0, 2.9Hz, 1H), 7.61–7.48 (m, 2H), 7.40 (dd, J = 14.9, 3.0Hz, 1H), 7.08–6.93 (m,3H),3.77(s,3H),2.59(s,3H).

Except that the compound a is different, the preparation method of the examples shown in the table below is the same as that of Example 408, see the table below.

The preparation of embodiment 412 compound 412

The compound (100mg, 1eq) was dissolved in 5mL trifluoroacetic acid, reacted at room temperature for 2h, and the reaction was completed. Quenched with saturated sodium bicarbonate, extracted with ethyl acetate (10mLx3), dried the organic layer with sodium sulfate, evaporated to dryness, and obtained compound 412 (47mg) by column chromatography. ¹ H NMR (400MHz, CDCl ₃ ) δ8.47(d, J=8.0Hz, 1H), 7.53–7.46(m, 2H), 7.35(d, J=8.0Hz, 1H), 7.06–6.99(m, 3H), 3.77(s,3H), 2.59(s,3H).

The preparation of embodiment 432 compound 432

Compound (100mg, 1eq) was dissolved in 5mL of anhydrous acetonitrile, SlectFluor (247mg, 1.3eq) was added, and the reaction was completed at 80°C for 3 hours. Quenched with 10 mL of water, extracted with ethyl acetate (10 mL x 3), dried the organic layer over sodium sulfate, evaporated to dryness, and obtained compound 623 (35 mg) by column chromatography. ¹ H NMR (400MHz, CDCl3) δ8.56(d, J=8.3Hz, 1H), 8.47(s, 2H), 7.41(d, J=9.0Hz, 1H), 7.04(t, J=7.9Hz, 1H), 3.84(s,3H), 2.59(s,3H).

Except that the compound a is different, the preparation method of the examples shown in the table below is the same as that of Example 432, see the table below.

The preparation of embodiment 433 compound 433

Compound (200mg, 1eq) was dissolved in acetonitrile/water (4mL/1mL) mixed solvent, trifluoroiodomethane (157.6mg, 1.5eq), sodium dithionite (93.4mg, 1eq) and sodium bicarbonate (45mg ), reacted at room temperature for 12 hours, and the reaction was completed. 20 mL of water was added, extracted with ethyl acetate (10 mL×3), the organic layer was dried over sodium sulfate, evaporated to dryness by rotary evaporation, and compound 622 (52 mg) was obtained by column chromatography. ¹ H NMR (400MHz, CDCl3) δ8.68(dd, J=7.9, 3.0Hz, 1H), 8.39(s, 2H), 7.33(dd, J=7.9, 3.0Hz, 1H), 6.96(t, J =8.0Hz,1H),3.76(s,3H),2.52(s,3H).

Except that the compound a is different, the preparation method of the examples shown in the table below is the same as that of Example 433, see the table below.

In vitro bioactivity testing of compounds

Determination of biochemical activity of microtubule-associated proteins

Assay principle: microtubules are multimers of tubulin. Tubulin α and β meet end-to-end to form heterodimers, which in turn multiplex into microtubule fibrils. Microtubules are composed of 13 fibrils, and each micron of microtubules is composed of 1650 heterodimers. In vitro, tubulin is capable of polymerizing. The effect of compounds on tubulin polymerization was detected using Tubulin polymerization assay kit (BK011P, Cytoskeleton, Inc.). The kit contains specific reporter fluorescence, which is inserted into the microtubules during the polymerization of the microtubules, and the polymerization reaction of the microtubules can be monitored according to the intensity of the fluorescence. First, add 5 μl of the above compounds or reference compounds at different concentrations to a 96 black plate, preheat at 37°C, and then add 45 μl of microtube polymerization mixture (243ul Buffer1, 112μl Tubulin Glycerol Buffer, 4.4μl GTP stock, 85μl Tubulin stock ), detect the fluorescence intensity with the wavelengths of Ex.=360nm and Em.=450nm every minute in a microplate reader at 37°C, detect for one hour, monitor the polymerization reaction of microtubules, and calculate the IC50 of compounds inhibiting tubulin polymerization, The test results are shown in Table 1. In Table 1, the expression method of microtubule polymerization inhibitory activity (IC ₅₀ ) is: + indicates 1-10 μM; ++ indicates 0.1-1 μM; +++ indicates <0.1 μM.

Table 1 Inhibition of microtubule polymerization activity test results

Test results and analysis:

IC ₅₀ in the above table refers to the inhibitory concentration at which microtubule polymerization is half inhibited (50% inhibitory concentration).

It can be seen from the results in the above table that the above compounds can also significantly inhibit the polymerization of tubulin compared with the positive control Vincristine (VCR).

Antitumor Activity Screening of Compounds in Vitro

Assay principle: Colon cancer cells HCT116 were cultured in modified 5A medium containing 10% fetal bovine serum, and passaged by trypsinization. After about 70% of cell confluency, trypsinize the cells, make cell suspension, count the cells under the microscope, and then inoculate in 96-well plates with 5×10 ³ cells per well. After culturing overnight, the above compounds were administered. The changes of cell proliferation were observed 72 hours after administration by MTT method. After compound treatment for 72 hours, add 10 μl of MTT working solution (5 mg/ml) to each well, incubate at 37°C for 2 hours, suck out the culture medium, add 100 μl of DMSO to each well, shake at room temperature for 15 minutes, and then measure the OD value with a microplate reader at a wavelength of 492 nm. Calculate the activity of the compound to inhibit the proliferation of HCT116 cells. The specific inhibition rates are shown in Tables 2 and 3, where the inhibitory cell proliferation activity (IC ₅₀ ) is expressed as follows: + indicates 1-10 μM; ++ indicates 0.1-1 μM; +++ indicates 0.01-0.1 μM; ++++ means 0.01-0.001 μM; +++++ means <0.001 μM; “-” means no activity. IC ₅₀ represents the drug concentration required for 50% growth inhibition of cells (50% growth inhibition).

The calculation method of cell viability (%) is:

Survival rate (%)=(administration well OD-blank well OD)/(control well OD-blank well OD)×100

Inhibition rate (%)=1-survival rate (%)

Other cancer cell lines used were Hela (human cervical cancer cells), MCF-7 (human breast cancer cells), LM3 (human liver cancer cells), NCI-N87 (human gastric cancer cells), Caki-1 (human kidney cancer cells ), A549 (human lung cancer cells), HT1080 (human fibrosarcoma cells), A431 (human epidermal squamous cell carcinoma cells), PC3 (human prostate cancer cells), HL60 (human leukemia cells), Panc-1 (human pancreatic cancer cells cells), KB (human oral cancer cells), U87-MG (human glioma cells), K562 (human chronic myelogenous leukemia cells), Kasumi-1 (human leukemia cells), THP-1 (human leukemia cells ), Jurkat (human T lymphocytic leukemia cells), REH (human B lymphocytic leukemia cells), Raji (human Burkitt cell leukemia cells), RNK-16 (human NK cell leukemia cells), KMS-1 (human multiple myeloid tumor cells), P39 (human myelodysplastic syndrome cells), U118-MG (human glioblastoma cells), H4 (human glioma cells), SK-N-SH (human neuroblastoma cells) , SH-SY5Y (human neuroblastoma cells), A549/Taxol (paclitaxel-resistant human lung cancer cells), KB/VCR (vincristine-resistant human oral cancer cells), K562/Adr (adriamycin-resistant human chronic granulocyte Leukemia cells) were cultured in DMEM+10% FBS medium or 1640+10% FBS respectively.

Table 2 compounds inhibit cancer cell growth broad-spectrum biological activity test results

It can be seen from the above experimental results that the compound of the present invention has inhibitory activity on the growth of different types of tumor cells, suggesting that the compound of the present invention has a broad spectrum of tumor inhibitory activity.

Table 3 Part of the compound inhibits the activity test results of hematological cancer cell growth

From the above experimental results, it can be seen that the compound of the present invention is effective for various types of blood cancer cells (acute myeloid leukemia cells, acute or chronic lymphocytic leukemia cells, multiple myeloma cells, myelodysplastic syndrome cells) ) growth inhibitory activity, suggesting that the compound of the present invention has a broad spectrum of hematological cancer cell growth inhibitory activity.

Table 4 Part of the compound inhibits the activity test results of brain cancer cell growth

As can be seen from the above experimental results, the compound of the present invention has inhibitory activity on the growth of brain tumor cells (glioma cells and neuroblastoma cells), suggesting that the compound of the present invention is suitable for inhibiting the growth of brain tumor cells. active.

Table 5 part of the compound to drug-resistant cancer cell growth inhibition test results

As can be seen from the results in the table above: compared with the positive controls vincristine (Vincristine, VCR), paclitaxel (Paclitaxel, Taxol) and adriamycin (Adriamycin, Adr), the above-mentioned compounds have significant inhibitory effect on the listed cancer cells. and drug-resistant cancer cell growth activity, especially for paclitaxel, vincristine or doxorubicin-resistant strains have excellent inhibitory activity, and also have a good inhibitory effect on the growth of chronic myeloid leukemia cell drug-resistant strains.

Compound 397 inhibits neutrophils and relieves symptoms of gout

Tubulin inhibitors have a wide range of uses. In addition to being used as antineoplastic agents, they are also used to treat gout, as well as antifungal agents and broad-spectrum anthelmintics.

Experimental content: 1 mg of sodium uric acid salt was dissolved in 0.5 ml of endotoxin-free phosphate buffer solution to prepare a solution. C57BL/6 mice were intraperitoneally injected with sodium urate solution to establish a peritonitis model. On the first 1-4 days after sodium urate solution injection, mice were treated with different concentrations of compound 397 (0, 0.25, 0.5 and 1 mg/kg) every day, and it was found that compound 397 could significantly inhibit the central granulocyte flow (Figure 1), inhibit inflammation, and relieve gout in mice.

It can be seen from Figure 1 that compound 397 can concentration-dependently inhibit the flow of neutrophils in mice with peritonitis induced by sodium urate crystals, suggesting that the compound has the effect of alleviating ventilation in mice.

It should be noted that the above-mentioned embodiments are only used to illustrate rather than limit the technical solutions of the present invention, and any equivalent replacement or modification shall be deemed to be included within the scope of the present invention.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (12)

1. a kind of formula (I) compound, or its isomers, racemic modification, pharmaceutically acceptable salt, crystalline hydrate, solvent are closed Thing：

Wherein：

X₁Selected from N or C-R₁(when R1 is H, being expressed as C)；

X₂Selected from N-R₁, O or S；

X₃It is selected from the group：NH, O, S, C=O, C=S, C=NH ,-(C=O)-NH- ,-(C=O)-O- ,-(C=O)-S- ,-(C= S)-NH- ,-(C=S)-O- ,-(C=S)-S- ,-(C=NH)-NH- ,-(C=NH)-O- or-(C=NH)-S-；

R₁It is selected from the group：Hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano group, carboxyl, C_2-6Ester group, C_1-6Amide groups, it is unsubstituted or The C of halo_1-12Alkyl or cycloalkyl ,-CH₂-Y-(C_1-12Alkyl or cycloalkyl) (wherein Y is O or NH or S), C_1-12Aryl is miscellaneous Aryl ,-CH₂-(C_1-12Aryl or heteroaryl)；

Ar₁Group is substituted or unsubstituted C_1-18Aryl or heteroaryl, substituted or unsubstituted-CH₂-(C_1-12Aryl or heteroaryl Base), substituted or unsubstituted C_1-18Heterocyclic radical, substituted or unsubstituted-CH₂-(C_1-12Heterocyclic radical)；Wherein, described Ar₁For Bicyclic radicals, and at least there is a C_1-12Alkyl or cycloalkyl substituent；

Ar₂Group is substituted or unsubstituted C_1-12Alkyl or cycloalkyl, substituted or unsubstituted-CH₂-Y-(C_1-12Alkyl or ring Alkyl) (wherein Y is O or NH or S), substituted or unsubstituted C_1-12Aryl or heteroaryl, substituted or unsubstituted-CH₂-(C_1-12 Aryl or heteroaryl), substituted or unsubstituted C_1-12Heterocyclic radical；Wherein, described Ar2 groups at least one alkoxy substitution Base；

And work as Ar₂For C_1-12During aryl, described Ar₁Also at least there is a halogenic substituent；

M is selected from 0,1,2,3,4,5,6；

N is selected from 0,1,2,3,4,5,6；

Wherein, described substitution is that the one or more substituents for being selected from the following group are replaced：Halogen, amino, hydroxyl, nitro, Cyano group, trifluoromethyl, C_1-12Alkyl or cycloalkyl, C_1-12It is alkoxy, oxygen atom (i.e.=O), unsubstituted or by C_1-4Alkylamino radical takes The C in generation_1-12Alkylamino radical, C_2-6Ester group, C_2-6Acyl group, C_1-6Amide groups, thio C_1-12It is alkyl, carboxyl, unsubstituted or by 1-5 halogen Element, amino, hydroxyl, nitro, cyano group, the C of trifluoromethyl substitution_1-12Aryl or heteroaryl, or it is unsubstituted or by 1-5 halogen, Amino, hydroxyl, nitro, cyano group, the C of trifluoromethyl substitution_1-12(containing 1-5, preferably 1-3 are selected from N, O or S to heterocyclic radical Hetero atom).

2. purposes as claimed in claim 1, wherein：

The X₃It is selected from the group：NH, O, S, C=O, C=S, C=NH ,-(C=O)-NH- ,-(C=O)-O- ,-(C=O)-S- ,- (C=S)-NH- ,-(C=S)-O- ,-(C=S)-S-；

The R₁It is selected from the group：Hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano group, carboxyl, ester group, amide groups, unsubstituted C_1-6 Alkyl or cycloalkyl, (1-3) fluoro C_1-6Alkyl or cycloalkyl, (1-3) C_1-6Amido replaces C_1-6Alkyl or cycloalkyl, (1-3) C_1-6Alkoxy replaces C_1-6Alkyl or cycloalkyl ,-CH₂-Y-(C_1-6Alkyl), C_1-12Aryl or heteroaryl ,-CH₂-(C_1-12Aryl Or heteroaryl).

3. purposes as claimed in claim 1, wherein, described Ar₁Or Ar₂In group, described C_5-12Aryl or heteroaryl choosing From the following group：

M is 0,1,2,3,4,5；

N is 0,1,2,3,4,5.

4. compound as claimed in claim 1, it is characterised in that described Ar₁Have to be substituted or unsubstituted such as following formula institute The structure shown：

Wherein, dotted line is chemical bond or nothing；Each A₁、A₂、A₃、A₄、A₅、A₆、A₇、A₈And A₉Be each independently O, S, N, NH, CH or CH₂；

Ra is H, halogen, C_1-6Alkyl, one or more halo C_1-6Alkyl or cycloalkyl, C_1-6Alkoxy, C_1-6Alkylthio group, C_1-6 Alkylamino.

Rb is fluorine, chlorine, C_1-6Alkyl, one or more halo C_1-6Alkyl or cycloalkyl or C_1-6Alkoxy or C_1-6Alkylthio group or C_1-6Alkylamino, substituted or unsubstituted C_5-12Aryl or aromatic heterocyclic；

And work as A₈During for N, Rb is nothing；

Substituted definition is as described in the appended claim 1.

5. compound as claimed in claim 1, it is characterised in that described Ar₂Have to be substituted or unsubstituted such as following formula institute The structure shown：

Wherein, each B₁、B₂、B₃、B₄、B₅、B₆It is each independently O, S, N, NH, CH or CH₂；

Rc is amino, trifluoromethyl, C_1-6Alkoxy, C_1-6Alkylamino, (1-3) halo C_1-6Alkyl or C_1-6Alkylthio.

6. compound as claimed in claim 1, it is characterised in that logical formula (I) compound is selected from compound shown in formula (Ia)：

Wherein, dotted line is chemical bond or nothing；Y=CH or N；R1, X1, X2, X3, Ar2, m and n definition such as claim 1；Ra、Rb Definition such as claim 4.

7. compound as claimed in claim 6, it is characterised in that X₁For C, X₂During for NH, O or S, lead to the choosing of formula (I) compound From compound (wherein thick horizontal line shown in below formula (Ia)Indicate coupling part)：

8. compound as claimed in claim 6, it is characterised in that formula (Ia) compound is selected from chemical combination shown in formula (Ib) Thing：

Wherein, dotted line is chemical bond or nothing；Y=CH or N；X2=NH, O or S；R1, X3 and Ar2 definition such as claim 1； Ra, Rb definition such as claim 4.

9. compound as claimed in claim 8, it is characterised in that during X2=NH or O, compound shown in formula (Ib) is preferably selected From following compound (short and thick line " one " represents coupling part)：

10. as claimed in claim 8, during X2=S, compound shown in formula (Ib) is selected from formula (Ic), (Id), (Ie) shownization Compound：

11. the purposes of pharmaceutical composition as claimed in claim 1, it is characterised in that be selected from down for preparing treatment or prevention The pharmaceutical composition of the disease of group：The mammalian diseases relevant with microtubule associated protein dysregulation；It is preferably selected from the following group Disease：Cancer, nerve degenerative diseases, malaria, AIDS, gout, diabetes.

12. a kind of preparation method of the compound shown in formula (I)：

Wherein, X₁、X₂、X₃、R₁、Ar₁、Ar₂, m and n definition as claim 1-10 it is any described in；

Characterized in that, the described method comprises the following steps：

(i-a) in atent solvent, reacted with formula a compounds and formula b compounds, obtain formula c compounds；

(ii-a) in atent solvent, reacted with formula c compounds and formula d compounds, obtain formula e compounds；

And work as Q=N-R₁When, in addition to following optional step：(iii-a) in atent solvent, it is deprotected with formula e compounds Base, obtains formula f compounds；

Wherein, X is halogen；U is selected from the group：Halogen, OMs, OTs, boric acid, boric acid pinacol ester；Q is O, S or N-R₁；P is selected from down Group：To methoxy-benzyl, benzyl, tertbutyloxycarbonyl；

Or the described method comprises the following steps：

(i-b) in atent solvent, formula g compounds are optionally substituted by halogen, and obtain formula h compounds；

Wherein, R₁For halogen (fluorine, chlorine, bromine or iodine)

The definition of remaining each group is with claim 1；

Or the described method comprises the following steps：

(i-c) in atent solvent, formula a compounds carry out ring closure reaction with formula b compounds, obtain formula c compounds；

Preferably, described ring closure reaction is catalyzed by inorganic salts and carried out；

Wherein, V is halogen, OMs, or OTs；The definition of remaining each group is with claim 1, but R₁For the group of non-halogen.