CN109293630A - Substituted pyrazole compounds and preparation method and application thereof - Google Patents

Abstract

Translated fromChinese

本发明提供一种含取代吡唑类化合物及其制备方法与应用，该化合物或其药学上可接受的盐，其具有式X所示结构：其中，Y选自C和N，n选自0和1；为单键或双键；R选自4‑苯氧基苯基和4‑吡啶甲酸氨基苯基；R₁选自甲酸、甲酸乙酯和羟甲基；R₂选自‑COR₄和H；R₃选自含或不含卤素的C_1‑6直链或支链烷基酰氨基、吡啶酰氨基和苯酰氨基；R₄选自含或不含卤素的C_1‑6直链或支链烷基、吡啶和苯基。The present invention provides a substituted pyrazole compound, a preparation method and application thereof, the compound or a pharmaceutically acceptable salt thereof, which has the structure shown in formula X: wherein, Y is selected from C and N, and n is selected from 0 and 1; is a single bond or a double bond; R is selected from₄ -phenoxyphenyl and₄ -picolinate aminophenyl; R is selected from formic acid, ethyl formate and hydroxymethyl; R is selected from_- COR and H; R₃ is selected from C_1-6 straight chain or branched chain alkyl amido, pyridine amido and phenylamido with or without halogen; R₄ is selected from C_1-6 straight chain or branched with or without halogen Alkyl, pyridine and phenyl.

Description

Compound of class containing substituted pyrazolecarboxylic and the preparation method and application thereof

Technical field

The present invention relates to organic compound synthesis and medical applications field, more particularly to the compound of class containing substituted pyrazolecarboxylic and itsPreparation method and application.

Background technique

Lymphoma mantle cell (Mantle cell lymphoma, MCL) be a kind of grade malignancy it is high, it is prognosis mala it is non-suddenlyOdd gold lymthoma (Non-Hodgkin lymphoma, NHL), it is characterized in that t (11；14)(q13；Q32) chromosome translocation, thusCyclin D1 is caused to over-express.MCL clinic is in invasion more, so far still to can not be cured lymthoma, at presentThe First-line chemotherapy scheme that there is no standard, compared with other B cell lymphomas, MCL is difficult to maintain long-term effect by chemotherapy.(ginsengSee: Zhou Y, Wang H, Fang W, Romaguer JE, Zhang Y, Delasalle KB, Kwak L, Yi Q, Du XL,Wang M:Incidence trends of mantle cell lymphoma in the United States between1992 and 2004.Cancer 2008,113 (4): 791.) in recent years with going deep into MCL study of incident mechanism, molecular targetIt is made some progress to treatment, including mTOR inhibitors, BTK inhibitor, hdac inhibitor and CDK inhibitor.BTK is BVital, BTK is played the role of in one regulatory factor in cell receptor signal path downstream, development and maturation to B cellUnconventionality expression and activate it is generally existing in MCL cell.(Winer ES,Ingham RR,Castillo JJ:PCI-32765:anovel Bruton's tyrosine kinase inhibitor for the treatment of lymphoidMalignancies.Expert Opinion on Investigational Drugs 2012,21 (3): 355-361.) according to ShandongIt is the BTK inhibitor of first listing for Buddhist nun (Ibrutinib, IBN), clinical signs go out to MCL good therapeutic effect,FDA approval for treat recurrent and refractory MCL (Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS,Jurczak W,Advani RH,Romaguera JE,Williams ME et al:Targeting BTK withibrutinib in relapsed or refractory mantle-cell lymphoma.N Engl J Med 2013,369 (6): 507-516.) it is extensive with clinical application, gradually show according to Shandong for the drug resistance of Buddhist nun, shows the site BTK481Cysteine mutation be serine, in addition there is also about the patient of one third to according to Shandong for Buddhist nun treatment it is unresponsive, how to mentionThe whole response rate and improvement drug resistance of this high some patients are a hot spots of current MCL Therapy study.(Woyach JA,Furman RR,Liu TM,Ozer HG,Zapatka M,Ruppert AS,Xue L,Li HH,Steggerda SM,Versele M:Resistance Mechanisms for the Bruton's Tyrosine Kinase InhibitorIbrutinib.New England Journal of Medicine 2014,370 (24): 2286-2294.) therefore design is closedAt structure novel, with the newtype drug of druggability, had a very important significance for treatment MCL.

Summary of the invention

The purpose of the present invention is to provide a kind of pair of MCL cell line have inhibitory activity the compound of class containing substituted pyrazolecarboxylic andPreparation method and activity rating, the compound activity have more prospect, while improving the molecular diversity and novelty of compoundProperty；Another object of the present invention is to provide the preparation method and applications of the substituted pyrazolecarboxylic class compound.

To achieve the above object, the present invention adopts the following technical solutions:

In the first aspect of the present invention, the present invention provides a kind of compound or its pharmaceutically acceptable salts, haveStructure shown in Formula X:

Wherein, Y is selected from C and N, and n is selected from 0 and 1；For singly-bound or double bond；

R is selected from 4- Phenoxyphenyl and Isonicotinic acid aminophenyl；

R₁Selected from formic acid, Ethyl formate and methylol；

R₂Selected from-COR₄And H；

R₃Selected from the C with or without halogen_1-6Linear or branched alkyl group acylamino-, pyridine acylamino- and benzoyl amino；

R₄Selected from the C with or without halogen_1-6Linear or branched alkyl group, pyridine and phenyl.

Preferably, the R₃The position of substitution be C-3 or C-4.

Preferably, R is selected from 4- Phenoxyphenyl and Isonicotinic acid aminophenyl；R₁Selected from formic acid, Ethyl formate and hydroxylMethyl；R₂Selected from-COR₄And H；R₃Selected from 3- acrylamido, 4- acrylamido, chloro acetylamino and Trans-2-butene acyl ammoniaBase；R₄Selected from vinyl, chloromethyl and trans- 1- acrylic.

Preferably, the compound of the present invention has a structure that

Wherein, R is 4- Phenoxyphenyl or Isonicotinic acid aminophenyl；R₁For formic acid, Ethyl formate or methylol；R₃Selected from the C with or without halogen_1-6Linear or branched alkyl group acylamino-, pyridine acylamino- and benzoyl amino；R₄Selected from or withoutThe C of halogen_1-6Linear or branched alkyl group, pyridine and phenyl.R₃The position of substitution be C-3 or C-4.

Preferably, R is 4- Phenoxyphenyl or Isonicotinic acid aminophenyl；R₁For formic acid, Ethyl formate or methylol；R₃For 3- acrylamido, 4- acrylamido, chloro acetylamino or Trans-2-butene acylamino-；R₄For vinyl, chloromethyl orTrans- 1- acrylic.

Preferably, the compound of the present invention has a structure that

Wherein, R is 4- Phenoxyphenyl or Isonicotinic acid aminophenyl；R₁For Ethyl formate or methylol；R₅For halogenElement is selected from F, Cl, Br and I, preferably Cl.-NHC(O)CH₂R₅The position of substitution be C-3 or C-4.

Preferably, above compound is selected from following compound:

1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (I-1)

1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (I-2)

1- (1- chloracetyl piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (I-3)

1- (1- acryloylpiperidine -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate (I-4)

1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid secondEster (I-5)

1- (1- chloracetyl piperidines -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate (I-6)

1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (I-7)

1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (I-8)

1- (1- chloracetyl piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (I-9)

1- (1- acryloylpiperidine -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (I-10)

1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (I-11)

1- (1- chloracetyl piperidines -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (I-12)

1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (I-13)

1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (I-14)

1- (1- chloracetyl piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (I-15)

1- (4- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (II-1)

1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (II-2)

1- (4- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (II-3)

1- (4- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate (II-4)

1- (4- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate (II-5)

1- (3- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (II-6)

1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (II-7)

1- (3- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (II-8)

1- (3- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate (II-9)

1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate(II-10)

1- (3- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate (II-11)

1- (4- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (II-12)

1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (II-13)

1- (4- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (II-14)

1- (4- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (II-15)

1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (II-16)

1- (4- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (II-17)

1- (3- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (II-18)

1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (II-19)

1- (3- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid (II-20)

1- (3- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (II-21)

1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (II-22)

1- (3- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid (II-23)

1- (4- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (II-24)

1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (II-25)

1- (4- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (II-26)

1- (4- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- methanol (II-27)

1- (4- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- methanol (II-28)

1- (3- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (II-29)

1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (II-30)

1- (3- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (II-31).

Compound of the present invention can in a free form or further exist in a salt form, in order to improve waterDissolubility increases bioavilability.

" pharmaceutically acceptable salt " of the present invention refers to conventional avirulent salt, mainly includes the application chemical combinationThe acidic carboxypolymer of object is formed by cationic salts, including alkali metal (such as sodium salt, sylvite), alkaline-earth metal (such as magnesium salts and calcium salt),Organic salt (such as ammonium salt).These salt be it is known to the ordinarily skilled artisan, those skilled in the art can prepare this fieldAny pharmaceutically acceptable salt provided by knowledge.In addition, those of skill in the art can also be according to solubility, stability, appearanceThe factors such as easy preparation take certain salt and cast out another salt.The measurements of these salt and optimize the experience model in those of skill in the artIn enclosing.

In the second aspect of the present invention, the present invention also provides the method for preparation formula (I) compound, the method includes intoThe following reaction route of row:

Wherein, R, R₁、R₄It is as defined above；

Preferably, describedIt is prepared by reacting as follows:

Wherein, R, R₁It is as defined above.

Preferably, the method includes carrying out following reaction route:

Wherein, R is Isonicotinic acid aminophenyl, R₁Selected from formic acid, Ethyl formate, R₄Selected from vinyl, chloromethyl andTrans- 1- acrylic.

Preferably, it the described method comprises the following steps:

(i) raw material A -1 and diethy-aceto oxalate are dissolved in ethyl alcohol, sodium ethoxide is added at 0 DEG C, reaction finishes, reaction solution is fallenEntering in ice water, filters, filter cake is washed with water, and it is dry, obtain intermediate A -2；

(ii) intermediate A -2 is dissolved in ethyl alcohol, 80% hydrazine hydrate, a few drop acetic acid is added, 80 DEG C of reflux 3h are removed under reduced pressureSolvent obtains yellow solid intermediate A -3；

(iii) by intermediate A -3 and 1-Boc-3- hydroxy piperidine, it is dissolved in anhydrous THF at 0 DEG C of triphenylphosphine, is added dropwiseDIAD reacts 3h；Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure obtains intermediate A -4；

(iv) intermediate A -4 is dissolved in ethyl alcohol: in the solution of water=3:1 (v/v), iron powder, ammonium chloride, 90 DEG C of reactions is added6h；Reaction is finished, and is filtered while hot, is removed filtrate solvent under reduced pressure, obtains intermediate A -5；

(v) raw material pyridine carboxylic acid is dissolved in DMF, triethylamine, HBTU is added, stirred 40 minutes, A-5 is added, reaction 12 is smallWhen；Reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is washed with water, dry, obtains intermediate A -6；

(vi) intermediate A -6 is dissolved in methylene chloride, 4N hydrochloric acid 5ml is added, is stirred at room temperature 12 hours, removes under reduced pressure moltenAgent obtains intermediate C-1 respectively；

(vii) intermediate C-1, triethylamine are dissolved in tetrahydrofuran, different substitution acyl chlorides is slowly added dropwise under ice bath, room temperature is stirredMix 4h；Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography, obtains formula (I) changeObject is closed, wherein R₁For methyl formate；

(viii) product of step (vii) is dissolved in methanol, sodium hydroxide is added, 2h, dilute hydrochloric acid tune PH is stirred at room temperatureTo 4~5, filtering, filter cake is washed with water, and drying obtains formula (I) compound, wherein R₁For formic acid.

Preferably, the method includes carrying out following reaction route:

Wherein, R is 4- Phenoxyphenyl, R₁Selected from formic acid, Ethyl formate, R₄Selected from vinyl, chloromethyl and trans- 1- acrylic.

Preferably, it the described method comprises the following steps:

Raw material B-1 and diethy-aceto oxalate are dissolved in ethyl alcohol by (i '), and sodium ethoxide is added at 0 DEG C, and reaction finishes, reaction solution is fallenEntering in ice water, filters, filter cake is washed with water, and it is dry, intermediate B -2 is obtained respectively；

Intermediate B -2 is dissolved in ethyl alcohol by (ii '), and 80% hydrazine hydrate, a few drop acetic acid, 80 DEG C of reflux 3h, decompression steaming is addedExcept solvent, yellow solid intermediate B -3 is obtained respectively；

Intermediate B -3 and 1-Boc-3- hydroxy piperidine are dissolved in anhydrous THF at 0 DEG C of triphenylphosphine, are added dropwise by (iii ')DIAD reacts 3h；Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, obtains intermediate respectivelyB-4；

Intermediate B -4 is dissolved in methylene chloride by (iv '), and 4N hydrochloric acid 5ml is added, is stirred at room temperature 12 hours, removes under reduced pressure moltenAgent obtains intermediate C-1 respectively；

Intermediate C-1, triethylamine are dissolved in tetrahydrofuran by (v '), and different substitution acyl chlorides are slowly added dropwise under ice bath, and room temperature is stirredMix 4h；Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography, obtains formula (I) changeObject is closed, wherein R₁For methyl formate；

The product of step (v ') is dissolved in methanol by (vi '), and sodium hydroxide is added, 2h, dilute hydrochloric acid tune PH to 4 is stirred at room temperature~5, filtering, filter cake is washed with water, dry, obtains formula (I) compound, wherein R₁For formic acid.

Preferably, the method includes carrying out following reaction route:

Wherein, R is 4- Phenoxyphenyl, R₁Selected from methylol, R₄Selected from vinyl, chloromethyl and trans- 1- acrylic；

Preferably, it the described method comprises the following steps:

Intermediate B -4 is dissolved in anhydrous THF by (i "), and Lithium Aluminium Hydride is added under ice bath, is stirred at room temperature 15 minutes, is slowly addedExcessive water is quenched, and is extracted with ethyl acetate, and evaporating solvent under reduced pressure obtains intermediate B -5；

Intermediate B -5 is dissolved in methylene chloride by (ii "), and 4N hydrochloric acid 5ml is added, is stirred at room temperature 12 hours, removes under reduced pressure moltenAgent obtains intermediate C-1 respectively；

Intermediate C-1, triethylamine are dissolved in tetrahydrofuran by (iii "), and different substitution acyl chlorides, room temperature are slowly added dropwise under ice bathStir 4h；Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography obtains formula (I)Compound, wherein R₁For methylol；

In the third aspect of the present invention, the present invention also provides the method for preparation formula (II) compound, the method includesCarry out following reaction route:

Wherein, R, R₁、R₃It is defined as above described；

Preferably, describedIt is prepared by reacting as follows:

Wherein, R, R₁It is defined as above described.

Preferably, the method includes carrying out following reaction route:

Wherein, R is Isonicotinic acid aminophenyl, R₁Selected from formic acid, Ethyl formate, R₃Selected from 3- acrylamido, 4- thirdAlkene acylamino-, chloro acetylamino and Trans-2-butene acylamino-；

Preferably, it the described method comprises the following steps:

(1) intermediate A -3 is in ethyl alcohol: in water=3:1 (v/v) solution, with reproducibility iron powder, ammonium chloride reaction is obtained intermediateBody A-7；

(2) raw material pyridine carboxylic acid is dissolved in DMF, triethylamine, HBTU is added, stirred 40 minutes, A-7 is added, reaction 12 is smallWhen；Reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is washed with water, dry, obtains intermediate A -9 respectively；

(3) intermediate A -9 is dissolved in DMF, potassium carbonate is added, slowly adds 3- or 4- nitrobenzyl bromine, 8h is stirred at room temperature, it will be anti-It answers liquid to pour into ice water, filters, filter cake is washed with water, and it is dry, intermediate D-1 is obtained respectively；

(4) intermediate D-1 is dissolved in ethyl alcohol: in water=3:1 (v/v) solution, iron powder, ammonium chloride, 90 DEG C of reaction 6h is added；Reaction is finished, and is filtered while hot, is removed filtrate solvent under reduced pressure, obtains intermediate D-2；

(5) intermediate D-2, triethylamine are dissolved in tetrahydrofuran, different substitution acyl chlorides is slowly added dropwise under ice bath, are stirred at room temperature4h；Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography, obtains formula (II) changeObject is closed, wherein R₁For methyl formate；

(6) product of step (6) is dissolved in methanol, sodium hydroxide is added, is stirred at room temperature 2h, dilute hydrochloric acid tune PH to 4~5, filtering, filter cake is washed with water, dry, obtains formula (II) compound, wherein R₁For formic acid.

Preferably, the method includes carrying out following reaction route:

Wherein, R is Isonicotinic acid aminophenyl, R₁Selected from methylol, R₃Selected from 3- acrylamido, 4- acrylamideBase, chloro acetylamino and Trans-2-butene acylamino-；

Preferably, it the described method comprises the following steps:

Intermediate A -7 is dissolved in anhydrous THF by (1 '), and Lithium Aluminium Hydride is added under ice bath, is stirred at room temperature 15 minutes, was slowly addedAmount water quenching is gone out, and is extracted with ethyl acetate, evaporating solvent under reduced pressure obtains intermediate A -8；Raw material pyridine carboxylic acid is dissolved in DMF by (2 '), is addedEnter triethylamine, HBTU, stir 40 minutes, be separately added into A-8, reacts 12 hours.Reaction is finished, and reaction solution is poured into ice water, mistakeFilter, filter cake are washed with water, dry, obtain intermediate A -9 respectively；

Intermediate A -9 is dissolved in DMF by (3 '), and potassium carbonate is added, slowly adds 3- or 4- nitrobenzyl bromine, 8h is stirred at room temperature, willReaction solution pours into ice water, and filtering, filter cake is washed with water, dry, obtains intermediate D-1 respectively；

Intermediate D-1 is dissolved in ethyl alcohol by (4 '): in water=3:1 (v/v) solution, iron powder, ammonium chloride, 90 DEG C of reactions are added6h；Reaction is finished, and is filtered while hot, is removed filtrate solvent under reduced pressure, obtains intermediate D-2；

Intermediate D-2, triethylamine are dissolved in tetrahydrofuran by (5 '), and different substitution acyl chlorides are slowly added dropwise under ice bath, and room temperature is stirredMix 4h；Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography obtains formula (II)Compound, wherein R₁For methylol；

Preferably, the method includes carrying out following reaction route:

Wherein, R is 4- Phenoxyphenyl, R₁Selected from formic acid, Ethyl formate, R₃Selected from 3- acrylamido, 4- acrylamideBase, chloro acetylamino and Trans-2-butene acylamino-；

Preferably, it the described method comprises the following steps:

Intermediate B -3 is dissolved in DMF by (1 "), and potassium carbonate is added, slowly adds 3- or 4- nitrobenzyl bromine, 8h is stirred at room temperature, willReaction solution pours into ice water, and filtering, filter cake is washed with water, dry, obtains intermediate D-1 respectively；Intermediate D-1 is dissolved in second by (2 ")Alcohol: in water=3:1 solution, iron powder, ammonium chloride, 90 DEG C of reaction 6h are added.Reaction is finished, and is filtered while hot, is removed filtrate solvent under reduced pressure,Obtain intermediate D-2；

Intermediate D-2, triethylamine are dissolved in tetrahydrofuran by (3 "), and different substitution acyl chlorides are slowly added dropwise under ice bath, and room temperature is stirredMix 4h.Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography obtains formula (II)Compound, wherein R₁For methyl formate or formic acid；

Preferably, the method includes carrying out following reaction route:

Wherein, R is 4- Phenoxyphenyl, R₁Selected from methylol, R₃Selected from 3- acrylamido, 4- acrylamido, chloroetheneAcylamino- and Trans-2-butene acylamino-；

Preferably, it the described method comprises the following steps:

Intermediate B -3 is dissolved in anhydrous THF by (1 " '), and Lithium Aluminium Hydride is added under ice bath, is stirred at room temperature 15 minutes, is slowly addedExcessive water is quenched, and is extracted with ethyl acetate, and evaporating solvent under reduced pressure obtains intermediate B -6；

Intermediate B -6 is dissolved in DMF by (2 " '), and potassium carbonate is added, slowly adds 3- or 4- nitrobenzyl bromine, 8h is stirred at room temperature, willReaction solution pours into ice water, and filtering, filter cake is washed with water, dry, obtains intermediate D-1 respectively；

Intermediate D-1 is dissolved in ethyl alcohol by (3 " '): in water=3:1 solution, iron powder, ammonium chloride, 90 DEG C of reaction 6h are added；InsteadIt should finish, filter while hot, remove filtrate solvent under reduced pressure, obtain intermediate D-2；

Intermediate D-2, triethylamine are dissolved in tetrahydrofuran by (4 " '), and different substitution acyl chlorides are slowly added dropwise under ice bath, and room temperature is stirredIt mixes 4h reaction to finish, reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography obtains formula (II) changeObject is closed, wherein R₁For methylol.

In the fourth aspect of the present invention, the present invention also provides a kind of compositions, contain above compound or its pharmacyUpper acceptable salt.

The pharmaceutical composition of the compounds of this invention, can be to grant: oral, spraying to suck, is straight selected from following any wayEnteral administration, nasal-cavity administration, vagina administration, local administration, parenterai administration be such as subcutaneous, in vein, intramuscular, peritonaeum, intrathecal, ventricleIn interior, breastbone or intracranial injection or input, or by a kind of reservoir medication of explant, wherein preferably take orally, intramuscular injection, in peritonaeum orIntravenous administration mode.

In the fifth aspect of the invention, the present invention also provides a kind of pharmaceutical preparations, and it includes above compound or its medicinesAcceptable salt or composition containing above compound or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary onMaterial and/or carrier.

The compounds of this invention can be administered in a unit containing its pharmaceutical composition.Form of administration can be liquidBody dosage form, solid dosage forms.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed dosage form.OtherDosage form such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspension, emulsion, granule, suppository, freeze-dried powderInjection, inclusion compound, landfill agent, patch, liniment etc..

Common carrier, pharmaceutical acceptable carrier packet described here can also be contained in pharmaceutical composition or pharmaceutical preparation of the inventionIt includes but is not limited to: ion-exchanger, aluminium oxide, aluminum stearate, lecithin, haemocyanin such as human albumin, buffer substanceSuch as phosphate, glycerol, sorb ester, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte,Such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, cabosil, magnesium trisilicate, polyvinyl pyrroleAlkanone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, wool grease etc..Carrier is in medicine groupThe content closed in object can be 1 weight %-98 weight %, generally about account for 80 weight %.For convenience, local anaesthesiaAgent, preservative, buffer etc. can be directly dissolved in carrier.

Oral tablet and capsule can contain excipient such as adhesive, such as syrup, Arabic gum, sorbierite, tragacanth, orPolyvinylpyrrolidone, filler, such as lactose, sucrose, cornstarch, calcium phosphate, sorbierite, amion acetic acid, lubricant are such as hardFatty acid magnesium, talcum, polyethylene glycol, tripoli, disintegrating agent, such as potato starch or acceptable dibutyl phthalate, such as laurel sodium alkoxide sulfuric acidSalt.Tablet can be coated with method well known in pharmaceutics.

The suspension of water and oil can be made in oral solution, and solution, emulsion, dry product can also be made in syrup, with preceding supplementWater or other suitable mediums.This liquid preparation may include conventional additive, such as suspending agent, sorbierite, cellulose firstEther, dextrose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, the edible oil and fat of hydrogenation, emulsificationAgent, such as lecithin, sorbitan mono-oleate, gum arabic；Or nonaqueous carrier (may include edible oil), such as almondOil, grease such as glycerol, ethylene glycol or ethyl alcohol；Preservative, such as methyl p-hydroxybenzoate or propyl ester, sorbic acid.As needed can to addAdd flavoring agent or colorant.

Suppository may include conventional suppository base, such as cocoa butter or other glyceride.

For parenteral, liquid forms are usually made of compound and a kind of carrier of disinfection.Carrier first choice water.According toAccording to the difference of selected carrier and drug concentration, compound, which both dissolves in, may be made as aaerosol solution in carrier, and injection is being madeIt is first that compound is soluble in water when solution, it is fitted into sealed bottle or ampoule after filtering disinfection.

It should be appreciated that general formula X, the best dosage of general formula I, II compound and interval are by compound property and allSuch as the form of administration, path and it is not and the external conditions such as the specific mammal treated determine, and this is most preferably givenPharmaceutical quantities can be determined with conventional technique.Simultaneously also it should be appreciated that the optimal course for the treatment of, i.e., simultaneously X compound when specifiedInterior daily dosage can be determined with method well known in the art.

In the sixth aspect of the present invention, the present invention also provides above compound or its pharmaceutically acceptable salt or containThe composition of above compound or its pharmaceutically acceptable salt is preparing the application in BTK inhibitor medicaments.

And the present invention also provides above compound or its pharmaceutically acceptable salt or containing above compound or itsApplication of the composition of pharmaceutically acceptable salt in the drug of preparation treatment lymphoma mantle cell.

Specific embodiment

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present inventionRather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional stripPart or according to the normal condition proposed by manufacturer.

Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the artJustice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen ZhongThe preferred implement methods and materials are for illustrative purposes only.

The embodiment of the present invention is carried out by synthetic route as follows:

The reagent and condition of said synthesis route: (a) diethy-aceto oxalate, sodium ethoxide, ethyl alcohol, 0 DEG C；(b) acetic acid, 80% waterConjunction hydrazine, ethyl alcohol, 90 DEG C；(c) 1-Boc-3- hydroxy piperidine, triphenylphosphine, DIAD, anhydrous THF, 0 DEG C；(d) reproducibility iron powder, chlorineChange ammonium, ethyl alcohol: water=3:1,90 DEG C of (e) pyridine carboxylic acids, HBTU, DMF, r.t.；(f) Lithium Aluminium Hydride, anhydrous THF, 0 DEG C；(g) denseHydrochloric acid, methylene chloride, r.t；(h) 3- or 4- nitrobenzyl bromine, potassium carbonate, DMF, r.t；(i) acryloyl chloride or chloracetyl chloride or trans-2- butyl chloride, THF, triethylamine, r.t；(j) sodium hydroxide, 1N hydrochloric acid, ethyl alcohol, r.t.

Synthesis step includes:

(1) starting material A-1, B-1 is respectively and diethy-aceto oxalate, sodium ethoxide generate intermediate A -2, B-2 in ethanol；

(2) intermediate A -2, B-2 are respectively with acetic acid, 80% hydrazine hydrate, and reaction generates intermediate A -3, B-3 in ethanol；

(3) intermediate A -3 is in anhydrous THF solution, and 1-Boc-3- hydroxy piperidine, triphenylphosphine, DIAD reaction, obtainsMesosome A-4；

(4) intermediate A -4 is in ethyl alcohol: in water=3:1 solution, with reproducibility iron powder, ammonium chloride reaction obtains intermediate A -5.

(5) intermediate A -5 is in DMF solution, and with pyridine carboxylic acid, HBTU reaction obtains intermediate A -6；

(6) intermediate B -3 is in anhydrous THF solution, and 1-Boc-3- hydroxy piperidine, triphenylphosphine, DIAD reaction, obtainsMesosome B-4；

(7) intermediate B -4 is reacted in anhydrous THF with Lithium Aluminium Hydride, obtains intermediate B -5；

(8) intermediate A -6, B-4, B-5 react respectively in dichloromethane solution with concentrated hydrochloric acid, take off Boc protecting group,Obtain intermediate C-1a, C-1b, C-1c；

(9) intermediate C-1, from triethylamine, different substitution acyl chloride reactions, obtains target product I-1~I- in THF solution12；

(10) target product I-1~I-3 reacts in methanol solution with sodium hydroxide, and dilute hydrochloric acid tune PH obtains target productI-13~I-15；

(11) intermediate A -3 is in ethyl alcohol: in water=3:1 solution, with reproducibility iron powder, ammonium chloride reaction obtains intermediate A -7；

(12) intermediate A -7 is reacted in anhydrous THF with Lithium Aluminium Hydride, obtains intermediate A -8；

(13) intermediate A -7, A-8 are respectively in DMF solution, and with pyridine carboxylic acid, HBTU reaction obtains intermediate A -9；

(14) intermediate B -3 is reacted in anhydrous THF with Lithium Aluminium Hydride, obtains intermediate B -6；

(15) intermediate A -9, B-3, B-6 be respectively in DMF solution, and 3- or 4- nitrobenzyl bromine, carbonic acid nak response, obtainsMesosome D-1a, D-1b, D-1c；

(16) intermediate D-1 is in ethyl alcohol: in water=3:1 solution, with reproducibility iron powder, ammonium chloride reaction obtains intermediate D-2；

(17) intermediate D-2 is in THF solution, and triethylamine, different substitution acyl chloride reactions, obtain target product II-1~II-23；

(18) target product II-1~II-8 reacts in methanol solution with sodium hydroxide, dilute hydrochloric acid tune PH, obtains target productionObject II-24~II-31；

In some embodiments of the present invention, compound I-1~I-15's the preparation method is as follows:

Synthetic route is as follows:

Reagent and condition: (a) diethy-aceto oxalate, sodium ethoxide, ethyl alcohol, 0 DEG C；(b) acetic acid, 80% hydrazine hydrate, ethyl alcohol, 90℃；(c) 1-Boc-3- hydroxy piperidine, triphenylphosphine, DIAD, anhydrous THF, 0 DEG C；(d) reproducibility iron powder, ammonium chloride, ethyl alcohol: water=3:1,90 DEG C of (e) pyridine carboxylic acids, HBTU, DMF, r.t.；(f) Lithium Aluminium Hydride, anhydrous THF, 0 DEG C；(g) concentrated hydrochloric acid, dichloromethaneAlkane, r.t；(h) acryloyl chloride or chloracetyl chloride or trans- 2- butyl chloride, THF, triethylamine；(i) sodium hydroxide, 1N hydrochloric acid, ethyl alcohol.

(i) raw material A -1, B-1 are dissolved in ethyl alcohol with diethy-aceto oxalate respectively, sodium ethoxide is added at 0 DEG C, reaction is finished, willReaction solution pours into ice water, and filtering, filter cake is washed with water, dry, obtains intermediate A -2, B-2 respectively；

(ii) intermediate A -2, B-2 are dissolved in ethyl alcohol respectively, 80% hydrazine hydrate of addition, a few drop acetic acid, 80 DEG C of reflux 3h,Evaporating solvent under reduced pressure obtains yellow solid intermediate A -3, B-3 respectively；

(II) intermediate A -3, B-3 are dissolved in anhydrous THF at 0 DEG C of triphenylphosphine respectively with 1-Boc-3- hydroxy piperidine, byIt is added dropwise to DIAD, reacts 3h.Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, respectivelyIntermediate A -4, B-4；

(iv) intermediate A -4 is dissolved in ethyl alcohol: in water=3:1 solution, iron powder, ammonium chloride, 90 DEG C of reaction 6h is added.ReactionFinish, filters while hot, remove filtrate solvent under reduced pressure, obtain intermediate A -5；

(v) raw material pyridine carboxylic acid is dissolved in DMF, triethylamine, HBTU is added, stirred 40 minutes, A-5 is added, reaction 12 is smallWhen.Reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is washed with water, dry, obtains intermediate A -6；

(vi) intermediate B -4 is dissolved in anhydrous THF, Lithium Aluminium Hydride is added under ice bath, be stirred at room temperature 15 minutes, slowly addedAmount water quenching is gone out, and is extracted with ethyl acetate, evaporating solvent under reduced pressure obtains intermediate B -5；

(vii) intermediate A -6, B-4, B-5 are dissolved in methylene chloride respectively, 4N hydrochloric acid 5ml is added, it is small to be stirred at room temperature 12When, evaporating solvent under reduced pressure obtains intermediate C-1a, C-1b, C-1c respectively；

(vII) intermediate C-1, triethylamine are dissolved in tetrahydrofuran, different substitution acyl chlorides is slowly added dropwise under ice bath, room temperature is stirredMix 4h.Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography, obtains target productionObject I1~I12；

(ix) target product I-1~I-3 is dissolved in methanol respectively, sodium hydroxide is added, 2h, dilute hydrochloric acid tune is stirred at room temperaturePH to 4~5, filtering, filter cake are washed with water, dry, obtain target product I-13~I-15 respectively.

In certain embodiments of the invention, compound II-1~II-12's the preparation method is as follows:

Synthetic route is as follows:

Reagent and condition: (a) Lithium Aluminium Hydride, anhydrous THF, 0 DEG C；(b) pyridine carboxylic acid, HBTU, DMF, r.t.；(c) 3- or4- nitrobenzyl bromine, potassium carbonate, DMF；(d) reproducibility iron powder, ammonium chloride, ethyl alcohol: water=3:1,90 DEG C of (e) acryloyl chlorides or chloroetheneAcyl chlorides or trans- 2- butyl chloride, THF, triethylamine；(f) sodium hydroxide, 1N hydrochloric acid, ethyl alcohol

(i) intermediate A -3 is in ethyl alcohol: in water=3:1 solution, with reproducibility iron powder, ammonium chloride reaction obtains intermediate A -7

(ii) intermediate A -7, B-3 are dissolved in anhydrous THF respectively, Lithium Aluminium Hydride is added under ice bath, is stirred at room temperature 15 minutes,Slowly plus excessive water is quenched, and is extracted with ethyl acetate, evaporating solvent under reduced pressure, obtains intermediate A -8, B-6 respectively；

(iii) raw material pyridine carboxylic acid is dissolved in DMF, triethylamine, HBTU is added, stirred 40 minutes, be separately added into A-8, A-7, it reacts 12 hours.Reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is washed with water, dry, obtains intermediate A-respectively9a,A-9b；

(iv) intermediate A -9, B-3, B-6 are dissolved in DMF respectively, potassium carbonate is added, slowly adds 3- or 4- nitrobenzyl bromine, roomTemperature stirring 8h, reaction solution is poured into ice water, is filtered, and filter cake is washed with water, dry, obtains intermediate D-1a, D-1b, D- respectively1c；

(v) intermediate D-1 is dissolved in ethyl alcohol: in water=3:1 solution, iron powder, ammonium chloride, 90 DEG C of reaction 6h is added.ReactionFinish, filters while hot, remove filtrate solvent under reduced pressure, obtain intermediate D-2；

(vi) intermediate D-2, triethylamine are dissolved in tetrahydrofuran, different substitution acyl chlorides is slowly added dropwise under ice bath, room temperature is stirredMix 4h.Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography, obtains target productionObject II-1~II-23；

(vi) target product II-1~II-23 is dissolved in methanol, sodium hydroxide is added, 2h, dilute hydrochloric acid tune is stirred at room temperaturePH to 4~5, filtering, filter cake are washed with water, dry, obtain target product II-24~II-31.

The preparation of 1. intermediate A -6 of embodiment

1) 4- (4- nitrobenzophenone) -2,4- diketone-ethyl butyrate (A-2) synthesis

Raw material p-nitroacetophenone (A-1,12mmol) and diethy-aceto oxalate (24mmol) are dissolved in ethyl alcohol, added at 0 DEG CEntering sodium ethoxide (24mmol), reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is washed with water, and it is dry, obtain intermediate A-2.Yellow solid, yield 94.6%.

2) synthesis of 3- (4- nitrobenzophenone) -1H- pyrazole-5-ethyl formate (A-3)

Intermediate A -2 (24mmol) is dissolved in ethyl alcohol, is added 80% hydrazine hydrate (48mmol), ten drop acetic acid, 80 DEG C are returned3h is flowed, evaporating solvent under reduced pressure obtains intermediate A -3.Yellow solid, yield 89.2%.

3) synthesis of 1- (1-boc piperazine -3- base) -3- (4- nitrobenzophenone) -1H- pyrazole-5-ethyl formate (A-4)

By intermediate A -3 (9.6mmol) respectively with 1-Boc-3- hydroxy piperidine (14.4mmol), triphenylphosphineIt is dissolved in anhydrous THF at 0 DEG C of (28.8mmol), is added dropwise DIAD (28.8mmol), 3h is reacted.Reaction is finished, and reaction solution is poured intoIn water, be extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography, elution system be petrol ether/ethyl acetate=30:1~15:1~8:1~4:1~1:1, obtains intermediate A -4.Yellow solid, yield 93.5%.

4) synthesis of 1- (1-boc piperazine -3- base) -3- (4- aminophenyl) -1H- pyrazole-5-ethyl formate (A-5)

Intermediate A -4 (4.5mmol) is dissolved in ethyl alcohol: in water=3:1 solution, being added iron powder (18mmol), ammonium chloride(9mmol), 90 DEG C of reaction 6h.Reaction is finished, and is filtered while hot, is removed filtrate solvent under reduced pressure, obtains intermediate A -5.Yellow solid, yieldIt is 95%.

5) 1- (1-boc piperazine -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate (A-6)Synthesis

Raw material pyridine carboxylic acid (4mmol) is dissolved in DMF, triethylamine (11mmol), HBTU (4mmol) is added, stirs 40 pointsClock is added A-5 (3.6mmol), reacts 12 hours.Reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is washed with water, and is doneIt is dry, obtain intermediate A -6；Yellow solid, yield 78.3%.

The preparation of 2. intermediate B -4 of embodiment

1) 4- (4- Phenoxyphenyl) -2,4- diketone-ethyl butyrate (B-2) synthesis

Raw material 4- metaphenoxy acetophenone (B-1,12mmol) and diethy-aceto oxalate (24mmol) are dissolved in ethyl alcohol, at 0 DEG CIt being added sodium ethoxide (24mmol), reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is washed with water, and it is dry, obtain intermediateB-2.Yellow solid, yield 92.5%.

2) synthesis of 3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (B-3)

Intermediate B -2 (24mmol) is dissolved in ethyl alcohol, is added 80% hydrazine hydrate (48mmol), ten drop acetic acid, 80 DEG C are returned3h is flowed, evaporating solvent under reduced pressure obtains intermediate B -3.Yellow solid, yield 85.3%.

3) synthesis of 1- (1-boc piperazine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (B-4)

By intermediate A -3 (9.6mmol) respectively with 1-Boc-3- hydroxy piperidine (14.4mmol), triphenylphosphineIt is dissolved in anhydrous THF at 0 DEG C of (28.8mmol), is added dropwise DIAD (28.8mmol), 3h is reacted.Reaction is finished, and reaction solution is poured intoIn water, be extracted with ethyl acetate, evaporating solvent under reduced pressure, silica gel column chromatography, elution system be petrol ether/ethyl acetate=30:1~15:1~8:1~4:1~1:1, obtains intermediate B -4.Yellow solid, yield 90.2%.

The preparation of 3. target compound B-5 of embodiment

1) synthesis of 1- (1-boc piperazine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (B-5)

Intermediate B -4 (15.3mmol) is dissolved in anhydrous THF, Lithium Aluminium Hydride (61.2mmol) is added under ice bath, room temperature is stirredIt mixes 15 minutes, slowly plus excessive water is quenched, and is extracted with ethyl acetate, evaporating solvent under reduced pressure obtains intermediate B -5.Yellow solid is receivedRate is 90.5%.

The preparation of 4. target compound I-1~I-15 of embodiment

1) synthesis of intermediate C-1

Intermediate A -6, B-4, B-5 (3.5mmol) are dissolved in methylene chloride respectively, 4N hydrochloric acid 5ml is added, is stirred at room temperature 12Hour, evaporating solvent under reduced pressure obtains intermediate C-1a, C-1b, C-1c respectively.

C-1a:1- (piperazine -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.Yellow is solidBody, yield 90.0%.

C-1b:1- (piperazine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.Yellow solid, yieldIt is 93.5%.

C-1c:1- (piperazine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.Yellow solid, yield are94.7%.

2) method is led in the synthesis of target product I1~I12

Intermediate C-1 (0.5mmol), triethylamine (1.5mmol) are dissolved in tetrahydrofuran, difference is slowly added dropwise under ice bath and takesFor acyl chlorides (0.6mmol), 4h is stirred at room temperature.Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, is removed under reduced pressure moltenAgent, silica gel column chromatography, elution system are petrol ether/ethyl acetate=5/1, obtain target product I1~I12.

I-1:1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate, whiteSolid, 108-110 DEG C of fusing point, yield 88.2%.¹H NMR(400MHz,CDCl₃) δ 7.77 (d, J=8.6Hz, 2H), 7.35(t, J=7.9Hz, 2H), 7.16-7.00 (m, 6H), 6.67-6.55 (m, 1H), 6.29 (d, J=16.8Hz, 1H), 5.68 (t, J=9.8Hz, 1H), 5.18 (s, 1H), 4.86 (d, J=11.7Hz, 0.5H), 4.62 (d, J=12.2Hz, 0.5H), 4.37 (q, J=7.0Hz, 2H), 4.22 (d, J=12.3Hz, 0.5H), 4.01 (d, J=12.4Hz, 0.5H), 3.61 (t, J=11.5Hz,0.5H), 3.33 (t, J=10.0Hz, 0.5H), 3.17 (t, J=12.8Hz, 0.5H), 2.83 (t, J=11.9Hz, 0.5H),2.33 (d, J=11.9Hz, 1H), 2.01-1.90 (m, 1H), 1.70 (dt, J=20.8,7.3Hz, 2H), 1.40 (t, J=7.1Hz,3H).¹³C NMR(101MHz,CDCl₃)δ165.81(s),159.72(s),159.63(s),157.29(s),157.16(s),149.72(s),133.41(s),129.79(s),127.836(s),127.81(s),127.11(s),123.39(s),119.11(s),118.90(s),107.89(s),61.26(s),56.69(s),55.72(s),51.02(s),46.80(s),46.01(s),42.25(s),31.34(s),30.93(s),25.30(s),24.03(s),14.28(s).

I-2:1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White solid, 127-130 DEG C of fusing point, yield 84.2%.¹H NMR(400MHz,CDCl₃) δ 7.77 (d, J=8.5Hz, 2H),7.35 (t, J=7.8Hz, 2H), 7.16-6.98 (m, 6H), 6.93-6.80 (m, 1H), 6.32 (d, J=14.4Hz, 1H), 5.16(s, 1H), 4.86 (d, J=12.1Hz, 0.5H), 4.63 (d, J=10.9Hz, 0.5H), 4.37 (d, J=6.4Hz, 2H), 4.23(d, J=12.8Hz, 0.5H), 4.02 (d, J=8.6Hz, 0.5H), 3.66-3.53 (m, 0.5H), 3.36-3.24 (m, 0.5H),3.21–3.09(m,0.5H),2.82–2.71(m,0.5H),2.25(s,2H),1.87(s,3H),1.65(s,2H),1.40(t,J=6.8Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ166.01(s),159.68(s),157.15(s),149.64(s),141.65(s),141.54(s),133.43(s),129.79(s),127.79(s),127.11(s),123.36(s),121.79(s),119.12(s),118.88(s),107.89(s),61.21(s),56.84(s),55.81(s),50.91(s),46.76(s),45.89(s),42.18(s),31.39(s),31.10(s),25.32(s),24.13(s),18.25(s),14.27(s).

I-3:1- (1- chloracetyl piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.WhiteSolid, 125-128 DEG C of fusing point, yield 85.7%.¹H NMR(400MHz,CDCl₃) δ 10.12 (s, 1H), 8.64 (d, J=4.6Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 7.93 (t, J=7.7Hz, 1H), 7.90-7.80 (m, 4H), 7.54-7.48(m, 1H), 7.14 (d, J=12.6Hz, 1H), 5.27-5.17 (m, 1H), 4.77 (dd, J=12.7,3.7Hz, 0.5H), 4.53(d, J=12.8Hz, 0.5H), 4.39 (dd, J=14.0,6.9Hz, 2H), 4.26 (d, J=12.5Hz, 0.5H), 4.18-4.04(m, 2H), 3.90 (d, J=13.1Hz, 0.5H), 3.63 (dd, J=13.2,10.3Hz, 0.5H), 3.40-3.32 (m, 0.5H),3.23 (d, J=12.0Hz, 0.5H), 2.85 (td, J=12.9,2.6Hz, 0.5H), 2.41 (ddd, J=15.2,12.5,3.8Hz, 0.5H), 2.25 (d, J=11.7Hz, 1H), 1.99 (dd, J=17.2,14.0Hz, 1H), 1.84-1.64 (m,1.5H),1.46–1.35(m,3H).¹³C NMR(101MHz,CDCl₃)δ165.46(s),165.17(s),159.86(s),157.38(s),157.21(s),157.09(s),149.83(s),133.40(s),129.81(s),127.63(s),127.11(s),123.45(s),123.36(s),119.11(s),118.96(s),118.89(s),107.90\9(s),107.82(s),61.40(s),61.26(s),56.55(s),55.56(s),51.43(s),46.89(s),46.51(s),42.63(s),41.31(s),41.16(s),31.05(s),30.47(s),24.97(s),23.87(s),14.28(s).

I-4:1- (1- acryloylpiperidine -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid secondEster.White solid, 155-158 DEG C of fusing point, yield 83.6%.¹H NMR(400MHz,CDCl₃)δ10.11(s,1H),8.63(d, J=4.6Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 7.93 (t, J=7.7Hz, 1H), 7.89-7.81 (m, 4H), 7.50(dd, J=7.0,5.3Hz, 1H), 7.14 (d, J=7.4Hz, 1H), 6.64 (dt, J=22.1,11.1Hz, 1H), 6.29 (d, J=16.7Hz, 1H), 5.69 (t, J=11.4Hz, 1H), 5.26-5.14 (m, 1H), 4.88 (d, J=13.0Hz, 0.5H), 4.65(d, J=12.7Hz, 0.5H), 4.45-4.30 (m, 2H), 4.23 (d, J=12.6Hz, 0.5H), 4.02 (d, J=16.3Hz,0.5H), 3.67-3.58 (m, 0.5H), 3.42-3.30 (m, 0.5H), 3.24-3.14 (m, 0.5H), 2.82 (t, J=11.8Hz,0.5H), 2.41-2.19 (m, 2H), 1.97 (d, J=13.8Hz, 1H), 1.70 (d, J=12.4Hz, 1H), 1.41 (t, J=6.9Hz,3H).¹³C NMR(101MHz,CDCl₃)δ165.86(s),161.98(s),159.73(s),149.76(s),148.00(s),137.76(s),133.37(s),128.83(s),128.57(s),127.88(s),127.83(s),126.53(s),126.34(s),122.43(s),119.79(s),107.99(s),107.85(s),61.27(s),61.19(s),56.73(s),51.02(s),46.82(s),46.01(s),42.25(s),31.33(s),30.96(s),25.32(s),24.06(s),14.28(s).

I-5:1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- firstAcetoacetic ester.White solid, 153-155 DEG C of fusing point, yield 81.9%.¹H NMR(400MHz,CDCl₃)δ10.11(s,1H),8.64 (d, J=4.6Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 7.93 (t, J=8.3Hz, 1H), 7.85 (s, 4H), 7.50(dd, J=7.2,5.5Hz, 1H), 7.14 (d, J=9.5Hz, 1H), 6.95-6.79 (m, 1H), 6.34 (d, J=15.2Hz,1H), 5.25-5.09 (m, 1H), 4.87 (dd, J=6.6,4.9Hz, 0.5H), 4.65 (d, J=11.7Hz, 0.5H), 4.38 (d,J=6.8Hz, 2H), 4.25 (d, J=11.6Hz, 0.5H), 4.10-3.97 (m, 0.5H), 3.67-3.56 (m, 0.5H), 3.38-3.26 (m, 0.5H), 3.20-3.09 (m, 1H), 2.82-2.71 (m, 0.5H), 2.30 (d, J=25.4Hz, 2H), 2.03-1.79(m, 4H), 1.69 (d, J=12.5Hz, 1H), 1.41 (t, J=6.7Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ166.01(s),161.98(s),159.69(s),149.76(s),148.00(s),141.73(s),141.57(s),137.75(s),133.39(s),126.53(s),126.33(s),122.43(s),121.82(s),119.79(s),119.79(s),107.98(s),61.22(s),56.86(s),55.79(s),50.91(s),46.80(s),45.87(s),42.21(s),31.15(s),29.73(s),25.42(s),24.17(s),18.27(s),14.28(s).

I-6:1- (1- chloracetyl piperidines -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid secondEster.White solid, 163-165 DEG C of fusing point, yield 87.9%.¹H NMR(400MHz,CDCl₃)δ10.12(s,1H),8.64(d, J=4.6Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 7.93 (t, J=7.7Hz, 1H), 7.90-7.80 (m, 4H), 7.54-7.48 (m, 1H), 7.14 (d, J=12.6Hz, 1H), 5.27-5.17 (m, 1H), 4.77 (dd, J=12.7,3.7Hz, 0.5H),4.53 (d, J=12.8Hz, 0.5H), 4.39 (dd, J=14.0,6.9Hz, 2H), 4.26 (d, J=12.5Hz, 0.5H), 4.18-4.04 (m, 2H), 3.90 (d, J=13.1Hz, 0.5H), 3.63 (dd, J=13.2,10.3Hz, 0.5H), 3.40-3.32 (m,0.5H), 3.23 (d, J=12.0Hz, 0.5H), 2.85 (td, J=12.9,2.6Hz, 0.5H), 2.41 (ddd, J=15.2,12.5,3.8Hz, 0.5H), 2.25 (d, J=11.7Hz, 1H), 1.99 (dd, J=17.2,14.0Hz, 1H), 1.84-1.64 (m,1.5H),1.46–1.35(m,3H).¹³C NMR(101MHz,CDCl₃)δ165.45(s),162.00(s),159.87(s),149.89(s),149.73(s),148.01(s),137.76(s),133.38(s),128.47(s),126.56(s),126.34(s),122.43(s),119.83(s),119.77(s),108.08(s),61.38(s),61.23(s),56.61(s),55.57(s),51.44(s),46.90(s),46.50(s),42.63(s),41.33(s),41.17(s),31.04(s),30.49(s),24.98(s),23.92(s),14.27(s).

I-7:1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.White solid,182-185 DEG C of fusing point, yield 84.8%.¹H NMR(400MHz,CDCl₃) δ 7.69 (s, 2H), 7.27 (t, J=7.2Hz,2H), 7.06 (d, J=18.4Hz, 2H), 6.96 (d, J=7.7Hz, 3H), 6.64-6.51 (m, 1H), 6.26 (dd, J=34.7,16.6Hz, 1H), 5.66 (dd, J=36.1,10.4Hz, 1H), 5.23 (dd, J=15.3,6.8Hz, 1H), 4.81 (d, J=10.5Hz, 0.5H), 4.61 (d, J=12.0Hz, 0.5H), 4.19 (d, J=13.3Hz, 0.5H), 3.96 (d, J=14.0Hz,0.5H), 3.63-3.54 (m, 0.5H), 3.36-3.26 (m, 0.5H), 3.17 (t, J=13.4Hz, 0.5H), 2.76 (t, J=12.6Hz, 0.5H), 2.21 (d, J=6.4Hz, 2H), 1.90 (dd, J=26.9,11.9Hz, 1H), 1.68 (d, J=12.5Hz,1H).¹³C NMR(101MHz,CDCl₃)δ166.97(s),166.32(s),161.78(s),157.13(s),149.83(s),149.61(s),129.79(s),127.81(s),127.10(s),123.41(s),123.33(s),119.11(s),118.92(s),118.89(s),108.65(s),108.54(s),56.68(s),55.52(s),51.28(s),47.71(s),46.50(s),42.73(s),31.07(s),30.90(s),25.27(s),23.95(s),12.73(s).

I-8:1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.WhiteSolid, 95-100 DEG C of fusing point, yield 80.4%.¹H NMR(400MHz,CDCl₃) δ 7.77 (d, J=8.5Hz, 2H), 7.35(t, J=7.8Hz, 2H), 7.16-6.98 (m, 6H), 6.93-6.80 (m, 1H), 6.32 (d, J=14.4Hz, 1H), 5.16 (s,1H), 4.86 (d, J=12.1Hz, 0.5H), 4.63 (d, J=10.9Hz, 0.5H), 4.23 (d, J=12.8Hz, 0.5H), 4.02(d, J=8.6Hz, 0.5H), 3.66-3.55 (m, 0.5H), 3.36-3.23 (m, 0.5H), 3.27-3.09 (m, 0.5H), 2.82-2.71(m,0.5H),2.25(s,2H),1.87(s,3H),1.65(s,2H).¹³C NMR(101MHz,CDCl₃)δ166.01(s),159.68(s),157.15(s),149.64(s),141.65(s),141.54(s),134.43(s),129.79(s),127.79(s),126.51(s),123.38(s),121.59(s),119.12(s),118.88(s),105.89(s),56.84(s),55.81(s),50.91(s),47.66(s),45.89(s),42.18(s),31.35(s),31.10(s),25.32(s),24.13(s),18.23(s).

I-9:1- (1- chloracetyl piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.White solid,175-178 DEG C of fusing point, yield 84.7%.¹H NMR(400MHz,CDCl₃) δ 7.76 (dd, J=8.4,4.6Hz, 2H), 7.35(t, J=7.1Hz, 2H), 7.19 (d, J=13.7Hz, 1H), 7.12 (t, J=7.3Hz, 1H), 7.05 (t, J=7.4Hz, 4H),5.34-5.21 (m, 1H), 4.78 (dd, J=12.6,3.4Hz, 0.5H), 4.58 (d, J=12.8Hz, 0.5H), 4.33-4.17(m, 2H), 4.10 (d, J=12.9Hz, 0.5H), 3.91 (d, J=13.1Hz, 0.5H), 3.63 (dd, J=13.1,10.6Hz,0.5H), 3.39 (t J=11.9Hz, 0.5H), 3.28 (t, J=11.9Hz, 0.5H), 2.86 (t, J=11.5Hz, 0.5H),2.41 (dq, J=15.7,3.9Hz, 0.5H), 2.28-2.23 (m, 1.5H), 2.06-1.94 (m, 1H), 1.88-1.65 (m,1H).¹³C NMR(101MHz,CDCl₃)δ166.82(s),162.26(s),157.47(s),157.02(s),150.10(s),132.88(s),129.82(s),127.47(s),127.15(s),123.49(s),119.10(s),119.00(s),109.05(s),56.63(s),51.70(s),46.75(s),41.42(s),30.45(s),23.91(s).

I-10:1- (1- acryloylpiperidine -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid is whiteColor solid, 190-193 DEG C of fusing point, yield 82.1%.¹H NMR(400MHz,CDCl₃) δ 10.10 (s, 1H), 8.63 (d, J=4.2Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 7.93 (t, J=7.5Hz, 1H), 7.84 (d, J=8.9Hz, 4H), 7.50 (s,1H), 7.17 (d, J=34.3Hz, 1H), 7.02-6.84 (m, 1H), 6.36 (d, J=15.0Hz, 1H), 5.28 (d, J=29.0Hz, 1H), 4.86 (d, J=11.7Hz, 0.5H), 4.71 (d, J=13.5Hz, 0.5H), 4.30 (d, J=12.9Hz,0.5H), 4.05 (d, J=11.8Hz, 0.5H), 3.75-3.64 (m, 0.5H), 3.46-3.35 (m, 0.5H), 3.31-3.16 (m,0.5H), 2.78 (dd, J=18.1,12.0Hz, 0.5H), 2.27 (s, 2.5H), 2.00 (d, J=12.1Hz, 0.5H), 1.80-1.68(m,1H).¹³C NMR(101MHz,CDCl₃)δ167.11(s),166.55(s),162.02(s),149.76(s),148.00(s),143.35(s),142.52(s),137.76(s),128.73(s),126.52(s),126.33(s),122.48(s),121.63(s),121.13(s),119.89(s),108.61(s),56.75(s),55.42(s),51.03(s),47.49(s),46.31(s),42.73(s),31.40(s),31.22(s),25.20(s),24.03(s).

I-11:1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- firstAcid.White solid, 213-215 DEG C of fusing point, yield 85.7%.¹H NMR(400MHz,CDCl₃)δ10.10(s,1H),8.63(d, J=4.2Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 7.93 (t, J=7.5Hz, 1H), 7.84 (d, J=8.9Hz, 4H),7.50 (s, 1H), 7.17 (d, J=34.3Hz, 1H), 7.02-6.84 (m, 1H), 6.36 (d, J=15.0Hz, 1H), 5.28 (d, J=29.0Hz, 1H), 4.86 (d, J=11.7Hz, 0.5H), 4.71 (d, J=13.5Hz, 0.5H), 4.30 (d, J=12.9Hz,0.5H), 4.05 (d, J=11.8Hz, 0.5H), 3.75-3.64 (m, 0.5H), 3.46-3.35 (m, 0.5H), 3.31-3.16 (m,0.5H), 2.78 (dd, J=18.1,12.0Hz, 0.5H), 2.27 (s, 2.5H), 2.00 (d, J=12.1Hz, 0.5H), 1.89(dd, J=25.3,6.2Hz, 3H), 1.80-1.68 (m, 1H)¹³C NMR(101MHz,CDCl₃)δ167.11(s),166.55(s),162.02(s),149.76(s),148.00(s),143.35(s),142.52(s),137.76(s),128.73(s),126.52(s),126.33(s),122.48(s),121.63(s),121.13(s),119.89(s),108.61(s),56.75(s),55.42(s),51.03(s),47.49(s),46.31(s),42.73(s),31.40(s),31.22(s),25.20(s),24.03(s),18.40(s).

I-12:1- (1- chloracetyl piperidines -3- base) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid.It is whiteColor solid, 165-167 DEG C of fusing point, yield 89.0%.¹H NMR(400MHz,CDCl₃) δ 10.12 (s, 1H), 8.64 (d, J=4.5Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 7.93 (t, J=7.7Hz, 1H), 7.88-7.79 (m, 3H), 7.55-7.46(m, 1H), 7.23 (d, J=13.1Hz, 1H), 5.26 (dd, J=12.9,8.8Hz, 1H), 4.79 (dd, J=12.7,3.3Hz,0.5H), 4.58 (d, J=13.5Hz, 0.5H), 4.19 (ddd, J=33.4,27.6,12.3Hz, 3H), 3.91 (d, J=14.0Hz, 0.5H), 3.64 (dd, J=13.2,10.5Hz, 0.5H), 3.41-3.22 (m, 1.5H), 2.90-2.80 (m, 1H),2.49-2.36 (m, 0.5H), 2.00 (dd, J=31.9,14.9Hz, 1H), 1.76-1.63 (m, 1H)¹³C NMR(101MHz,CDCl₃)δ166.43(s),162.10(s),161.76(s),150.07(s),149.74(s),148.01(s),137.79(s),132.92(s),128.48(s),126.58(s),126.37(s),122.51(s),119.99(s),119.92(s),109.02(s),56.65(s),55.62(s),51.63(s),51.45(s),46.73(s),42.95(s),41.41(s),41.06(s),30.47(s),23.93(s).

3) method is led in the synthesis of target product I13~I15

Target product I-1~I-3 (0.5mmol) is dissolved in methanol respectively, is added sodium hydroxide (10mmol), room temperature is stirred2h, dilute hydrochloric acid tune PH to 4~5 to be mixed, is filtered, filter cake is washed with water, and it is dry, target product I-13~I-15 is obtained respectively.

I-13:1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White is solidBody, 67-70 DEG C of fusing point, yield 85.2%.¹H NMR (400MHz, DMSO) δ 7.78 (d, J=8.3Hz, 2H), 7.40 (t, J=7.9Hz, 2H), 7.15 (t, J=7.4Hz, 1H), 7.03 (dd, J=8.4,2.1Hz, 4H), 6.91-6.74 (m, 1H), 6.59(s, 1H), 6.11 (t, J=17.9Hz, 1H), 5.67 (dd, J=33.2,10.3Hz, 1H), 5.44-5.35 (m, 1H), 4.60-4.53(m,2.5H),4.41–4.31(m,1H),4.29-4.20(m,1H),4.14–4.04(m,0.5H),3.51–3.41(m,0.5H), 3.15-3.02 (m, 1H), 2.81 (t, J=12.8Hz, 0.5H), 2.23-2.08 (m, 2H), 1.88 (d, J=11.9Hz,1H),1.59-1.48(m,1H).¹³C NMR(101MHz,DMSO)δ165.00(s),157.13(s),156.40(s),148.76(s),144.30(s),130.55(s),129.46(s),128.81(s),127.75(s),127.17(s),123.94(s),119.27(s),119.03(s),102.67(s),55.02(s),54.07(s),50.97(s),47.04(s),31.20(s),25.49(s).

I-14:1- [1- (trans- 2- bytyry) piperidines -3- base] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.It is whiteColor solid, 65-67 DEG C of fusing point, yield 89.6%.¹H NMR (400MHz, DMSO) δ 7.78 (d, J=8.6Hz, 2H), 7.40(t, J=7.9Hz, 2H), 7.15 (t, J=7.4Hz, 1H), 7.03 (d, J=7.3Hz, 4H), 6.68 (ddd, J=22.4,15.2,7.6Hz, 1H), 6.62-6.49 (m, 2H), 5.44 (d, J=19.1Hz, 1H), 4.55 (d, J=8.6Hz, 3H), 4.43-4.19 (m, 2H), 4.10 (d, J=12.6Hz, 1H), 3.07 (dd, J=26.1,12.9Hz, 1H), 2.72 (t, J=11.9Hz,1H), 2.17 (dd, J=29.1,22.1Hz, 2H), 1.82 (dd, J=24.6,5.5Hz, 4H), 1.50 (s, 1H)¹³C NMR(101MHz,DMSO)δ165.10(s),157.13(s),156.40(s),148.74(s),144.30(s),141.57(s),130.55(s),129.47(s),127.17(s),123.94(s),122.58(s),119.28(s),119.02(s),102.66(s), 54.17 (d, J=19.0Hz), 50.91 (s), 49.07 (s), 45.52 (s), 30.91 (s), 24.28 (s)

I-15:1- (1- chloracetyl piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White is solidBody, 60-65 DEG C of fusing point, yield 65-68%.¹H NMR(400MHz,CDCl₃) δ 7.73 (d, J=8.4Hz, 2H), 7.34 (t, J=7.3Hz, 2H), 7.10 (t, J=6.8Hz, 1H), 7.04-7.01 (m, 4H), 6.44 (d, J=4.7Hz, 1H), 4.76-4.67(m, 2.5H), 4.51 (d, J=12.9Hz, 0.5H), 4.42-4.36 (m, 0.5H), 4.33-4.26 (m, 0.5H), 4.14-4.01(m, 2.5H), 3.87 (d, J=13.4Hz, 0.5H), 3.69-3.61 (m, 0.5H), 3.25-3.18 (m, 1H), 2.80 (t, J=11.5Hz, 0.5H), 2.45-2.35 (m, 1H), 2.20 (t, J=10.2Hz, 1H), 2.06-1.91 (m, 1H), 1.80-1.60(m,2H).¹³C NMR(101MHz,CDCl₃)δ165.37(s),157.25(s),156.91(s),150.10(s),142.38(s),129.77(s),128.66(s),127.04(s),123.28(s),119.18(s),118.80(s),102.88(s),55.13(s),51.66(s),47.72(s),42.51(s),41.14(s),30.65(s),29.72(s),23.95(s).

The preparation of 5. intermediate A -8 of embodiment

1) synthesis of 3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate (A-7)

Intermediate A -3 (15.3mmol) is dissolved in anhydrous THF, Lithium Aluminium Hydride (61.2mmol) is added under ice bath, room temperature is stirredIt mixes 15 minutes, slowly plus excessive water is quenched, and is extracted with ethyl acetate, evaporating solvent under reduced pressure obtains intermediate A -7.White solid is receivedRate is 80.0%.

2) synthesis of intermediate A -8

Raw material pyridine carboxylic acid (4mmol) is dissolved in DMF, triethylamine (11mmol), HBTU (4mmol) is added, stirs 40 pointsClock is separately added into A-3, A-7 (3.6mmol), is reacted 12 hours.Reaction is finished, and reaction solution is poured into ice water, is filtered, and filter cake is usedWater washing, it is dry, intermediate A -8a, A-8b are obtained respectively；

A-8a:3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- methyl formate.White solid, yield 78.5%.

A-8b:3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid.White solid, yield 71.4%.

The preparation of 6. intermediate B -6 of embodiment

1) synthesis of 3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol (B-6)

Intermediate B -3 (15.3mmol) is dissolved in anhydrous THF, Lithium Aluminium Hydride (61.2mmol) is added under ice bath, room temperature is stirredIt mixes 15 minutes, slowly plus excessive water is quenched, and is extracted with ethyl acetate, evaporating solvent under reduced pressure obtains intermediate B -6.White solid is receivedRate is 85.3%.

The preparation of 7. target compound II-1~II-25 of embodiment

2) method is led in the synthesis of intermediate D-1

Intermediate A -8, B-3, B-6 (5.1mmol) are dissolved in DMF respectively, are added potassium carbonate (7.6mmol), slowly plus 3-Or 4- nitrobenzyl bromine (6.1mmol), 8h is stirred at room temperature, reaction solution is poured into ice water, filters, filter cake is washed with water, and it is dry, pointIntermediate D-1a, D-1b, D-1c, column chromatographic purifying, elution system DCM/MeOH=150/1 are not obtained

D-1aa:1- (3- nitrobenzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, yield 90.5%.

D-1ab:1- (4- nitrobenzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, yield 94.2%.

D-1ba:1- (3- nitrobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White solid is receivedRate is 92.7%.

D-1bb:1- (4- nitrobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White solid is receivedRate is 92.5%.

D-1ca:1- (3- nitrobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White solid, yield are91.4%.

D-1cb:1- (4- nitrobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White solid, yield are89.4%.

3) method is led in the synthesis of intermediate D-2

Intermediate D-1 (4.5mmol) is dissolved in ethyl alcohol: in water=3:1 solution, being added iron powder (18mmol), ammonium chloride(9mmol), 90 DEG C of reaction 6h.Reaction is finished, and is filtered while hot, is removed filtrate solvent under reduced pressure, obtains intermediate D-2,

D-2a:1- (3- aminobenzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, yield 94.5%.

D-2b:1- (4- aminobenzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, yield 95.1%.

D-2c:1- (3- aminobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White solid, yieldIt is 91.4%.

D-2d:1- (4- aminobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White solid, yieldIt is 92.5%.

D-2e:1- (3- aminobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White solid, yield are89.2%.

D-2f:1- (4- aminobenzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White solid, yield are86.3%.

4) method is led in the synthesis of target product II-1~II-23

Intermediate D-2 (0.5mmol), triethylamine (1.5mmol) are dissolved in tetrahydrofuran, difference is slowly added dropwise under ice bath and takesFor acyl chlorides (0.6mmol), 4h is stirred at room temperature.Reaction is finished, and reaction solution is poured into water, is extracted with ethyl acetate, is removed under reduced pressure moltenAgent, column chromatographic purifying, elution system DCM/MeOH=150/1 obtain target product II-1~II-23；

II-1:1- (4- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, 156-159 DEG C of fusing point, yield 85.8%.¹H NMR(400MHz,CDCl₃) δ 7.79 (d, J=8.6Hz, 2H), 7.50 (d,J=8.4Hz, 3H), 7.34 (t, J=7.9Hz, 2H), 7.27-7.24 (m, 2H), 7.14-7.08 (m, 1H), 7.04 (dd, J=8.1,4.4Hz, 4H), 6.39 (d, J=16.8Hz, 1H), 6.21 (dd, J=16.8,10.2Hz, 1H), 5.75 (s, 2H), 5.72(d, J=10.3Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 1.35 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ163.51(s),159.62(s),157.27(s),157.11(s),149.85(s),137.23(s),133.39(s),133.32(s),131.08(s),129.81(s),128.34(s),127.92(s),127.80(s),127.15(s),123.40(s),120.03(s),119.09(s),118.95(s),108.30(s),61.19(s),54.63(s),14.25(s).

II-2:1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.It is whiteColor solid, 138-140 DEG C of fusing point, yield 87.3%.¹H NMR(400MHz,CDCl₃) δ 7.79 (d, J=8.6Hz, 2H),7.48 (d, J=7.7Hz, 2H), 7.34 (t, J=7.9Hz, 2H), 7.29-7.05 (m, 3H), 7.13-7.09 (m, 1H), 7.04(dd, J=8.2,4.4Hz, 4H), 6.95 (dq, J=13.8,6.8Hz, 1H), 5.91 (d, J=15.1Hz, 1H), 5.74 (s,2H), 4.31 (q, J=7.1Hz, 2H), 1.87 (d, J=6.9Hz, 3H), 1.35 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ159.61(s),157.24(s),157.13(s),149.80(s),141.72(s),137.51(s),133.36(s),133.02(s),129.80(s),128.35(s),127.85(s),127.15(s),125.29(s),123.38(s),119.94(s),119.86(s),119.09(s),118.93(s),108.27(s),61.16(s),54.64(s),17.87(s),14.25(s).

II-3:1- (4- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, 127-130 DEG C of fusing point, yield 87.8%.¹H NMR(400MHz,CDCl₃) δ 8.19 (s, 1H), 7.79 (d, J=8.7Hz,2H), 7.48 (d, J=8.5Hz, 2H), 7.38-7.25 (m, 4H), 7.14-7.10 (m, 1H), 7.05 (dd, J=8.1,5.3Hz,4H), 5.77 (s, 2H), 4.32 (q, J=7.1Hz, 2H), 4.16 (s, 2H), 1.36 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ163.76(s),159.59(s),157.29(s),157.12(s),149.87(s),136.10(s),134.17(s),133.37(s),129.80(s),128.49(s),127.77(s),127.16(s),123.39(s),120.21(s),119.09(s),118.95(s),108.28(s),61.18(s),54.57(s),42.85(s),14.25(s).

II-4:1- (4- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.White solid, 243-245 DEG C of fusing point, yield 88.4%.¹H NMR(400MHz,DMSO)δ10.74(s,1H),10.19(s,1H), 8.76 (d, J=4.3Hz, 1H), 8.18 (d, J=7.8Hz, 1H), 8.08 (t, J=8.3Hz, 1H), 7.99 (d, J=8.6Hz, 2H), 7.88 (d, J=8.6Hz, 2H), 7.72-7.66 (m, 1H), 7.62 (d, J=8.4Hz, 2H), 7.41 (s, 1H),7.20 (d, J=8.5Hz, 2H), 6.42 (dd, J=16.9,10.1Hz, 1H), 6.24 (dd, J=16.9,1.8Hz, 1H), 5.74(dd, J=10.3,1.7Hz, 1H), 5.71 (s, 2H), 4.31 (q, J=7.1Hz, 2H), 1.30 (t, J=7.1Hz, 3H)¹³CNMR(101MHz,DMSO)δ163.60(s),162.99(s),159.50(s),150.29(s),149.71(s),148.93(s),138.84(s),139.76(s),138.65(s),133.71(s),132.84(s),132.44(s),132.22(s),128.20(s),128.09(s),127.45(s),126.16(s),126.04(s),122.88(s),120.86(s),119.91(s),108.59(s),61.56(s),54.50(s),14.51(s).

II-5:1- (4- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.White solid, 245-248 DEG C of fusing point, yield 83.7%.¹H NMR(400MHz,DMF)δ10.74(s,1H),10.31(s,1H), 8.75 (d, J=3.9Hz, 1H), 8.17 (d, J=7.5Hz, 1H), 8.08 (t, J=7.6Hz, 1H), 7.99 (d, J=8.6Hz, 2H), 7.88 (d, J=7.6Hz, 2H), 7.71-7.65 (m, 1H), 7.54 (d, J=8.4Hz, 2H), 7.41 (s, 1H),7.19 (d, J=8.4Hz, 2H), 5.71 (s, 2H), 4.31 (dd, J=13.2,6.2Hz, 2H), 1.29 (t, J=7.1Hz, 3H).¹³C NMR(101MHz,DMSO)δ165.11(s),163.00(s),159.48(s),150.28(s),149.73(s),148.94(s),138.77(s),138.65(s),138.29(s),138.29(s),133.72(s),133.21(s),128.24(s),128.07(s),128.46(s),127.46(s),126.15(s),122.89(s),120.86(s),119.96(s),108.60(s),61.56(s),54.47(s),43.98(s),14.51(s).

II-6:1- (3- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, 113-115 DEG C of fusing point, yield 83.0%.¹H NMR(400MHz,CDCl₃) δ 7.79 (d, J=8.6Hz, 2H), 7.70 (d,J=7.4Hz, 1H), 7.35 (t, J=7.7Hz, 3H), 7.31-7.22 (m, 3H), 7.14-7.10 (m, 1H), 7.07-7.00 (m,5H), 6.39 (d, J=16.8Hz, 1H), 6.18 (dd, J=16.8,10.2Hz, 1H), 5.76 (s, 2H), 5.72 (d, J=10.3Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 1.34 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ163.43(s),159.55(s),157.32(s),157.08(s),149.88(s),138.17(s),137.97(s),133.56(s),131.10(s),129.82(s),129.39(s),127.89(s),127.72(s),127.16(s),123.46(s),123.43(s),119.39(s),119.07(s),118.96(s),118.52(s),108.30(s),61.23(s),54.88(s),14.22(s).

II-7:1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.It is whiteColor solid, 107-110 DEG C of fusing point, yield 87.3%.¹H NMR(400MHz,CDCl₃) δ 7.80 (d, J=8.6Hz, 2H),7.68 (d, J=6.0Hz, 1H), 7.35 (t, J=7.9Hz, 2H), 7.29-7.19 (m, 3H), 7.14-7.10 (m, 1H), 7.08-6.89 (m, 6H), 5.88 (d, J=15.1Hz, 1H), 5.76 (s, 2H), 4.31 (q, J=7.1Hz, 2H), 1.87 (d, J=6.8Hz, 3H), 1.34 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ163.92(s),159.54(s),157.29(s),157.10(s),149.85(s),141.67(s),138.31(s),138.11(s),133.56(s),129.81(s),129.33(s),127.78(s),127.16(s),125.34(s),123.41(s),123.17(s),119.35(s),118.95(s),118.45(s),108.28(s),61.21(s),54.91(s),17.87(s),14.23(s).

II-8:1- (3- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazole-5-ethyl formate.White is solidBody, 125-130 DEG C of fusing point, yield 82.4%.¹H NMR(400MHz,CDCl₃) δ 8.19 (s, 1H), 7.80 (d, J=8.7Hz,2H), 7.56 (d, J=8.1Hz, 1H), 7.40-7.24 (m, 5H), 7.12-7.01 (m, 6H), 5.79 (s, 2H), 4.32 (q, J=7.1Hz, 2H), 4.15 (s, 2H), 1.35 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ163.80(s),159.59(s),157.33(s),157.09(s),149.98(s),138.40(s),136.88(s),133.52(s),129.81(s),129.43(s),127.73(s),127.18(s),124.25(s),123.42(s),119.54(s),119.07(s),119.01(s),118.97(s),108.31(s),61.24(s),54.83(s),42.86(s),14.24(s).

II-9:1- (3- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.Yellow solid, 175-177 DEG C of fusing point, yield 87.4%.¹H NMR(400MHz,DMF)δ10.75(s,1H),10.14(s,1H), 8.75 (d, J=4.6Hz, 1H), 8.17 (d, J=7.8Hz, 1H), 8.08 (td, J=7.7,1.5Hz, 1H), 8.00 (d, J=8.7Hz, 2H), 7.89 (d, J=8.7Hz, 2H), 7.74-7.63 (m, 2H), 7.44 (d, J=3.9Hz, 2H), 7.29 (t, J=7.9Hz, 1H), 6.93 (d, J=7.7Hz, 1H), 6.40 (dd, J=17.0,10.1Hz, 1H), 6.23 (dd, J=17.0,1.9Hz, 1H), 5.73 (dd, J=15.3,4.3Hz, 3H), 4.31 (q, J=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H).¹³C NMR(101MHz,DMF)δ164.03(s),163.42(s),159.87(s),150.75(s),150.21(s),149.35(s),140.15(s),139.24(s),139.08(s),138.97(s),134.28(s),132.68(s),129.88(s),128.51(s),127.88(s),127.85,126.60(s),123.32(s),123.06(s),121.28(s),119.34(s),118.53(s),109.07(s),61.97(s),55.34(s),14.93(s).

II-10:1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acidEthyl ester.White solid, 153-155 DEG C of fusing point, yield 80.5%.¹H NMR(400MHz,DMSO)δ10.74(s,1H),9.94(s, 1H), 8.76 (d, J=4.6Hz, 1H), 8.18 (d, J=7.8Hz, 1H), 8.09 (td, J=7.7,1.4Hz, 1H), 8.00(d, J=8.6Hz, 2H), 7.89 (d, J=8.6Hz, 2H), 7.69 (dd, J=6.9,5.4Hz, 1H), 7.63 (d, J=8.3Hz,1H), 7.43 (s, 2H), 7.27 (t, J=7.9Hz, 1H), 6.82-6.71 (m, 1H), 6.08 (d, J=15.2Hz, 1H), 5.73(s, 2H), 4.31 (q, J=7.1Hz, 2H), 1.84 (d, J=6.1Hz, 3H), 1.30 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,DMSO)δ163.94(s),163.00(s),159.45(s),150.33(s),149.77(s),148.94(s),140.38(s),140.01(s),139.00–138.28(m),133.86(s),129.37(s),128.10(s),127.46(s),126.41(s),126.18(s),122.90(s),122.29(s),120.86(s),118.82(s),118.04(s),108.64(s),61.55(s),54.94(s),17.98(s),14.51(s).

II-11:1- (3- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazole-5-ethyl formate.White solid, 175-180 DEG C of fusing point, yield 88.4%.¹H NMR(400MHz,DMF)δ10.75(s,1H),10.30(s,1H), 8.76 (d, J=4.6Hz, 1H), 8.17 (d, J=7.8Hz, 1H), 8.08 (t, J=7.7Hz, 1H), 8.00 (d, J=8.4Hz, 2H), 7.89 (d, J=8.4Hz, 2H), 7.72-7.65 (m, 1H), 7.57 (d, J=8.0Hz, 1H), 7.44 (s, 1H),7.35 (s, 1H), 7.30 (t, J=7.9Hz, 1H), 6.96 (d, J=7.6Hz, 1H), 5.74 (s, 2H), 4.31 (q, J=7.0Hz, 2H), 4.21 (s, 2H), 1.29 (t, J=7.0Hz, 3H)¹³C NMR(101MHz,DMF)δ165.53(s),163.42(s),159.86(s),150.75(s),150.23(s),149.36(s),139.63(s),139.24(s),139.09(s),134.28(s),129.96(s),128.49(s),127.88(s),126.60(s),123.41(s),123.39(s),123.32(s),121.29(s),119.32(s),118.50(s),109.08(s),61.98(s),55.28(s),44.44(s),14.93(s).

II-12:1- (4- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.Yellow solid,193-195 DEG C of fusing point, yield 83.8%.¹H NMR(400MHz,DMSO)δ13.48(s,1H),10.09(s,1H),7.81(d, J=8.6Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.34 (t, J=7.9Hz, 2H), 7.25 (s, 1H), 7.10 (d, J=8.6Hz, 3H), 6.98 (dd, J=8.1,4.3Hz, 4H), 6.35 (dd, J=17.0,10.1Hz, 1H), 6.17 (dd, J=17.0,1.8Hz,1H),5.71–5.60(m,3H).¹³C NMR(101MHz,DMSO)δ163.56(s),161.03(s),157.01(d, J=17.9Hz), 149.26 (s), 138.81 (s), 134.84 (s), 133.07 (s), 132.27 (s), 130.58 (s),128.18(s),128.04(s),127.49(s),127.38(s),124.13(s),119.87(s),119.29(s),119.22(s),108.56(s),54.19(s).

II-13:1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.WhiteSolid, 243-245 DEG C of fusing point, yield 80.6%.¹H NMR(400MHz,DMSO)δ13.53(s,1H),9.96(s,1H),7.88 (d, J=8.5Hz, 2H), 7.59 (d, J=8.3Hz, 2H), 7.41 (t, J=7.8Hz, 2H), 7.32 (s, 1H), 7.17(t, J=7.0Hz, 3H), 7.10-7.01 (m, 4H), 6.78 (dq, J=13.8,6.7Hz, 1H), 6.10 (d, J=15.3Hz,1H), 5.71 (s, 2H), 1.85 (d, J=6.7Hz, 3H)¹³C NMR(101MHz,DMSO)δ163.89(s),161.04(s),157.09(s),156.92(s),149.23(s),140.34(s),139.11(s),134.84(s),132.72(s),130.58(s),128.15(s),128.05(s),127.48(s),126.41(s),124.13(s),119.74(s),119.28(s),119.21(s),108.54(s),54.18(s),17.99(s).

II-14:1- (4- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.White solid,178-180 DEG C of fusing point, yield 83.4%.¹H NMR(400MHz,DMSO)δ13.44(s,1H),10.27(s,1H),7.80(d, J=8.6Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.34 (t, J=7.9Hz, 2H), 7.25 (s, 1H), 7.10 (t, J=8.8Hz, 3H), 6.98 (dd, J=8.1,4.8Hz, 4H), 5.65 (s, 2H), 4.16 (s, 2H)¹³C NMR(101MHz,DMSO)δ165.07(s),161.02(s),157.10(s),156.91(s),149.27(s),138.25(s),134.88(s),133.46(s),130.59(s),128.23(s),128.03(s),127.49(s),124.13(s),119.93(s),119.29(s),119.21(s),108.55(s),54.14(s),43.99(s).

II-15:1- (4- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid.YellowSolid, 187-190 DEG C of fusing point, yield 83.8%.¹H NMR(400MHz,DMF)δ13.42(s,1H),10.74(s,1H),10.16 (s, 1H), 8.75 (d, J=4.4Hz, 1H), 8.17 (d, J=7.7Hz, 1H), 8.08 (t, J=7.7Hz, 1H), 7.99(d, J=8.5Hz, 2H), 7.86 (d, J=8.5Hz, 2H), 7.72-7.65 (m, 1H), 7.62 (d, J=8.4Hz, 1H), 7.46-7.28 (m, 1H), 7.28-7.10 (m, 2H), 6.42 (dd, J=16.9,10.1Hz, 1H), 6.24 (d, J=15.6Hz, 1H),5.74 (d, J=10.4Hz, 2H)¹³C NMR(101MHz,DMF)δ163.98(s),163.39(s),161.49(s),150.76(s),149.93(s),149.38(s),149.35(s),139.23(s),139.10(s),139.07(s),133.53(s),132.69(s),128.76(s),128.63(s),127.86(s),127.80(s),126.50(s),123.31(s),121.26(s),120.29(s),108.96(s),54.60(s).

II-16:1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- firstAcid.White solid, 253-255 DEG C of fusing point,¹H NMR(400MHz,DMF)δ13.54(s,2H),10.74(s,1H),9.97(d,J=4.4Hz, 1H), 8.76 (d, J=4.4Hz, 1H), 8.18 (d, J=7.8Hz, 1H), 8.09 (td, J=7.7,1.5Hz, 1H),7.99 (d, J=8.7Hz, 2H), 7.85 (d, J=8.5Hz, 2H), 7.69 (dd, J=6.4,4.9Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 7.53 (d, J=8.5Hz, 1H), 7.33 (s, 1H), 7.16 (dd, J=8.6,2.8Hz, 2H), 6.77 (dd, J=15.2,6.9Hz, 1H), 6.10 (dd, J=15.3,1.4Hz, 1H), 1.85 (d, J=5.7Hz, 3H)¹³C NMR(101MHz,DMF)δ163.98(s),163.39(s),161.49(s),150.76(s),149.93(s),149.38(s),149.35(s),139.23(s),139.10(s),139.07(s),133.53(s),132.69(s),128.76(s),128.63(s),127.86(s),127.80(s),126.50(s),123.31(s),121.26(s),120.29(s),108.96(s),54.60(s)17.98(s).

II-17:1- (4- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid.WhiteSolid, 227-230 DEG C of fusing point, yield 82.9%.¹H NMR(400MHz,DMF)δ13.53(s,1H),10.74(s,1H),10.32 (s, 1H), 8.75 (d, J=4.6Hz, 1H), 8.17 (d, J=7.8Hz, 1H), 8.08 (td, J=7.7,1.5Hz, 1H),7.99 (d, J=8.7Hz, 2H), 7.85 (d, J=8.7Hz, 2H), 7.69 (dd, J=6.9,5.4Hz, 1H), 7.54 (d, J=8.5Hz, 2H), 7.36 (d, J=12.9Hz, 1H), 7.19 (d, J=8.5Hz, 2H), 5.74 (d, J=14.8Hz, 2H), 4.25(d, J=14.8Hz, 2H)¹³C NMR(101MHz,DMSO)δ165.11(s),163.00(s),159.48(s),150.28(s),149.73(s),148.94(s),138.77(s),138.65(s),138.29(s),138.29(s),133.72(s),133.21(s),128.24(s),128.07(s),128.46(s),127.46(s),126.15(s),122.89(s),120.86(s),119.96(s),108.60(s),54.47(s),43.98(s).

II-18:1- (3- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.White solid,205-208 DEG C of fusing point, yield 89.4%.¹H NMR(400MHz,DMSO)δ13.51(s,1H),10.15(s,1H),7.89(d, J=8.1Hz, 2H), 7.65 (d, J=7.5Hz, 1H), 7.36 (ddd, J=36.7,15.1,7.4Hz, 5H), 7.16 (t, J=7.0Hz, 1H), 7.06 (d, J=6.6Hz, 4H), 6.92 (d, J=7.2Hz, 1H), 6.41 (dd, J=16.8,10.1Hz,1H), 6.24 (d, J=16.8Hz, 1H), 5.74 (d, J=16.7Hz, 3H)¹³C NMR(101MHz,DMSO)δ163.61(s),160.96(s),157.13(s),156.92(s),149.35(s),139.71(s),138.79(s),134.97(s),132.28(s),130.58(s),129.40(s),128.04(s),127.52(s),127.39(s),124.13(s),122.65(s),119.29(s),119.22(s),118.88(s),118.17(s),108.60(s),54.57(s).

II-19:1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.WhiteSolid, 229-230 DEG C of fusing point, yield 85.7%.¹H NMR(400MHz,DMSO)δ13.51(s,1H),9.98(s,1H),7.89 (d, J=8.6Hz, 2H), 7.63 (d, J=8.1Hz, 1H), 7.49-7.33 (m, 4H), 7.26 (t, J=7.9Hz, 1H),7.16 (t, J=7.4Hz, 1H), 7.05 (dd, J=8.5,2.8Hz, 4H), 6.88 (d, J=7.6Hz, 1H), 6.77 (dq, J=13.9,6.8Hz, 1H), 6.11 (d, J=16.2Hz, 1H), 5.75 (s, 2H), 1.84 (s, 3H)¹³C NMR(101MHz,DMSO)δ163.94(s),160.95(s),157.12(s),156.93(s),149.33(s),140.30(s),140.01(s),138.70(s),134.97(s),130.58(s),129.30(s),128.05(s),127.52(s),126.45(s),124.12(s),122.27 (s), 119.25 (d, J=5.9Hz), 118.78 (s), 118.09 (s), 108.58 (s), 54.58 (s), 17.98 (s)

II-20:1- (3- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- formic acid.Yellow solid,188-190 DEG C of fusing point, yield 88.3%.¹H NMR (400MHz, DMSO) δ 10.32 (s, 1H), 7.88 (d, J=8.5Hz,2H), 7.56 (d, J=7.9Hz, 1H), 7.41 (t, J=7.8Hz, 2H), 7.34-7.27 (m, 3H), 7.16 (t, J=7.3Hz,1H), 7.05 (dd, J=8.1,3.7Hz, 4H), 6.94 (d, J=7.4Hz, 1H), 5.76 (s, 2H), 4.21 (s, 2H)¹³C NMR(101MHz,DMSO)δ165.09(s),161.00(s),157.11(s),156.93(s),149.31(s),139.18(s),138.95(s),135.27(s),130.58(s),129.47(s),128.07(s),127.50(s),124.13(s),122.98(s),119.29(s),119.22(s),118.84(s),118.15(s),108.49(s),54.47(s),44.02(s).

II-21:1- (3- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid.WhiteSolid, 220-221 DEG C of fusing point, yield 82.6%.¹H NMR(400MHz,DMF)δ13.51(s,1H),10.74(s,1H),9.94 (s, 1H), 8.75 (d, J=4.5Hz, 1H), 8.17 (d, J=7.7Hz, 1H), 8.08 (t, J=7.7Hz, 1H), 7.99(d, J=8.6Hz, 2H), 7.86 (d, J=8.5Hz, 2H), 7.72-7.65 (m, 1H), 7.57 (d, J=8.1Hz, 1H), 7.37(d, J=3.4Hz, 2H), 7.26 (dd, J=15.2,7.4Hz, 1H), 6.88 (d, J=7.6Hz, 1H), 5.74 (s, 2H)¹³CNMR(101MHz,DMF)δ170.21(s),163.40(s),161.41(s),150.77(s),149.99(s),149.35(s),140.33 (s), 139.11 (d, J=7.0Hz), 135.36 (s), 129.72 (s), 128.75 (s), 127.87 (s), 126.53(s),123.31(s),122.62(s),121.25(s),118.94(s),118.27(s),108.99(s),66.86(s),66.25(s),54.98(s),38.04(s),15.95(s).

II-22:1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- firstAcid.White solid, 235-238 DEG C of fusing point, yield 87.5%.¹H NMR(400MHz,DMF)δ13.51(s,1H),10.74(s, 1H), 9.95 (s, 1H), 8.75 (d, J=4.4Hz, 1H), 8.17 (d, J=7.8Hz, 1H), 8.08 (td, J=7.7,1.4Hz, 1H), 7.99 (d, J=8.7Hz, 2H), 7.86 (d, J=8.6Hz, 2H), 7.69 (dd, J=6.9,5.4Hz, 1H),7.56 (d, J=8.2Hz, 1H), 7.35 (d, J=5.9Hz, 2H), 7.25 (t, J=7.9Hz, 1H), 6.89 (d, J=7.6Hz,1H), 6.76 (dd, J=15.3,7.0Hz, 1H), 6.08 (d, J=15.1Hz, 1H), 1.84 (d, J=7.6Hz, 3H)¹³C NMR(101MHz,DMF)δ170.21(s),163.40(s),161.41(s),150.77(s),149.99(s),149.35(s),140.33 (s), 139.11 (d, J=7.0Hz), 135.36 (s), 129.72 (s), 128.75 (s), 127.87 (s), 126.53(s),123.31(s),122.62(s),121.25(s),118.94(s),118.27(s),108.99(s),66.86(s),66.25(s),54.98(s),38.04(s),15.95(s).235-240

II-23:1- (3- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- formic acid.WhiteSolid, 247-248 DEG C of fusing point, yield 87.5%.¹H NMR(400MHz,DMF)δ13.53(s,1H),10.74(s,1H),10.30 (s, 1H), 8.75 (d, J=3.9Hz, 1H), 8.17 (d, J=7.7Hz, 1H), 8.08 (t, J=7.6Hz, 1H), 7.99(d, J=8.4Hz, 2H), 7.86 (d, J=8.4Hz, 2H), 7.72-7.65 (m, 1H), 7.57 (d, J=8.0Hz, 1H), 7.41-7.25 (m, 3H), 6.95 (d, J=7.3Hz, 1H), 5.76 (s, 2H), 4.21 (s, 2H)¹³C NMR(101MHz,DMF)δ170.10(s),165.51(s),163.40(s),150.76(s),149.35(s),139.60(s),139.37(s),139.13(s),139.08(s),129.92(s),128.74(s),127.87(s),126.53(s),123.42(s),123.32(s),121.26(s),119.25(s),118.56(s),109.00(s),54.90(s),44.45(s).

5) method is led in the synthesis of target product II-24~II-31

Target product I-1~I-8 (0.5mmol) is dissolved in methanol respectively, is added sodium hydroxide (10mmol), room temperature is stirred2h, dilute hydrochloric acid tune PH to 4~5 to be mixed, is filtered, filter cake is washed with water, and it is dry, target product I-24~I-32 is obtained respectively.

II-24:1- (4- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White solid,138-140 DEG C of fusing point, yield 80.5%.¹H NMR (400MHz, DMSO) δ 10.16 (s, 1H), 7.78 (d, J=8.6Hz,2H), 7.62 (d, J=8.4Hz, 2H), 7.40 (t, J=7.8Hz, 2H), 7.22-7.11 (m, 3H), 7.03 (t, J=8.1Hz,4H), 6.63 (s, 1H), 6.42 (dd, J=16.9,10.1Hz, 1H), 6.24 (dd, J=16.9,1.6Hz, 1H), 5.74 (dd, J=10.1,1.6Hz, 1H), 5.43 (t, J=5.5Hz, 1H), 5.33 (s, 2H), 4.50 (d, J=5.5Hz, 2H)¹³C NMR(101MHz,DMSO)δ163.56(s),157.12(s),156.48(s),148.93(s),144.89(s),138.73(s),133.02(s),132.29(s),130.54(s),129.39(s),128.24(s),127.37(s),127.13(s),123.96(s),119.86(s),119.25(s),119.11(s),102.81(s),54.54(s),52.57(s).

II-25:1- [4- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.WhiteSolid, 135-147 DEG C of fusing point, yield 88.8%.¹H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 7.78 (d, J=8.6Hz, 2H), 7.59 (d, J=8.4Hz, 2H), 7.40 (t, J=7.9Hz, 2H), 7.15 (dd, J=12.2,8.0Hz, 3H),7.02 (t, J=8.3Hz, 4H), 6.77 (dq, J=13.9,6.8Hz, 1H), 6.62 (s, 1H), 6.10 (d, J=15.2Hz,1H), 5.42 (t, J=5.5Hz, 1H), 5.31 (s, 2H), 4.49 (d, J=5.5Hz, 2H), 1.85 (d, J=6.8Hz, 3H)¹³CNMR(101MHz,DMSO)δ163.89(s),157.13(s),156.47(s),148.91(s),144.87(s),140.31(s),139.02(s),132.64(s),130.54(s),129.40(s),128.20(s),127.13(s),126.44(s),123.95(s),119.73(s),119.25(s),119.11(s),102.80(s),54.55(s),52.59(s),17.99(s).

II-26:1- (4- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.Yellow solid,133-135 DEG C of fusing point, yield 89.7%.¹H NMR (400MHz, DMSO) δ 10.32 (s, 1H), 7.78 (d, J=8.7Hz,2H), 7.54 (d, J=8.5Hz, 2H), 7.40 (t, J=7.9Hz, 2H), 7.25-7.12 (m, 3H), 7.03 (t, J=8.0Hz,4H),6.63(s,1H),5.33(s,2H),4.50(s,2H),4.24(s,2H),2.50(s,3H).¹³C NMR(101MHz,DMSO)δ165.08(s),157.11(s),156.48(s),148.96(s),144.90(s),138.16(s),133.41(s),130.55(s),129.36(s),128.30(s),127.14(s),123.96(s),119.91(s),119.25(s),119.11(s),102.83(s),54.52(s),52.52(s),44.00(s).

II-27:1- (4- acrylamido benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- methanol.WhiteSolid, 173-175 DEG C of fusing point, yield 85.7%.¹H NMR(400MHz,DMSO)δ10.69(s,1H),10.15(s,1H),8.75 (d, J=4.6Hz, 1H), 8.17 (d, J=7.8Hz, 1H), 8.09 (dd, J=7.6,1.4Hz, 1H), 7.96 (d, J=8.7Hz, 2H), 7.79 (d, J=8.6Hz, 2H), 7.69 (dd, J=7.3,4.8Hz, 1H), 7.62 (d, J=8.5Hz, 2H),7.17 (d, J=8.5Hz, 2H), 6.86 (s, 1H), 6.49-6.36 (m, 2H), 6.26 (d, J=2.3Hz, 1H), 6.22 (d, J=2.9Hz, 1H), 6.07 (dd, J=17.2,10.3Hz, 1H), 5.92 (dd, J=10.4,1.3Hz, 1H), 5.74 (dd, J=10.1,1.9Hz,1H),5.40(s,2H),5.27(s,2H).¹³C NMR(101MHz,DMF)δ163.40(s),161.41(s),150.77 (s), 149.99 (s), 149.35 (s), 140.33 (s), 139.11 (d, J=7.0Hz), 135.36 (s), 129.72(s),128.75(s),127.87(s),126.53(s),123.31(s),122.62(s),121.25(s),118.94(s),118.27(s),108.99(s),66.86(s),66.25(s),52.52(s),38.04(s),.

II-28:1- (4- chloro acetylamino benzyl) -3- (4- pyridinecarboxylic aminophenyl) -1H- pyrazoles -5- methanol.WhiteSolid, 173-175 DEG C of fusing point, yield 87.4%.¹H NMR(400MHz,DMSO)δ10.67(s,1H),10.33(s,1H),8.75 (d, J=4.3Hz, 1H), 8.17 (d, J=7.7Hz, 1H), 8.08 (t, J=7.5Hz, 1H), 7.94 (d, J=8.5Hz,2H), 7.77 (d, J=8.5Hz, 2H), 7.70-7.65 (m, 1H), 7.55 (d, J=8.3Hz, 2H), 7.21 (d, J=8.3Hz,2H),6.65(s,1H),5.34(s,2H),4.50(s,2H),4.24(s,2H).¹³C NMR(101MHz,DMF)δ165.51(s),163.40(s),150.76(s),149.35(s),139.60(s),139.37(s),139.13(s),139.08(s),129.92(s),128.74(s),127.87(s),126.53(s),123.42(s),123.32(s),121.26(s),119.25(s),118.56(s),109.00(s),54.90(s),44.45(s).

II-29:1- (3- acrylamido benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.Yellow solid,125-127 DEG C of fusing point, yield 87.5%.¹H NMR (400MHz, DMSO) δ 10.18 (s, 1H), 7.80 (d, J=8.6Hz,2H), 7.64 (d, J=8.1Hz, 1H), 7.47 (s, 1H), 7.40 (t, J=7.9Hz, 2H), 7.29 (t, J=7.9Hz, 1H),7.15 (t, J=7.4Hz, 1H), 7.03 (dd, J=7.9,5.8Hz, 4H), 6.93 (d, J=7.6Hz, 1H), 6.65 (s, 1H),6.41 (dd, J=17.0,10.1Hz, 1H), 6.24 (d, J=18.7Hz, 1H), 5.74 (d, J=11.8Hz, 1H), 5.48 (t, J=5.5Hz, 1H), 5.37 (s, 2H), 4.50 (d, J=5.4Hz, 2H)¹³C NMR(101MHz,DMSO)δ163.65(s),157.09(s),156.49(s),148.99(s),144.97(s),139.66(s),138.66(s),132.21(s),130.55(s), 129.39 (d, J=11.1Hz), 127.49 (s), 127.17 (s), 123.97 (s), 122.79 (s), 119.09 (t, J=17.4Hz),118.35(s),102.87(s),54.57(s),49.07(s).

II-30:1- [3- (trans- 2- butyrylamino) benzyl] -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.WhiteSolid, 137-140 DEG C of fusing point, yield 84.1%.¹H NMR (400MHz, DMSO) δ 9.98 (s, 1H), 7.79 (d, J=8.7Hz, 2H), 7.61 (d, J=8.0Hz, 1H), 7.46 (s, 1H), 7.40 (t, J=7.9Hz, 2H), 7.26 (t, J=7.9Hz,1H), 7.15 (t, J=7.4Hz, 1H), 7.03 (dd, J=8.0,5.8Hz, 4H), 6.89 (d, J=7.6Hz, 1H), 6.82-6.73 (m, 1H), 6.65 (s, 1H), 6.10 (d, J=16.6Hz, 1H), 5.48 (t, J=5.4Hz, 1H), 5.36 (s, 2H),4.49 (d, J=5.4Hz, 2H), 1.84 (d, J=6.8Hz, 3H)¹³C NMR(101MHz,DMSO)δ163.99(s),157.09(s),156.48(s),148.97(s),144.96(s),140.49(s),139.94(s),138.57(s),130.56(s),129.38(s),129.34(s),127.17(s),126.35(s),123.97(s),122.45(s),119.26(s),119.09(s),118.81(s),118.27(s),102.86(s),54.57(s),53.01(s),18.00(s).

II-31:1- (3- chloro acetylamino benzyl) -3- (4- Phenoxyphenyl) -1H- pyrazoles -5- methanol.White solid,93-95 DEG C of fusing point, yield 82.4%.¹H NMR (400MHz, DMSO) δ 10.35 (s, 1H), 7.80 (d, J=8.7Hz, 2H),7.57 (d, J=8.1Hz, 1H), 7.42-7.37 (m, 3H), 7.30 (t, J=7.8Hz, 1H), 7.15 (t, J=7.4Hz, 1H),7.03 (t, J=7.5Hz, 5H), 6.95 (d, J=7.6Hz, 1H), 6.66 (s, 1H), 5.37 (s, 2H), 4.49 (s, 2H), 4.23(s,2H).¹³C NMR(101MHz,DMSO)δ165.12(s),157.10(s),156.50(s),149.00(s),144.99(s),139.17(s),138.81(s),130.55(s),129.52(s),129.34(s),127.16(s),123.97(s),123.07(s),119.25(s),119.12(s),118.86(s),118.31(s),102.87(s),54.56(s),52.91(s),44.02(s).

Experimental example compound is tested BTK inhibitory activity and is surveyed to the growth inhibition of lymphoma mantle cell (MCL) cell strainFixed experiment (experiment in vitro)

1) compound tests BTK kinase inhibiting activity:

Experimental material and instrument: this experiment is assisted to complete by UK corporation Eurofins Pharma.TR-FRET enzymatic activityAssay kit (German Cisbio company), dimethyl sulfoxide DMSO (Sigma-Aldrich), electronic analytical balanceER-182A type (Japanese A&D company), BTK kinases 200ng/ μ L (Japanese Carna Biosciences company), 384 microwell plates(Perkin Elmer company of the U.S.), microplate reader (Perkin Elmer Inspire multi-function microplate reader), carbon dioxide cultureCase (Forma Scientific company of the U.S.), desk centrifuge (Thermo Scientific company of the U.S.).

Experimental method: by BTK (h) and 8mMMOPSpH7.0,0.2mMEDTA, 250 μM of KVEKIGEGTYGVVYK (Cdc2Peptide), 10mM magnesium acetate and [9-33P]-ATP (specific activity and concentration as needed) incubate together.It is mixed by addition Mg/ATPClose object initiation reaction.It incubates at room temperature after forty minutes, the concentration by the way that phosphoric acid to 0.5% is added terminates reaction.Then by 10 μL react object point on P30 filter bed, wash 4 times, 4 minutes every time, washed once in 0.425% phosphoric acid in methyl alcohol, then intoRow drying and scinticounting.

Setting compound test group (c), positive controls (p) and negative control group (n) are needed in experiment.Test group is will notBe added in 384 orifice plates with concentration testing compound solution (4 hole μ L/), positive controls then be added same volume 1 × swashEnzyme buffer liquid, other are identical as test group；Untested compound is not added in negative control group, and BTK kinase solution is also not added, with 6 holes μ L/1 × kinase buffer liquid replace, other are identical as test group.

The calculation formula of inhibiting rate are as follows:

Wherein c is test group, and n is background group, and p is blank group.

Target compound under 1 μM of concentration to the inhibiting rate of BTK kinases in 0-20%, have certain inhibition to BTK kinasesActivity.

2) compound tests the growth inhibitory activity of MCL cell strain:

Experimental material and instrument: cell and cultivate reagent: people lymphoma mantle cell cell strain Mino, Rec-1, Jeko-1,Maver-1, Z-138, Granta-519, JVM-2, JVM-13 (American type culture collection-American TypeCulture Collection, ATCC), RPMI-1640 culture medium (Sigma Co., USA), (U.S. Sigma is public for fetal calf serumDepartment), HEPES buffer solution (CORNING company of the U.S.), penicillin receive (10000units/mL)-streptomycin sulphate (10mg/mL)(Sigma Co., USA), trypan blue reagent-Trypan blue solution (Sigma Co., USA), inverted light microscope(Fisher Scientific company of the U.S.), cell incubator (NUAIER company of the U.S.), superclean bench (U.S. NUAIERCompany), cell counter-TC20^TMAutomated Cell Counter) (Bio-Rad company of the U.S.), electric-heated thermostatic water bath(Fisher Scientific company of the U.S.), desk centrifuge (Thermo Scientific company of the U.S.), microplate reader(BioTek Synergy HTX multi-tester), ultra low temperature freezer (Thermo Scientific company of the U.S.).

Experimental method: logarithmic growth phase MCL cell strain is inoculated in 96 well culture plates, and cell number is 1 × 104/ hole,Be added the surveyed compound of various concentration cell culture fluid, make its final concentration of 0.93-60 μM, at the same set up positive controls withDMSO blank control group adjusts DMSO concentration≤1 ‰.Each concentration sets 3 multiple holes, finishes, and sets 37 DEG C, 5%CO₂Constant temperature incubation72h is incubated in case.Then 30 μ L CellTiter- are added in every holeReagent, with BioTek Synergy HTX multifunctional examiningIt surveys instrument (BioTek, USA) detector and measures its luminance value under 570nm wavelength, institute's value and feminine gender DMSO control groupIt is normalized, calculates IC using 6.0 software of Prism (GraphPad Software, USA)₅₀Value.Compound inhibiting rateBy formula: inhibiting rate (IR%)=(blank group OD value-administration group OD value)/blank group OD value × 100% calculates, further according to suppressionRate concentration curve processed obtains IC₅₀Value.

Compound is shown in Table 2 to the growth inhibitory activity measurement result of MCL cell strain

Growth inhibitory activity determination data of 2. compound of table to MCL cell strain

2 experimental data of table shows that I and II series compound have part of compounds pair compared with IBN (i.e. according to Shandong for Buddhist nun)The growth inhibitory activity of MCL significantly improves, and half-inhibitory concentration is all in low micromolar grade (1 μM or so), growth inhibitory activityIt quite or is substantially better than according to Shandong for Buddhist nun according to Shandong for Buddhist nun with MCL marketed drug.

Claims (10)

Translated fromChinese

1.化合物或其药学上可接受的盐，其具有式X所示结构：1. A compound or a pharmaceutically acceptable salt thereof, which has the structure shown in formula X:其中，Y选自C和N，n选自0和1；为单键或双键；wherein, Y is selected from C and N, and n is selected from 0 and 1; is a single bond or a double bond;R选自4-苯氧基苯基和4-吡啶甲酸氨基苯基；R is selected from 4-phenoxyphenyl and 4-picolinate aminophenyl;R₁选自甲酸、甲酸乙酯和羟甲基；R₁ is selected from formic acid, ethyl formate and hydroxymethyl;R₂选自-COR₄和H；R₂ is selected from -COR₄ and H;R₃选自含或不含卤素的C_1-6直链或支链烷基酰氨基、吡啶酰氨基和苯酰氨基；R₃ is selected from C_1-6 straight or branched chain alkyl amido, pyridine amido and phenylamido with or without halogen;R₄选自含或不含卤素的C_1-6直链或支链烷基、吡啶和苯基。R₄ is selected from C_1-6 straight or branched chain alkyl, pyridine and phenyl with or without halogen.2.根据权利要求1所述的化合物，其特征在于，R₃的取代位置为C-3位或C-4位；2. compound according to claim 1, is characterized in that, the substitution position of R₃ is C-3 position or C-4 position;优选地，R选自4-苯氧基苯基和4-吡啶甲酸氨基苯基；R₁选自甲酸、甲酸乙酯和羟甲基；R₂选自-COR₄和H；R₃选自3-丙烯酰氨基、4-丙烯酰氨基、氯乙酰氨基和反-2-丁烯酰氨基；R₄选自乙烯基、氯甲基和反-1-丙烯基。Preferably, R is selected from 4-phenoxyphenyl and 4-picolinate aminophenyl; R₁ is selected from formic acid, ethyl formate and hydroxymethyl; R₂ is selected from -COR₄ and H; R₃ is selected from 3-acrylamido, 4-acrylamido, chloroacetamido and trans-2-butenoamido; R₄ is selected from vinyl, chloromethyl and trans-1-propenyl.3.根据权利要求1或2所述的化合物，其特征在于，其选自以下化合物：3. The compound according to claim 1 or 2, characterized in that, it is selected from the following compounds:其中，R₁、R₃和R₄的定义同权利要求1或2中所述；Wherein, the definitions of R₁ , R₃ and R₄ are the same as those described in claim 1 or 2;优选地，所述化合物选自以下结构：Preferably, the compound is selected from the following structures:其中，R为4-苯氧基苯基或4-吡啶甲酸氨基苯基；R₁为甲酸乙酯或羟甲基；R₅为卤素，选自F、Cl、Br和I，优选为Cl；Wherein, R is 4-phenoxyphenyl or 4-picolinate aminophenyl; R₁ is ethyl formate or hydroxymethyl; R₅ is halogen, selected from F, Cl, Br and I, preferably Cl;优选地，-NHC(O)CH₂R₅的取代位置为C-3位或C-4位。Preferably, the substitution position of -NHC(O)_CH2R5 is C-₃ or C-4.4.根据权利要求1至3中任一项所述的化合物，其特征在于，其选自以下化合物：4. The compound according to any one of claims 1 to 3, characterized in that it is selected from the following compounds:1-(1-丙烯酰基哌啶-3-基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-(1-Acryloylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-[1-(反-2-丁酰基)哌啶-3-基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-[1-(Trans-2-butyryl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(1-氯乙酰基哌啶-3-基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-(1-Chloroacetylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(1-丙烯酰基哌啶-3-基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-(1-Acryloylpiperidin-3-yl)-3-(4-picolinamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-[1-(反-2-丁酰基)哌啶-3-基]-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-[1-(Trans-2-butyryl)piperidin-3-yl]-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(1-氯乙酰基哌啶-3-基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-(1-Chloroacetylpiperidin-3-yl)-3-(4-picolinamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(1-丙烯酰基哌啶-3-基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-(1-Acryloylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-[1-(反-2-丁酰基)哌啶-3-基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-[1-(trans-2-butyryl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-(1-氯乙酰基哌啶-3-基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-(1-Chloroacetylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-(1-丙烯酰基哌啶-3-基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-(1-Acryloylpiperidin-3-yl)-3-(4-picolinamidophenyl)-1H-pyrazole-5-carboxylic acid;1-[1-(反-2-丁酰基)哌啶-3-基]-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-[1-(Trans-2-butyryl)piperidin-3-yl]-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid;1-(1-氯乙酰基哌啶-3-基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-(1-Chloroacetylpiperidin-3-yl)-3-(4-picolinamidophenyl)-1H-pyrazole-5-carboxylic acid;1-(1-丙烯酰基哌啶-3-基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-(1-Acryloylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-[1-(反-2-丁酰基)哌啶-3-基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-[1-(trans-2-butyryl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-(1-氯乙酰基哌啶-3-基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-(1-Chloroacetylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-(4-丙烯酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-(4-Acrylamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-[4-(反-2-丁酰氨基)苄基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-[4-(Trans-2-butyrylamino)benzyl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(4-氯乙酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-(4-Chloroacetamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(4-丙烯酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-(4-Acrylamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(4-氯乙酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-(4-Chloroacetamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(3-丙烯酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-(3-Acrylamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-[3-(反-2-丁酰氨基)苄基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-[3-(Trans-2-butyrylamino)benzyl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(3-氯乙酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸乙酯；1-(3-Chloroacetamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(3-丙烯酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-(3-Acrylamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-[3-(反-2-丁酰氨基)苄基]-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-[3-(Trans-2-butyrylamino)benzyl]-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(3-氯乙酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸乙酯；1-(3-Chloroacetamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester;1-(4-丙烯酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-(4-Acrylamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-[4-(反-2-丁酰氨基)苄基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-[4-(Trans-2-butyrylamino)benzyl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-(4-氯乙酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-(4-Chloroacetamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-(4-丙烯酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-(4-Acrylamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid;1-[4-(反-2-丁酰氨基)苄基]-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-[4-(Trans-2-butyrylamino)benzyl]-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid;1-(4-氯乙酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-(4-Chloroacetamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid;1-(3-丙烯酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-(3-Acrylamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-[3-(反-2-丁酰氨基)苄基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-[3-(Trans-2-butyrylamino)benzyl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-(3-氯乙酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲酸；1-(3-Chloroacetamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid;1-(3-丙烯酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-(3-Acrylamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid;1-[3-(反-2-丁酰氨基)苄基]-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-[3-(Trans-2-butyrylamino)benzyl]-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid;1-(3-氯乙酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲酸；1-(3-Chloroacetamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-carboxylic acid;1-(4-丙烯酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-(4-Acrylamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-[4-(反-2-丁酰氨基)苄基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-[4-(Trans-2-butyrylamino)benzyl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-(4-氯乙酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-(4-Chloroacetamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-(4-丙烯酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲醇；1-(4-Acrylamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-methanol;1-(4-氯乙酰氨基苄基)-3-(4-吡啶甲酰氨基苯基)-1H-吡唑-5-甲醇；1-(4-Chloroacetamidobenzyl)-3-(4-pyridinecarboxamidophenyl)-1H-pyrazole-5-methanol;1-(3-丙烯酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-(3-Acrylamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-[3-(反-2-丁酰氨基)苄基]-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇；1-[3-(trans-2-butyrylamino)benzyl]-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol;1-(3-氯乙酰氨基苄基)-3-(4-苯氧基苯基)-1H-吡唑-5-甲醇。1-(3-Chloroacetamidobenzyl)-3-(4-phenoxyphenyl)-1H-pyrazole-5-methanol.5.一种制备式(X)所示化合物的方法，所述方法包括进行如下反应路线：5. a method for preparing compound shown in formula (X), described method comprises carrying out following reaction scheme:其中，R、R₁、R₄的定义同权利要求1至3中任一项所述；Wherein, the definitions of R, R₁ and R₄ are as described in any one of claims 1 to 3;优选地，所述通过如下反应制备得到：Preferably, the Prepared by the following reaction:其中，R、R₁的定义同权利要求1至3中任一项所述；Wherein, the definitions of R and R₁ are the same as any one of claims 1 to 3;优选地，所述方法包括进行如下反应路线：Preferably, the method comprises carrying out the following reaction scheme:其中，R为4-吡啶甲酸氨基苯基，R₁选自甲酸、甲酸乙酯，R₄选自乙烯基、氯甲基和反-1-丙烯基；Wherein, R is 4-picolinate aminophenyl, R₁ is selected from formic acid, ethyl formate, R₄ is selected from vinyl, chloromethyl and trans-1-propenyl;优选地，所述方法包括以下步骤：Preferably, the method includes the following steps:(i)将原料A-1和草酸二乙酯溶于乙醇中，0℃下加入乙醇钠，反应毕，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，得中间体A-2；(i) Dissolve raw material A-1 and diethyl oxalate in ethanol, add sodium ethoxide at 0°C, and after the reaction is completed, pour the reaction solution into ice water, filter, wash the filter cake with water, and dry to obtain intermediate A- 2;(ii)将中间体A-2溶于乙醇中，加入80％水合肼，几滴乙酸，80℃回流3h，减压蒸除溶剂，得黄色固体中间体A-3；(ii) Dissolve intermediate A-2 in ethanol, add 80% hydrazine hydrate, a few drops of acetic acid, reflux at 80° C. for 3 h, and evaporate the solvent under reduced pressure to obtain yellow solid intermediate A-3;(iii)将中间体A-3和1-Boc-3-羟基哌啶，三苯基膦0℃下溶于无水THF，逐滴加入DIAD，反应3h；反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，得中间体A-4；(iii) Dissolve intermediate A-3 and 1-Boc-3-hydroxypiperidine, triphenylphosphine in anhydrous THF at 0°C, add DIAD dropwise, and react for 3 hours; after the reaction is completed, pour the reaction solution into water , extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to obtain intermediate A-4;(iv)将中间体A-4溶于乙醇：水＝3：1(v/v)的溶液中，加入铁粉，氯化铵，90℃反应6h；反应毕，趁热过滤，减压蒸除滤液溶剂，得中间体A-5；(iv) Dissolve intermediate A-4 in a solution of ethanol:water=3:1 (v/v), add iron powder, ammonium chloride, and react at 90°C for 6h; after the reaction is completed, filter while hot, and evaporate under reduced pressure. Remove the filtrate solvent to obtain intermediate A-5;(v)将原料吡啶甲酸溶于DMF，加入三乙胺、HBTU，搅拌40分钟，加入A-5，反应12小时；反应毕，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，得中间体A-6；(v) Dissolving the raw picolinic acid in DMF, adding triethylamine and HBTU, stirring for 40 minutes, adding A-5, and reacting for 12 hours; after the reaction is completed, pour the reaction solution into ice water, filter, wash the filter cake with water, and dry , to obtain intermediate A-6;(vi)将中间体A-6溶于二氯甲烷，加入4N盐酸5ml，室温搅拌12小时，减压蒸除溶剂，分别得中间体C-1；(vi) Dissolving intermediate A-6 in dichloromethane, adding 5 ml of 4N hydrochloric acid, stirring at room temperature for 12 hours, and evaporating the solvent under reduced pressure to obtain intermediate C-1;(vii)将中间体C-1、三乙胺溶于四氢呋喃，冰浴下缓慢滴加不同取代酰氯，室温搅拌4h；反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，硅胶柱层析，得式(I)化合物，其中R₁为甲酸甲酯；(vii) Dissolve intermediate C-1 and triethylamine in tetrahydrofuran, slowly add different substituted acid chlorides dropwise under an ice bath, and stir at room temperature for 4 h; after the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, and evaporate under reduced pressure. Remove the solvent and perform silica gel column chromatography to obtain the compound of formula (I), wherein R₁ is methyl formate;(viii)将步骤(vii)的产物溶于甲醇中，加入氢氧化钠，室温搅拌2h，稀盐酸调PH至4～5，过滤，滤饼用水洗涤，干燥，得式(I)化合物，其中，R₁为甲酸；(viii) dissolving the product of step (vii) in methanol, adding sodium hydroxide, stirring at room temperature for 2 h, adjusting the pH to 4-5 with dilute hydrochloric acid, filtering, washing the filter cake with water, and drying to obtain the compound of formula (I), wherein , R₁ is formic acid;优选地，所述方法包括进行如下反应路线：Preferably, the method comprises carrying out the following reaction scheme:其中，R为4-苯氧基苯基，R₁选自甲酸、甲酸乙酯，R₄选自乙烯基、氯甲基和反-1-丙烯基；Wherein, R is 4-phenoxyphenyl, R₁ is selected from formic acid, ethyl formate, R₄ is selected from vinyl, chloromethyl and trans-1-propenyl;优选地，所述方法包括以下步骤：Preferably, the method includes the following steps:(i’)将原料B-1和草酸二乙酯溶于乙醇中，0℃下加入乙醇钠，反应毕，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，分别得中间体B-2；(i') Dissolve raw material B-1 and diethyl oxalate in ethanol, add sodium ethoxide at 0°C, and after the reaction is completed, pour the reaction solution into ice water, filter, wash the filter cake with water, and dry to obtain intermediates respectively B-2;(ii’)将中间体B-2溶于乙醇中，加入80％水合肼，几滴乙酸，80℃回流3h，减压蒸除溶剂，分别得黄色固体中间体B-3；(ii') Dissolve intermediate B-2 in ethanol, add 80% hydrazine hydrate, a few drops of acetic acid, reflux at 80°C for 3 h, evaporate the solvent under reduced pressure, and obtain yellow solid intermediate B-3;(iii’)将中间体B-3和1-Boc-3-羟基哌啶，三苯基膦0℃下溶于无水THF，逐滴加入DIAD，反应3h；反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，分别得中间体B-4；(iii') Dissolve intermediate B-3 and 1-Boc-3-hydroxypiperidine, triphenylphosphine in anhydrous THF at 0°C, add DIAD dropwise, and react for 3h; after the reaction, pour the reaction solution into In water, extract with ethyl acetate, and evaporate the solvent under reduced pressure to obtain intermediate B-4;(iv’)将中间体B-4溶于二氯甲烷，加入4N盐酸5ml，室温搅拌12小时，减压蒸除溶剂，分别得中间体C-1；(iv') Dissolve intermediate B-4 in dichloromethane, add 5 ml of 4N hydrochloric acid, stir at room temperature for 12 hours, and evaporate the solvent under reduced pressure to obtain intermediate C-1;(v’)将中间体C-1、三乙胺溶于四氢呋喃，冰浴下缓慢滴加不同取代酰氯，室温搅拌4h；反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，硅胶柱层析，得式(I)化合物，其中R₁为甲酸甲酯；(v') Dissolve intermediate C-1 and triethylamine in tetrahydrofuran, slowly add different substituted acid chlorides dropwise under an ice bath, and stir at room temperature for 4 h; after the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, and reduce the pressure. The solvent is evaporated and subjected to silica gel column chromatography to obtain the compound of formula (I), wherein R₁ is methyl formate;(vi’)将步骤(v’)的产物溶于甲醇中，加入氢氧化钠，室温搅拌2h，稀盐酸调PH至4～5，过滤，滤饼用水洗涤，干燥，得式(I)化合物，其中，R₁为甲酸；(vi') dissolving the product of step (v') in methanol, adding sodium hydroxide, stirring at room temperature for 2 h, adjusting the pH to 4-5 with dilute hydrochloric acid, filtering, washing the filter cake with water, and drying to obtain the compound of formula (I) , wherein, R₁ is formic acid;优选地，所述方法包括进行如下反应路线：Preferably, the method comprises carrying out the following reaction scheme:其中，R为4-苯氧基苯基，R₁选自羟甲基，R₄选自乙烯基、氯甲基和反-1-丙烯基；Wherein, R is 4-phenoxyphenyl, R₁ is selected from methylol, and R₄ is selected from vinyl, chloromethyl and trans-1-propenyl;优选地，所述方法包括以下步骤：Preferably, the method includes the following steps:(i”)即将中间体B-4溶于无水THF，冰浴下加入四氢铝锂，室温搅拌15分钟，缓慢加过量水淬灭，用乙酸乙酯萃取，减压蒸除溶剂，得中间体B-5；(i") is to dissolve intermediate B-4 in anhydrous THF, add lithium aluminum tetrahydride under ice bath, stir at room temperature for 15 minutes, slowly add excess water to quench, extract with ethyl acetate, and evaporate the solvent under reduced pressure to obtain Intermediate B-5;(ii”)将中间体B-5溶于二氯甲烷，加入4N盐酸5ml，室温搅拌12小时，减压蒸除溶剂，分别得中间体C-1；(ii") intermediate B-5 was dissolved in dichloromethane, 5 ml of 4N hydrochloric acid was added, stirred at room temperature for 12 hours, and the solvent was evaporated under reduced pressure to obtain intermediate C-1;(iii”)将中间体C-1、三乙胺溶于四氢呋喃，冰浴下缓慢滴加不同取代酰氯，室温搅拌4h；反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，硅胶柱层析，得式(I)化合物，其中R₁为羟甲基。(iii") Dissolve intermediate C-1 and triethylamine in tetrahydrofuran, slowly add different substituted acid chlorides dropwise under ice bath, and stir at room temperature for 4h; after the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, reduce pressure The solvent is evaporated and subjected to silica gel column chromatography to obtain the compound of formula (I), wherein R₁ is hydroxymethyl.6.一种制备式(X)所示化合物的方法，所述方法包括进行如下反应路线：6. a method for preparing compound shown in formula (X), described method comprises carrying out following reaction scheme:其中，R、R₁、R₃的定义同权利要求1至3中任一项所述；Wherein, the definitions of R, R₁ and R₃ are the same as those described in any one of claims 1 to 3;优选地，所述通过如下反应制备得到：Preferably, the Prepared by the following reaction:其中，R、R₁的定义同权利要求1至3中任一项所述；Wherein, the definitions of R and R₁ are the same as any one of claims 1 to 3;优选地，所述方法包括进行如下反应路线：Preferably, the method comprises carrying out the following reaction scheme:其中，R为4-吡啶甲酸氨基苯基，R₁选自甲酸、甲酸乙酯，R₃选自3-丙烯酰氨基、4-丙烯酰氨基、氯乙酰氨基和反-2-丁烯酰氨基；Wherein, R is 4-picolinic acid aminophenyl, R₁ is selected from formic acid, ethyl formate, R₃ is selected from 3-acrylamido, 4-acrylamido, chloroacetamido and trans-2-butenoamido ;优选地，所述方法包括以下步骤：Preferably, the method includes the following steps:(1)中间体A-3在乙醇：水＝3:1(v/v)溶液中，与还原性铁粉，氯化铵反应，得中间体A-7；(1) Intermediate A-3 reacts with reducing iron powder and ammonium chloride in ethanol:water=3:1 (v/v) solution to obtain Intermediate A-7;(2)将原料吡啶甲酸溶于DMF，加入三乙胺、HBTU，搅拌40分钟，加入A-7，反应12小时；反应毕，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，分别得中间体A-9；(2) The raw picolinic acid was dissolved in DMF, triethylamine and HBTU were added, stirred for 40 minutes, A-7 was added, and the reaction was carried out for 12 hours; after the reaction was completed, the reaction solution was poured into ice water, filtered, and the filter cake was washed with water and dried. , respectively to obtain intermediate A-9;(3)将中间体A-9溶于DMF，加入碳酸钾，缓慢加3-或4-硝基苄溴，室温搅拌8h，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，分别得中间体D-1；(3) Dissolve intermediate A-9 in DMF, add potassium carbonate, slowly add 3- or 4-nitrobenzyl bromide, stir at room temperature for 8h, pour the reaction solution into ice water, filter, wash the filter cake with water, and dry, Obtain intermediate D-1 respectively;(4)将中间体D-1溶于乙醇：水＝3:1(v/v)溶液中，加入铁粉，氯化铵，90℃反应6h；反应毕，趁热过滤，减压蒸除滤液溶剂，得中间体D-2；(4) Dissolve intermediate D-1 in ethanol:water=3:1 (v/v) solution, add iron powder, ammonium chloride, and react at 90°C for 6h; after the reaction is completed, filter while hot, and evaporate under reduced pressure Filtrate solvent to obtain intermediate D-2;(5)将中间体D-2、三乙胺溶于四氢呋喃，冰浴下缓慢滴加不同取代酰氯，室温搅拌4h；反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，硅胶柱层析，得式(II)化合物，其中R₁为甲酸甲酯；(5) Dissolve intermediate D-2 and triethylamine in tetrahydrofuran, slowly add different substituted acid chlorides dropwise under ice bath, and stir at room temperature for 4 h; after the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, and evaporate under reduced pressure. Remove the solvent and perform silica gel column chromatography to obtain the compound of formula (II), wherein R₁ is methyl formate;(6)将步骤(6)的产物溶于甲醇中，加入氢氧化钠，室温搅拌2h，稀盐酸调PH至4～5，过滤，滤饼用水洗涤，干燥，得式(II)化合物，其中，R₁为甲酸；(6) Dissolve the product of step (6) in methanol, add sodium hydroxide, stir at room temperature for 2 h, adjust the pH to 4-5 with dilute hydrochloric acid, filter, wash the filter cake with water, and dry to obtain the compound of formula (II), wherein , R₁ is formic acid;优选地，所述方法包括进行如下反应路线：Preferably, the method comprises carrying out the following reaction scheme:其中，R为4-吡啶甲酸氨基苯基，R₁选自羟甲基，R₃选自3-丙烯酰氨基、4-丙烯酰氨基、氯乙酰氨基和反-2-丁烯酰氨基；Wherein, R is 4-picolinic acid aminophenyl, R₁ is selected from hydroxymethyl, R₃ is selected from 3-acrylamido, 4-acrylamido, chloroacetamido and trans-2-butenoamido;优选地，所述方法包括以下步骤：Preferably, the method includes the following steps:(1’)将中间体A-7溶于无水THF，冰浴下加入四氢铝锂，室温搅拌15分钟，缓慢加过量水淬灭，用乙酸乙酯萃取，减压蒸除溶剂，得中间体A-8；(1') Dissolve intermediate A-7 in anhydrous THF, add lithium aluminum tetrahydride under ice bath, stir at room temperature for 15 minutes, slowly add excess water to quench, extract with ethyl acetate, and evaporate the solvent under reduced pressure to obtain Intermediate A-8;(2’)将原料吡啶甲酸溶于DMF，加入三乙胺、HBTU，搅拌40分钟，分别加入A-8，反应12小时。反应毕，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，分别得中间体A-9；(2') Dissolve raw picolinic acid in DMF, add triethylamine and HBTU, stir for 40 minutes, add A-8 respectively, and react for 12 hours. After the reaction, the reaction solution was poured into ice water, filtered, and the filter cake was washed with water and dried to obtain intermediate A-9;(3’)将中间体A-9溶于DMF，加入碳酸钾，缓慢加3-或4-硝基苄溴，室温搅拌8h，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，分别得中间体D-1；(3') Dissolve intermediate A-9 in DMF, add potassium carbonate, slowly add 3- or 4-nitrobenzyl bromide, stir at room temperature for 8h, pour the reaction solution into ice water, filter, wash the filter cake with water, and dry , respectively to obtain intermediate D-1;(4’)将中间体D-1溶于乙醇：水＝3:1(v/v)溶液中，加入铁粉，氯化铵，90℃反应6h；反应毕，趁热过滤，减压蒸除滤液溶剂，得中间体D-2；(4') Dissolve intermediate D-1 in ethanol:water=3:1 (v/v) solution, add iron powder, ammonium chloride, and react at 90°C for 6h; after the reaction, filter while hot, steam under reduced pressure Remove the filtrate solvent to obtain intermediate D-2;(5’)将中间体D-2、三乙胺溶于四氢呋喃，冰浴下缓慢滴加不同取代酰氯，室温搅拌4h；反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，硅胶柱层析，得式(II)化合物，其中R₁为羟甲基；(5') Dissolve intermediate D-2 and triethylamine in tetrahydrofuran, slowly add different substituted acid chlorides dropwise under ice bath, and stir at room temperature for 4h; after the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, and reduce the pressure. The solvent is evaporated and subjected to silica gel column chromatography to obtain the compound of formula (II), wherein R₁ is hydroxymethyl;优选地，所述方法包括进行如下反应路线：Preferably, the method comprises carrying out the following reaction scheme:其中，R为4-苯氧基苯基，R₁选自甲酸、甲酸乙酯，R₃选自3-丙烯酰氨基、4-丙烯酰氨基、氯乙酰氨基和反-2-丁烯酰氨基；Wherein, R is 4-phenoxyphenyl, R₁ is selected from formic acid, ethyl formate, R₃ is selected from 3-acrylamido, 4-acrylamido, chloroacetamido and trans-2-butenoamido ;优选地，所述方法包括以下步骤：Preferably, the method includes the following steps:(1”)将中间体B-3溶于DMF，加入碳酸钾，缓慢加3-或4-硝基苄溴，室温搅拌8h，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，分别得中间体D-1；(1") Dissolve intermediate B-3 in DMF, add potassium carbonate, slowly add 3- or 4-nitrobenzyl bromide, stir at room temperature for 8h, pour the reaction solution into ice water, filter, wash the filter cake with water, and dry , respectively to obtain intermediate D-1;(2”)将中间体D-1溶于乙醇：水＝3:1溶液中，加入铁粉，氯化铵，90℃反应6h。反应毕，趁热过滤，减压蒸除滤液溶剂，得中间体D-2；(2") Dissolve intermediate D-1 in ethanol:water=3:1 solution, add iron powder, ammonium chloride, and react at 90°C for 6h. After the reaction is completed, filter while hot, and evaporate the filtrate solvent under reduced pressure to obtain Intermediate D-2;(3”)将中间体D-2、三乙胺溶于四氢呋喃，冰浴下缓慢滴加不同取代酰氯，室温搅拌4h。反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，硅胶柱层析，得式(II)化合物，其中R₁为甲酸甲酯或甲酸；(3") Dissolve intermediate D-2 and triethylamine in tetrahydrofuran, slowly add different substituted acid chlorides dropwise under ice bath, and stir at room temperature for 4h. After the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, and reduce the pressure. The solvent is evaporated and subjected to silica gel column chromatography to obtain the compound of formula (II), wherein R₁ is methyl formate or formic acid;优选地，所述方法包括进行如下反应路线：Preferably, the method comprises carrying out the following reaction scheme:其中，R为4-苯氧基苯基，R₁选自羟甲基，R₃选自3-丙烯酰氨基、4-丙烯酰氨基、氯乙酰氨基和反-2-丁烯酰氨基；Wherein, R is 4-phenoxyphenyl, R₁ is selected from hydroxymethyl, R₃ is selected from 3-acrylamido, 4-acrylamido, chloroacetamido and trans-2-butenoamido;优选地，所述方法包括以下步骤：Preferably, the method includes the following steps:(1”’)将中间体B-3溶于无水THF，冰浴下加入四氢铝锂，室温搅拌15分钟，缓慢加过量水淬灭，用乙酸乙酯萃取，减压蒸除溶剂，得中间体B-6；(1"') Dissolve intermediate B-3 in anhydrous THF, add lithium aluminum tetrahydride under ice bath, stir at room temperature for 15 minutes, slowly add excess water to quench, extract with ethyl acetate, evaporate the solvent under reduced pressure, Obtain intermediate B-6;(2”’)将中间体B-6溶于DMF，加入碳酸钾，缓慢加3-或4-硝基苄溴，室温搅拌8h，将反应液倒入冰水中，过滤，滤饼用水洗涤，干燥，分别得中间体D-1；(2"') Dissolve intermediate B-6 in DMF, add potassium carbonate, slowly add 3- or 4-nitrobenzyl bromide, stir at room temperature for 8 h, pour the reaction solution into ice water, filter, and wash the filter cake with water, Dry to obtain intermediate D-1;(3”’)将中间体D-1溶于乙醇：水＝3:1溶液中，加入铁粉，氯化铵，90℃反应6h；反应毕，趁热过滤，减压蒸除滤液溶剂，得中间体D-2；(3"') Dissolve intermediate D-1 in ethanol:water=3:1 solution, add iron powder, ammonium chloride, and react at 90°C for 6h; after the reaction is completed, filter while hot, and evaporate the filtrate solvent under reduced pressure, Obtain intermediate D-2;(4”’)将中间体D-2、三乙胺溶于四氢呋喃，冰浴下缓慢滴加不同取代酰氯，室温搅拌4h反应毕，将反应液倒入水中，用乙酸乙酯萃取，减压蒸除溶剂，硅胶柱层析，得式(II)化合物，其中R₁为羟甲基。(4"') Dissolve intermediate D-2 and triethylamine in tetrahydrofuran, slowly add different substituted acid chlorides dropwise under ice bath, stir at room temperature for 4 h after the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, reduce pressure The solvent is evaporated, and silica gel column chromatography is used to obtain the compound of formula (II), wherein R₁ is hydroxymethyl.7.组合物，其含有权利要求1至4中任一项所述的化合物或其药学上可接受的盐。7. A composition comprising the compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.8.药物制剂，其包含权利要求1至4中任一项所述的化合物或其药学上可接受的盐或权利要求7所述的组合物和药学上可接受的辅料和/或载体。8. A pharmaceutical preparation comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or the composition of claim 7 and a pharmaceutically acceptable adjuvant and/or carrier.9.权利要求1至4中任一项所述的化合物或其药学上可接受的盐或权利要求7所述的组合物在制备BTK抑制剂药物中的应用。9. Use of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or the composition of claim 7 in the preparation of a BTK inhibitor medicine.10.权利要求1至4中任一项所述的化合物或其药学上可接受的盐或权利要求7所述的组合物在制备治疗套细胞淋巴瘤的药物中的应用。10. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or the composition according to claim 7 in the preparation of a medicament for the treatment of mantle cell lymphoma.