CN115650974A

CN115650974A - N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-pentadiene amide derivative and application thereof

Info

Publication number: CN115650974A
Application number: CN202210935672.6A
Authority: CN
Inventors: 马军安; 张发光; 聂晶
Original assignee: Tianjin University
Current assignee: Tianjin University
Priority date: 2022-08-04
Filing date: 2022-08-04
Publication date: 2023-01-31
Anticipated expiration: 2042-08-04
Also published as: CN115650974B

Abstract

The invention provides an N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl group as shown in formula (I)]Cis-2,4-pentadiene amide derivative and preparation and application thereof as an EGFR inhibitor have the activity of inhibiting mutant L858R EGFR, T790M EGFR and exon-19 deletion activation mutant. The compounds of formula (I) and pharmaceutically acceptable salts thereof are therefore useful as EGFR modulators for the treatment or prevention of cancer.

Description

N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-pentadiene amide derivative and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-pentadiene amide derivative and application thereof.

Background

EGFR is an important member of HER/erbB family, widely distributed on cell membranes of various tissues of human body, and has a structure divided into extracellular region, transmembrane region and intracellular region. After the EGFR receptor is acted by a corresponding ligand, the EGFR receptor can be induced to form a homodimer or a heterodimer to cause the conformational change of an extracellular structure, so that intracellular tyrosine kinase is activated, residues of the tyrosine kinase are phosphorylated, downstream signal paths such as a MARK path and a PI3K path are further activated, and finally a series of biological behaviors of tumors such as the generation, the development, the proliferation, the invasion and the metastasis of the tumors are caused.

Many cancers in humans (e.g., gastric, lung, breast, bladder, head and neck squamous cell carcinomas, etc.) have increased EGFR expression. erbB therefore possesses a rational target for binding to anticancer drugs, and many inhibitors targeting EGFR or erbB2 are now in clinical use, such as gefitinib, erlotinib, lapatinib, afatinib, canertinib, dacomitinib, etc., as discussed in detail in Biochemical and biological Research Communications (2004,319,1-11) and New England Journal of medicine (2008, 358, 1160-1174). The EGFR Tyrosine Kinase Inhibitor (TKI) is a small molecule EGFR inhibitor, and competitively binds to EGFR through an endogenous ligand to inhibit the activation of tyrosine kinase, so as to block an EGFR signal channel, and finally generate a series of biological effects of inhibiting the proliferation and the metastasis of tumor cells, promoting the apoptosis of the tumor cells and the like.

With the widespread use of these anticancer drugs, acquired resistance has emerged during cancer therapy, for example due to mutation of the gatekeeper residue T790M, which has been reported to be detected in 50-60% of clinically resistant patients; such mutations were detected in 10-15% of clinically resistant patients due to C797S EGFR mutations. Therefore, there is a great need and urgent need to develop new EGFR mutant inhibitors.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide an N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative and its application, wherein the derivative has high bioavailability, increased blood drug concentration, prolonged retention time in vivo, enlarged administration time interval, and finally reduced medical dosage.

The invention provides an N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative, which is a compound shown as a formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof:

wherein A is selected from substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted hydropyrazolopyridyl, substituted or unsubstituted indolyl; the substituent groups in the substituted pyrazolopyridyl group, the substituted hydrogenated pyrazolopyridyl group and the substituted indolyl group are respectively and independently selected from C1-C5 alkyl;

R ¹ selected from hydrogen, halogen, C1-C5 alkyl, cyano or C1-C5 alkoxycarbonyl;

R ² is selected from C1-C5 alkoxy or C1-C5 fluoroalkoxy;

R ³ selected from substituted or unsubstituted azaheterocyclyl groups or substituents of formula (II):

wherein R is ⁴ Is selected from C1-C3 alkyl; r ⁵ And R ⁶ Each independently selected from hydrogen or C1-C3 alkyl and not simultaneously hydrogen, or R ⁵ And R ⁶ Connecting to form a ring; n is an integer of 2 to 5;

the substituent in the substituted nitrogen heterocyclic group is selected from C1-C5 alkyl or C1-C5 alkylamino.

The invention also provides application of the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative in preparation of an epidermal growth factor receptor inhibitor drug.

The invention also provides application of the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative in preparation of a medicine for treating and/or preventing cancers.

Preferably, the cancer is selected from lung cancer, brain cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, mesothelioma, and complications thereof.

Preferably, the cancer is a non-small cell cancer.

The invention also provides a pharmaceutical composition which comprises the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative.

The invention provides an N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl]-cis-2,4-pentadiene amide derivatives, such as compounds of formula (I), pharmaceutically acceptable salts thereof or prodrugs thereof; wherein A is selected from substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted hydropyrazolopyridyl, substituted or unsubstituted indolyl; the substituent groups in the substituted pyrazolopyridyl group, the substituted hydrogenated pyrazolopyridyl group and the substituted indolyl group are respectively and independently selected from C1-C5 alkyl; r ¹ Selected from hydrogen, halogen, C1-C5 alkyl, cyano or C1-C5 alkoxycarbonyl; r ² Is selected from C1-C5 alkoxy or C1-C5 fluoroalkoxy; r ³ Is selected from substituted or unsubstituted nitrogen heterocyclic group or substituent shown in formula (II); r ⁴ Selected from C1-C3 alkyl; r ⁵ And R ⁶ Each independently selected from hydrogen or C1-C3 alkyl and not simultaneously hydrogen, or R ⁵ And R ⁶ Connecting to form a ring; n is an integer of 2 to 5; said substitutionThe substituent in the nitrogen heterocyclic group in (b) is selected from a C1-C5 alkyl group or a C1-C5 alkylamino group. Compared with the prior art, the cis-2,4-pentadiene amide is connected to the mother ring, has a conjugated structure, is used as an EGFR modulator for treating or preventing cancers, has high bioavailability, increases blood concentration, prolongs the retention time in vivo, enlarges the administration time interval and finally reduces the medical dose.

Experiments show that the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative provided by the invention has the activity of inhibiting mutants L858R EGFR, T790M EGFR and exon-19 deletion activation mutants, so that the compound shown in the formula (I) and pharmaceutically acceptable salts thereof can be used as an EGFR modulator for treating or preventing cancers.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a target product obtained in example 28 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

wherein A is a substituted or unsubstituted pyrazolopyridyl group, a substituted or unsubstituted hydropyrazolopyridyl group, a substituted or unsubstituted indolyl group; the substituents in the substituted pyrazolopyridyl group, the substituted hydropyrazolopyridyl group and the substituted indolyl group are independently C1-C5 alkyl, preferably C1-C3 alkyl, more preferably C1-C2 alkyl, and even more preferably methyl; in the present invention, said A is most preferably 4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-cyclopropyl-1H-indol-3-yl or pyrazolo [1,5-a ] pyridin-3-yl.

R ¹ Is hydrogen, halogen, C1-C5 alkyl, cyano or C1-C5 alkoxycarbonyl; preferably hydrogen, chlorine, C1-C3 alkyl, cyano or C2-C4 alkoxycarbonyl; more preferably hydrogen, chlorine, C1-C2 alkyl, cyano or C2-C3 alkoxycarbonyl; further preferred is hydrogen, chlorine, methyl, cyano or isopropyloxycarbonyl.

R ² Is C1-C5 alkoxy or C1-C5 fluoroalkoxy; preferably C1-C3 alkoxy or C1-C3 fluoroalkoxy; more preferably C1-C2 alkoxy or C1-C2 fluoroalkoxy; more preferably methoxy or fluoromethoxy; most preferably methoxy, difluoromethoxy or trifluoromethoxy;

R ³ is a substituted or unsubstituted azaheterocyclyl group or a substituent represented by formula (II):

wherein R is ⁴ Is C1-C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl; r ⁵ And R ⁶ Each independently selected from hydrogen or C1-C3 alkyl and not simultaneously hydrogen, preferably hydrogen or C1-C2 alkyl, more preferably hydrogen or methyl; or R ⁵ And R ⁶ Linked to form a ring, preferably a C4-C6 ring; preferably containing heteroatoms in the ring, more preferably containing O; n is an integer of 2 to 5, preferably an integer of 2 to 4, and more preferably an integer of 2 to 3.

The substituent in the substituted nitrogen heterocyclic group is C1-C5 alkyl or C1-C5 alkylamino, preferably C1-C3 alkyl or C1-C3 alkylamino, more preferably C1-C2 alkyl or C1-C2 alkylamino, and most preferably methyl, methylamino or dimethylamino.

The nitrogen heterocyclic group may be any nitrogen heterocyclic group known to those skilled in the art, and may be saturated or unsaturated, and is not particularly limited, and in the present invention, it is preferably a pyridyl group, a hydropyridyl group, a piperazinyl group, a pyrrolyl group, a pyrrolidinyl group, a C2 to C6 azacycloalkyl group, an azaspiro ring group, or any two of the above groups forming a condensed ring.

In the present invention, said R ³ Most preferred are (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl](methyl) amino, [2- (methylamino) ethyl](methyl) amino, 5-methyl-2,5-diazaspiro [3,4]Oct-2-yl, (3aR, 6aR) -5-methylhexahydropyrrolo [3,4-b]Pyrrol-1 (2H) -yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4- [2- (dimethylamino) -1-oxoethyl]Piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl) ethyl]Amino, methyl [2- (morpholin-4-yl) ethyl]Amino or 4- [ (2S) -2-aminopropionyl group]Piperazin-1-yl.

According to the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is a pharmaceutically acceptable salt well known to those skilled in the art, and may be a salt of the compound represented by formula (I) with an inorganic acid or a salt of the compound represented by formula (I) with an organic acid, and is not particularly limited, and in the present invention, an acid addition salt formed by one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, oxalic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid and the compound represented by formula (I) is preferred.

The N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative provided by the invention is most preferably one or more of compounds shown in formulas (I-1) to (I-91):

the prodrug of the compound of formula (I) is not particularly limited as long as it is known to those skilled in the art, and the prodrug can be decomposed in the human body or animal body to produce the compound of formula (I), and in the present invention, an in vivo hydrolysable ester of the compound of formula (I) is preferred. An internally hydrolysable ester may be formed by esterifying a hydroxyl group in a compound of formula (I).

The cis-2,4-pentadiene amide is connected to the mother ring, has a conjugated structure, is used as an EGFR modulator for treating or preventing cancers, has high bioavailability, increases blood concentration, prolongs the retention time in vivo, enlarges the administration time interval and finally reduces the medical dose. The N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative provided by the invention has the activity of inhibiting L858R EGFR, T790M EGFR and exon-19 deletion activation mutants, so that the compound shown in the formula (I) and pharmaceutically acceptable salts thereof can be used as an EGFR modulator for treating or preventing cancers.

The invention also provides application of the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative as an epidermal growth factor receptor inhibitor, and the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative can treat and/or prevent epidermal growth factor receptor EGFR (EGFR) regulation diseases under effective treatment dosage.

The invention also provides an application of the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative in preparing a medicament for treating and/or preventing cancers; the cancer is an epidermal growth factor receptor EGFR-mediated disease well known to those skilled in the art, preferably lung cancer, brain cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, mesothelioma, and complications thereof, more preferably non-small cell cancer. When the compound is used for preparing a medicament for treating and/or preventing cancer, the compound can be independently administered or can be administered together with other medicaments.

The dosage form of the pharmaceutical composition is well known to those skilled in the art, and is not particularly limited, but in the present invention, preferred are tablets, capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, creams, ointments, gels, aqueous solutions, oily solutions, fine powders, liquid aerosol veins, sterile aqueous or sterile oily solutions; the administration can be oral (e.g., tablets, capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups); topical application (e.g., creams, ointments, gels, or aqueous or oily solutions); administration by inhalation (e.g., fine powder or liquid aerosol); by insufflation (e.g. fine powders) or parenterally (e.g. sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration).

The pharmaceutical composition further comprises a pharmaceutically acceptable diluent or carrier; the compounds of formula (I), pharmaceutically acceptable salts thereof and prodrugs thereof, as active ingredients, may be intimately admixed with pharmaceutical carriers according to conventional pharmaceutical compounding techniques, which carriers may be formulated for administration by any of a wide variety of means, including oral or intravenous injection. Pharmaceutically acceptable carriers are well known in the art and, for example, a description of some of these pharmaceutically acceptable carriers can be found in the handbook of pharmaceutical excipients, which is published by the American society for pharmacy and British pharmaceutical society in combination. In the present invention, the carrier preferably includes an inert diluent, a filler, water, and various organic solvents. If pre-designed, the pharmaceutical formulation may include additional ingredients such as flavorings, antidiarrheal agents, excipients, and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid, may be combined with various disintegrants, such as starch, alginic acid, certain silicate complexes and some antidiarrheal agents, such as sucrose, gelatin and acacia; additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, talc, and the like are also useful for making pharmaceutical tablets; solid compounds of a similar type may also be used for either soft or hard gel capsule filling; therefore, preferred materials include lactose or milk sugar and high molecular weight polyethylene ethers. When the aqueous suspension or the liqueur is used as a necessary product for oral administration, the active ingredients may be combined with different sweeteners or other flavorings, coloring agents and coloring agents, and optionally an emulsifier or suspending agent, and a diluent such as water, alcohol, propylene glycol, glycerin or a mixture thereof.

Administration of the active ingredient may be effected by any means which is capable of delivering the ingredient to the site of action (e.g.tumour cells). These modes may include oral routes, rectal routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, and the like. The dosage of the active ingredient to be administered will depend on the subject being treated, the severity of the pain, the mode of administration and the judgment of the prescribing physician. However, an effective dose is preferably between about 0.001 mg and 400 mg (usually between about 0.01 mg and 100mg, more suitably between about 0.1 mg and 40 mg), and a specific dose may be from about 0.001 mg per kg of body weight per day to about 400 mg per kg of body weight per day (more usually 0.01 mg per kg of body weight per day to 100mg per kg of body weight per day, more suitably 0.1 mg per kg of body weight per day to 40mg per kg of body weight per day).

The term "subject" as used herein refers to an animal, particularly a mammal, most often a human, who is often treated as a prophylactic, therapeutic, observation or test subject. The term "therapeutically effective amount" refers to an amount of active compound or pharmaceutical ingredient that will elicit the biological or medical response of a tissue, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. The term "ingredient" refers to a product resulting, directly or indirectly, from the specified amount of the specified ingredient or ingredients, and any mixtures of the specified ingredients in the specified amount. Therefore, pharmaceutical ingredients including the compounds of the present invention or pharmaceutically acceptable salts thereof as active ingredients, and processes for preparing these compounds or pharmaceutically acceptable salts thereof are all aspects of the present invention. Moreover, certain compounds and salts thereof may be prepared in crystalline forms, which may exist as polymorphs and as such are included in the present invention. In addition, some compounds and salts thereof may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the present invention. The term "combination" refers to administration in parallel, simultaneously, sequentially, or separately with a compound of the invention or a salt thereof.

The invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps: mixing cis 2,4-pentadienoic acid and/or cis 2,4-pentadienoyl chloride with the intermediate 4 in an organic solvent for reaction to obtain a compound shown in a formula (I); the reaction formula is as follows:

the preparation of said intermediate 4 can be carried out according to published procedures such as d.j.abraham, burger's Medicinal Chemistry and Drug Discovery (Wiley, 2003) and r.a.ward et al, j.med.chem. (2013,56,7025-7048); the 2,4-pentadienoic acid is preferably cis-2,4-pentadienoic acid; the 2,4-pentadienoyl chloride is preferably cis-2,4-pentadienoyl chloride; the organic solvent is an organic solvent well known to those skilled in the art, and is not particularly limited, and in the present invention, a weak polar organic solvent is preferred, and one or more of N, N-Dimethylformamide (DMF), dichloromethane and tetrahydrofuran are more preferred; in the present invention, the mixing reaction is preferably carried out in the presence of a base or an organic acid activator; the base is a base well known to those skilled in the art, and is not particularly limited, and in the present invention, an organic base is preferable, an amine organic base is more preferable, and Diisopropylethylamine (DIPEA) is further preferable; the organic acid activator is not particularly limited as long as it is well known to those skilled in the art, and in the present invention, an organic acid activator synthesized by a peptide bond is preferable, and N, N' -Dicyclohexylthiourea (DCC) and/or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) are more preferable; the temperature of the mixing reaction is preferably 0-30 ℃; the time of the mixing reaction is preferably 30 min-10 h; the mixing reaction is preferably carried out in a protective atmosphere; the protective atmosphere is not particularly limited as long as it is known to those skilled in the art, and nitrogen is preferred in the present invention; after mixing and reacting, sodium bicarbonate solution can be directly added to quench and react with a small amount of methanol; or dissolving in an organic solvent after concentration, adding a sodium bicarbonate solution and a small amount of methanol to quench reaction, quenching reaction, preferably washing with water, drying, removing the organic solvent, and performing chromatographic purification to obtain the compound shown in the formula (I); or directly adding distilled water, adjusting pH to alkalinity, extracting with organic solvent, removing organic solvent, and purifying by chromatography to obtain compound shown in formula (I); the organic solvent for extraction is preferably dichloromethane.

According to the invention, the preparation process is preferably as follows: mixing an organic acid activator or alkali, the intermediate 4 and an organic solvent, then dropwise adding a cis-2,4-pentadienoic acid and/or cis-2,4-pentadienoyl chloride solution, and reacting to obtain the compound shown in the formula (I).

To further illustrate the present invention, the following examples are provided to describe the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivatives and their uses in detail.

The reagents used in the following examples are all commercially available; unless otherwise specified, all parts and percentages are parts by mass and percentages by mass, and the temperatures indicated are in degrees centigrade; abbreviations in the examples are as follows: TFA, trifluoroacetic acid; ATP, adenosine triphosphate; DMF, N-dimethylformamide; DMSO, dimethyl sulfoxide; etOAc, ethyl acetate; THF, tetrahydrofuran; DCC, N' -dicyclohexylthiourea; EDCI,1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DIPEA, diisopropylethylamine; GSR, glutathione-S-transferase; crK, CT10, chicken tumor retrovirus 10; SDS, sodium dodecyl sulfate; SDS-PAGE, sodium dodecyl sulfate-polyamide electrophoresis gel; rt, room temperature; TLC, thin layer chromatography.

All chemicals were purchased from commercial suppliers and used directly without further purification treatment unless otherwise specified. The Qingdao ocean chemical industry standard silica gel of 200-300 meshes is used for the rapid column chromatography; a Qingdao ocean chemical industry 0.20mm standard plate for thin-layer chromatography; nuclear magnetic resonance spectroscopy data (NMR) were obtained using Bruker (Bruker) 400 or 600 million nuclear magnetic resonance spectroscopy measurements with tetramethylsilane as an internal standard, deuterated chloroform, deuterated dimethyl sulfoxide, or deuterated methanol as a solvent (s represents a single peak, d represents a doublet, t represents a triplet, q represents a quadruplet, m represents a multiplet, br represents a broad peak); mass spectral data were obtained using a MicroTOF-QII or Waters Micromass GCT Premier instrument.

Example 1

N- { 4-methoxy-2- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5- { [ 5-methyl-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-1)

The method comprises the following steps: at 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23.0 mg,0.2mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to 6-methoxy-4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -N' - { 5-methyl-4-pyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (88.0mg, 0.2mmol) and DIPEA (39.0mg, 0.3mmol) in CH ₂ Cl ₂ (6 mL) and the resulting mixture was stirred at 0 ℃ for reaction 4h, then saturated NaHCO is added ₃ (4 mL) and 3-5 drops of methanol, washing the organic phase with 4mL of water, and adding MgSO ₄ Drying, and removing the organic solvent by using a film rotary evaporator. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (60.5mg, 58%) with MeOH (MeOH, 5-25% by volume) as eluent.

The second method comprises the following steps: at N ₂ Under protection, cis-2,4-pentadienoic acid (29.4mg, 0.3mmol), 6-methoxy-4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -N' - { 5-methyl-4-pyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (88mg, 0.2mmol), triethylamine (30.7 mg, 0.3mmol) and anhydrous DMF (4 mL) were added to a reaction flask, stirred and the temperature of the mixture was reduced to 0 ℃, EDCI (57.5 mg, 0.3mmol) was added in portions, stirring was continued at that temperature for 30 minutes, the mixture was allowed to warm to room temperature for reaction for 8h, tlc assay (DCM/MeOH = volume ratio 20/1,2-3 drops of 30% ammonia) confirmed complete reaction of the starting polyarylamine. Adding distilled water into the reaction system, stirring, adjusting pH to about 10 with saturated sodium carbonate aqueous solution, extracting with 30mL dichloromethane for three times, mixing extractive solutions, adding MgSO ₄ Drying, and removing the organic solvent by using a film rotary evaporator. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (63.6 mg, 61%) with MeOH (MeOH at 5-25% by volume) as eluent.

Analyzing the target product obtained in the first method by utilizing nuclear magnetic resonance and mass spectrometry to obtain a result ¹ HNMR(DMSO-d6)δ:2.21(3H,s),2.34(2H,m),2.38(3H,s),2.48-2.52(2H,m),2.93(2H,m),3.82(3H,d),5.18(1H,dd),5.23(1H,d),5.35(1H,d),6.31(1H,m),6.55(1H,m),6.75(1H,s),7.00(1H,t),7.34-7.40(2H,m),7.92(1H,s),8.13(1H,s),8.27(1H,s),8.43(1H,d),8.52(1H,s),8.71(1H,d),9.24(1H,S)；ES(m/z):M+H ⁺ 522.2。

And (3) analyzing the product obtained in the second method by utilizing nuclear magnetic resonance and mass spectrometry to obtain a result similar to that of the first method, and determining that the obtained product is a target product.

Example 2: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl } -cis-2,4-pentadiene-amide (I-2)

At-10 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to N' - [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl chloride with protection]-4-methoxy-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) benzene-1,3-diamine (230 mg,0.5 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL); stirring the obtained mixture at 0 ℃ for reacting for 4h, and then concentrating in vacuum; the residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and 3-5 drops of methanol, washing the organic phase with 4mL of water, and adding MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation; the crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (124.4 mg, 46%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.23(3H,s),2.32(2H,m),2.51(2H,m),2.90(2H,d),3.85(3H,s),5.22(1H,dd),5.27(1H,d),5.44(1H,d),6.27(1H,m),6.56(1H,m),6.80(1H,s),7.04(1H,t),7.21(1H,t),7.38(1H,dd),7.40(1H,d),7.90(1H,s),8.31(1H,s),8.34(1H,d),8.43(1H,s),8.50(1H,s),9.28(1H,s),11.80(1H,S)；ES(m/z):M+H ⁺ 541.2。

Example 3: n- {5- { [4- (1H-indol-3-yl) -5-methylpyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-3)

At-5 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to N' - [4- (1H-indol-3-yl) -5-methylpyrimidin-2-yl chloride with protection]-4-methoxy-6- (4-methylpiperidin-1-yl) benzene-1,3-diamine (222mg, 0.5 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6)mL) in solution. The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (115.2mg, 44%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.25(3H,s),2.33(3H,s),2.43-2.52(4H,m),2.81-2.89(4H,m),3.85(3H,s),5.20(1H,dd),5.27(1H,d),5.42(1H,d),6.54(1H,m),6.80(1H,s),7.07(1H,dd),7.19(1H,t),7.40-7.43(2H,m),7.81(1H,s),7.92(1H,d),8.22(1H,s),8.30(1H,d),8.47(1H,s),8.95(1H,s),11.66(1H,s)；ES(m/z):M+H ⁺ 524.2。

Example 4: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-4)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47.0mg, 0.4mmol, in 0.5mL CH) was added under protection ₂ Cl ₂ Middle) was added dropwise to N- { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) -6-methoxybenzene-1,3-diamine (192.0mg, 0.4mmol) and DIPEA (65mg, 0.5mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 3h. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (80.5mg, 36%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.56-1.75(1H,m),2.00-2.11(1H,m),2.14(6H,s),2.60-2.70(1H,m),3.12-3.23(3H,m),3.30-3.41(1H,m),3.73(3H,s),5.17(1H,dd),5.24(1H,d),5.41(1H,d),6.48(1H,s),6.55(1H,m),7.09(1H,t),7.32(1H,t),7.40-7.44(2H,m),8.25-8.40(2H,m),8.51(1H,s),8.82(1H,d),8.90(1H,s),9.31(1H,s)；ES(m/z):M+H ⁺ 559.2。

Example 5: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene-amide (I-5)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to N- { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -4- [ 3-dimethylaminoazetidin-1-yl) -6-methoxybenzene-1,3-diamine (176mg, 0.4 mmol) and DIPEA (65mg, 0.5 mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 4 hours. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (109mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.03(6H,s),3.06(1H,p),3.50-3.57(2H,m),3.71(3H,s),3.94(2H,t),5.20(1H,dd),5.25(1H,d),5.34(1H,d),6.51(1H,m),7.07(1H,dd),7.35(1H,s),7.40-7.44(2H,m),8.26-8.32(1H,m),8.38(1H,s),8.45(1H,s),8.80(1H,d),8.92(1H,s),9.23(1H,s)；ES(m/z):M+H ⁺ 545.2。

Example 6: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-6)

At-5 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to N under protection ⁴ - { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-5-methoxybenzene-1,2,4-triamine (233.5mg, 0.5mmol) and DIPEA (78mg, 0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (131.2mg, 48%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.21(6H,s),2.32(2H,t),2.70(3H,s),3.80-2.87(2H,m),3.80(3H,s),5.21(1H,dd),5.27(1H,d),5.40(1H,d),6.44(1H,m),6.80(1H,s),7.04(1H,td),7.25-7.33(1H,m),7.40-7.46(2H,m),8.40(1H,s),8.51(1H,d),8.52(1H,d),8.89(1H,s),9.34(1H,s),10.12(1H,s)；ES(m/z):M+H ⁺ 547.2。

Example 7: n- {2- { (3aR, 6aR) -5-Methylhexahydropyrrolo [3,4-b ] pyrrol-1 (2H) -yl } -5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-7)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4- { (3aR, 6 aR) -5-methylhexahydropyrrolo [3,4-b ] with protection]Pyrrol-1 (2H) -yl } -N- {5- { [ 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -6-methoxybenzene-1,3-diamine (98mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (3 mL). Will be describedThe mixture is stirred and reacted for 30min at the temperature of 0 ℃, then is heated to room temperature for reaction for 4h, and is concentrated in vacuum. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (59.4mg, 52%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.73-1.77(1H,m),1.94-2.12(5H,m),2.23-2.30(1H,m),2.35-2.42(1H,m),2.86-2.92(1H,m),3.16-3.21(1H,m),3.35-3.41(1H,m),3.76(3H,s),4.32-4.38(1H,m),5.20(1H,dd),5.26(1H,d),5.35(1H,d),6.50(1H,m),6.62(1H,s),7.12(1H,dt),7.35-7.39(1H,m),7.51(1H,dd),7.69(1H,s),8.32-8.39(2H,m),8.54(1H,s),8.77(1H,d),8.91(1H,s),9.35(1H,s)；ES(m/z):M+H ⁺ 571.2。

Example 8: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (5-methyl-2,5-diazaspiro [3,4] oct-2-yl) phenyl } -cis-2,4-pentadiene amide (I-8)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (12mg, 0.1mmol in 0.2mL THF) was added dropwise to N- {5- { [ 5-chloro-4-pyrazolo [1,5-a) with protection]Pyridin-3-ylpyrimidin-2-yl]-4-methoxy-6- (5-methyl-2,5-diazaspiro [3,4)]Oct-2-yl) benzene-1,3-diamine (49mg, 0.1mmol) and DIPEA (26mg, 0.2mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 6h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (volume of MeOH)Content 5-25%) as eluent, and the obtained solution was concentrated to obtain the objective product (27.4 mg, 48%). ¹ H NMR(DMSO-d6)δ:1.65(2H,dd),1.98-2.09(2H,m),2.32(3H,s),2.61(2H,t),3.65(2H,d),3.76(3H,s),3.95(2H,d),5.22(1H,dd),5.28(1H,d),5.39(1H,d),6.44(1H,s),6.62(1H,m),7.15(1H,t),7.29(1H,s),7.33-7.42(2H,m),8.37(2H,s),8.42(1H,s),8.82(1H,d),8.95(1H,s),9.23(1H,s)；ES(m/z):M+H ⁺ 571.2。

Example 9: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl } -cis-2,4-pentadiene amide (I-9)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to N- {5- { [ 5-chloro-4-pyrazolo [1,5-a with protection]Pyridin-3-ylpyrimidin-2-yl]-4-methoxy-6- (1-methyl-3,6-dihydro-2H-pyridin-4-yl) benzene-1,3-diamine (231mg, 0.5 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 4h and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (94.9 mg, 35%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(3H,s),2.34(2H,s),2.55(2H,t),2.97(2H,d),3.82(3H,s),5.25(1H,dd),5.29(1H,d),5.35(1H,d),6.12(1H,dd),6.57(1H,m),6.88(1H,s),7.18(1H,dt),7.37-7.43(2H,m),7.82(1H,s),8.39-8.43(2H,m),8.63(1H,s),8.85(1H,d),8.97(1H,s),9.36(1H,s)；ES(m/z):M+H ⁺ 542.2。

Example 10: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [4- (2-dimethylamino-1-oxyethyl) piperazin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-10)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (12mg, 0.1mmol, in 0.2mL THF) was added dropwise to N- {5- { [ 5-chloro-4-pyrazolo [1,5-a under protection]Pyridin-3-ylpyrimidin-2-yl]-4-methoxy-2- [4- (2-dimethylamino-1-oxyethyl) piperazin-1-yl]Benzene-1,3-diamine (54mg, 0.1mmol) and DIPEA (26mg, 0.2mmol) in THF (4 mL). The resulting mixture was stirred at 0 ℃ for 5h and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (29mg, 48%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.70(4H,s),2.87-2.92(4H,m),2.98(3H,s),3.12(3H,s),3.25(2H,s),3.88(3H,s),5.21(1H,dd),5.29(1H,d),5.47(1H,d),6.59(1H,m),6.80(1H,s),6.89(1H,t),7.24(1H,d),7.36-7.40(2H,m),8.42(1H,s),8.47-8.52(3H,m),8.97(1H,s),9.34(1H,s)；ES(m/z):M+H ⁺ 616.4。

Example 11: (S) -N- {2- [4- (2-aminopropionyl) piperazin-1-yl ] -5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxyphenyl } -cis-2,4-pentadienamide (I-11)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.5mL CH ₂ Cl ₂ Middle) was added dropwise to (S) -tert-butyl N- [1- (4- { 2-amino-4- [ (5-chloro-4-pyrazolo [1,5-a)]Pyridin-3-ylpyrimidin-2-yl) amino]-5-methoxyphenyl } piperazin-1-yl) -1-Oxypropyl-2-yl]Carbamate (121mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was allowed to warm to room temperature and stirred for 4h. Then 2M Na was added ₂ CO ₃ The reaction was quenched with a small amount of water (5 mL) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. Dissolving the residue in CH ₂ Cl ₂ After the solution (5 mL) was treated with TFA (0.2 mL), the solution was allowed to stand for 30 minutes, and then treated with TFA (0.2 mL) again, followed by standing for another 30 minutes. Removing organic solvent by thin film rotary evaporation, purifying the obtained crude product by silica gel column chromatography, and purifying with CH ₂ Cl ₂ MeOH (MeOH volume content 5-25%) and 1 ‰ volume ratio-Et ₃ N as an eluent, the resulting solution was concentrated to obtain the objective product (56.6 mg, 47%). ¹ H NMR(DMSO-d6)δ:1.25(3H,d),2.85-3.06(4H,m),3.62-3.86(7H,m),4.23-4.30(1H,m),5.22(1H,dd),5.28(1H,d),5.45(1H,d),6.50(1H,m),6.70(1H,s),7.12-7.17(1H,m),7.34-7.40(2H,m),8.21-8.29(2H,m),8.35-8.40(2H,m),8.70(1H,s),8.85-8.92(1H,m),8.97(1H,s),9.21-9.25(1H,m)；ES(m/z):M+H ⁺ 602.2。

Example 12: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ (3S) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-12)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to N- { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -4- [ (3S) -3-dimethylaminopyrrolidin-1-yl) -6-methoxybenzene-1,3-diamine (192mg, 0.4 mmol) and DIPEA (65mg, 0.5 mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 5h. Then saturated NaHCO is added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, removing by rotary evaporationAn organic solvent. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (114mg, 51%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.67-1.80(1H,m),2.01-2.15(1H,m),2.15(6H,s),2.62-2.75(1H,m),3.15-3.26(3H,m),3.33-3.45(1H,m),3.75(3H,s),5.21(1H,dd),5.25(1H,d),5.42(1H,d),6.54-6.58(2H,m),7.10(1H,t),7.34(1H,t),7.40-7.45(2H,m),8.30-8.45(2H,m),8.51(1H,s),8.80(1H,d),8.91(1H,s),9.34(1H,s)；ES(m/z):M+H ⁺ 559.2。

Example 13: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-13)

At 5 ℃ and N ₂ Under the protection, cis-2,4-pentadienoyl chloride (58mg, 0.5mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to N' -5- { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -4-methoxy-6- (4-methylpiperazin-1-yl) benzene-1,3-diamine (233mg, 0.5 mmol) and DIPEA (78mg, 0.6 mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was allowed to warm to room temperature and stirred for 4h. Then saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (133mg, 49%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.23(3H,s),2.52-2.58(4H,m),2.80-2.91(4H,m),3.72(3H,s),5.21(1H,dd),5.27(1H,d),5.45(1H,d),6.54(1H,m),6.89(1H,s),7.12(1H,t),7.28-7.36(1H,m),7.45(1H,dd),8.12(1H,s),8.26-8.42(2H,m),8.76(1H,s),8.88(1H,d),8.95(1H,s),9.12(1H,s)；ES(m/z):M+H ⁺ 545.2。

Example 14: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-14)

At 0 ℃ and N ₂ Under the protection, cis-2,4-pentadienoyl chloride (58mg, 0.5mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to N' -5- { 5-cyano-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -4-methoxy-6- (4-methylpiperazin-1-yl) benzene-1,3-diamine (228mg, 0.5mmol) and DIPEA (78mg, 0.6mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4h. Then saturated NaHCO is added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (110mg, 41%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.24(3H,s),2.50-2.57(4H,m),2.92-2.99(4H,m),3.74(3H,s),5.25(1H,dd),5.29(1H,d),5.48(1H,d),6.56(1H,m),6.97(1H,s),7.16(1H,t),7.36-7.41(2H,m),8.24(1H,s),8.36(1H,d),8.67(1H,s),8.68(1H,br),8.79(1H,d),8.96(1H,s),9.05(1H,s)；ES(m/z):M+H ⁺ 536.4。

Example 15: n- {5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-15)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to N' - [4- (1H-indol-3-yl) pyrimidin-2-yl ester with protection]-4-methoxy-6- (4-methylpiperidin-1-yl) benzene-1,3-diamine (215mg, 0.5 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). Mixing the obtained mixtureThe mixture is stirred and reacted for 30min at the temperature of 0 ℃, then is heated to room temperature for reaction for 5h, and is concentrated in vacuum. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (114.7mg, 45%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.26(3H,s),2.50-2.57(4H,m),2.82-2.94(4H,m),3.87(3H,d),5.25(1H,dd),5.35(1H,d),5.46(1H,d),6.59(1H,m),6.89(1H,s),7.12-7.24(2H,m),7.29(1H,d),7.43-7.49(2H,m),7.86(1H,s),8.35(1H,d),8.46(1H,d),8.51(1H,s),8.70(1H,s),9.02(1H,s)；ES(m/z):M+H ⁺ 510.2。

Example 16: n- { 4-methoxy-2- (4-methylpiperazin-1-yl) -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-16)

At 0 ℃ and N ₂ Under the protection, cis-2,4-pentadienoyl chloride (58mg, 0.5mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to 4-methoxy-6- (4-methylpiperazin-1-yl) -N' - { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1,3-diamine (215mg, 0.5mmol) and DIPEA (78mg, 0.6mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 5 hours. Then saturated NaHCO is added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (115mg, 45%) with MeOH (5-25% MeOH by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.32-2.42(3H,m),2.64-2.77(4H,m),2.95(4H,s),3.88(3H,s),5.27(1H,dd),5.35(1H,d),5.46(1H,d),6.59(1H,m),6.89(1H,s),7.12-7.18(1H,m),7.27(1H,d),7.35-7.42(2H,m),8.18(1H,s),8.35(1H,d),8.47(1H,d),8.56(1H,s),8.77(1H,d),8.86(1H,s),9.18(1H,s)；ES(m/z):M+H ⁺ 511.2。

Example 17: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) -pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-17)

At 25 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to N' - [ 5-chloro-4- (1H-indol-3-yl) -pyrimidin-2-yl chloride with protection]-4-methoxy-6- (4-methylpiperidin-1-yl) benzene-1,3-diamine (232mg, 0.5 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). The resulting mixture was allowed to react at this temperature for 4h and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (114mg, 42%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.23(3H,s),2.52-2.59(4H,m),2.86-2.95(4H,m),3.79(3H,s),5.20(1H,dd),5.26(1H,d),5.49(1H,d),6.56(1H,m),6.90(1H,s),7.10(1H,t),7.23(1H,t),7.40-7.44(2H,m),8.18(1H,s),8.32(1H,d),8.38(1H,s),8.49(1H,s),8.61(1H,d),8.97(1H,s),11.50(1H,s)；ES(m/z):M+H ⁺ 544.2。

Example 18: n- { 4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-18)

At 10 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to 4-methoxy-N' - [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl with protection]-6- (4-methylpiperidin-1-yl) benzene-1,3-diamine (229mg, 0.5mmol) and DIPEA (78mg, 0.6mmol) in THF (6 mL). The resulting mixture was stirred at this temperature for 30min, allowed to warm to room temperature for 5h, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (113mg, 42%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.24(3H,s),2.34(3H,s),2.45-2.50(4H,m),2.82-2.91(4H,m),3.84(3H,s),3.89(3H,s),5.22(1H,dd),5.29(1H,d),5.42(1H,d),6.50(1H,m),6.85(1H,s),7.12(1H,t),7.25(1H,t),7.47-7.50(2H,m),7.86(1H,s),8.11(1H,s),8.25(1H,s),8.39(1H,d),8.48(1H,s),9.56(1H,s)；ES(m/z):M+H ⁺ 538.4。

Example 19: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-19)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.5mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methyl-N ⁴ - { 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1,2,4-triamine (230mg, 0.5 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) in combination withSaturated NaHCO is added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (124mg, 46%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.25-2.31(2H,m),2.37(3H,s),2.75(3H,s),2.95(2H,t),3.82(3H,s),3.89(3H,s),5.22(1H,dd),5.27(1H,d),5.45(1H,d),6.60(1H,m),6.92(1H,s),7.14(1H,d),7.20-7.26(1H,m),7.41-7.47(2H,m),7.97(1H,s),8.12(1H,s),8.28(1H,s),8.33(1H,d),8.78(1H,s),8.90(1H,s),10.00(1H,s)；ES(m/z):M+H ⁺ 540.4。

Example 20: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-20)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (35mg, 0.3mmol in 0.4mL THF) was added dropwise to 4- [ (3R) -3-dimethylaminopyrrolidin-1-yl chloride with protection]-6-methoxy-N- { 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (142mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 5 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (84.4 mg, 51%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.67-1.81(1H,m),2.10(1H,s),2.18(6H,s),2.35(3H,s),2.78(1H,s),3.20(3H,t),3.32-3.38(1H,m),3.80(3H,s),3.92(3H,s),5.25(1H,dd),5.30(1H,d),5.41(1H,d),6.56(1H,m),6.71(1H,s),7.18(1H,t),7.28(1H,t),7.40-7.47(2H,m),7.80(1H,s),7.92(1H,s),8.14(1H,s),8.24(1H,s),8.45(1H,d),9.37(1H,s)；ES(m/z):M+H ⁺ 552.2。

Example 21: n- {5- { [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-21)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (12mg, 0.1mmol in 0.2mL THF) was added dropwise to N- { 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) with protection]-6-methoxybenzene-1,3-diamine (49mg, 0.1mmol) and DIPEA (26mg, 0.2mmol) in THF (4 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (31.5mg, 55%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.67-1.72(1H,m),2.05-2.10(1H,m),2.18(6H,s),2.60-2.71(1H,m),3.25(3H,dd),3.33-3.40(1H,m),3.85(3H,s),3.96(3H,s),5.20(1H,dd),5.28(1H,d),5.46(1H,d),6.50-6.59(2H,m),7.14(1H,t),7.26(1H,t),7.45-7.52(2H,m),7.67(1H,s),8.32-8.40(3H,m),8.57(1H,s),9.39(1H,s)；ES(m/z):M+H ⁺ 572.2。

Example 22: n- {5- { [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-22)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to N- { 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] chloride with protection]-6-methoxybenzene-1,3-diamine (97mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (4 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (MeOH 5-25% by volume) as eluent, and the resulting solution was concentrated to obtain the desired product (56.3mg, 50%). ¹ H NMR(DMSO-d6)δ:1.85(1H,dq),2.02-2.10(1H,m),2.28(6H,d),2.87(1H,dd),3.25-3.41(4H,m),3.79(3H,s),3.95(3H,s),5.25(1H,dd),5.30(1H,d),5.51(1H,d),6.57-6.62(2H,m),7.14(1H,t),7.29(1H,t),7.40-7.46(2H,m),7.77(1H,s),8.35(1H,d),8.49(1H,s),8.56(1H,s),8.81(1H,s),9.21(1H,s)；ES(m/z):M+H ⁺ 563.2。

Example 23: n- {5- { [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-23)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47mg, 0.4mmol in 0.5mL THF) was added dropwise to 4-methoxy-N' - [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl with protection]-6- (4-methylpiperidin-1-yl) benzene-1,3-diamine (187mg, 0.4 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. Then the residue is mixed with waterIs dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (98.8mg, 45%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.25(3H,s),2.52-2.60(4H,m),2.88-2.93(4H,m),3.76(3H,s),3.90(3H,s),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55(1H,m),6.89(1H,s),7.03(1H,br),7.22(1H,s),7.43(1H,m),7.54(1H,d),7.86(1H,br),8.03(1H,s),8.47(1H,s),8.50(1H,s),8.70(1H,s),9.08(1H,s),9.45(1H,s)；ES(m/z):M+H ⁺ 549.2。

Example 24: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-24)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (12mg, 0.1mmol in 0.2mL THF) was added dropwise to N- { 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) with protection]-6-methoxybenzene-1,3-diamine (49mg, 0.1mmol) and DIPEA (26mg, 0.2mmol) in THF (4 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (33.5mg, 60%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.70-1.79(1H,m),2.05-2.15(1H,m),2.20(6H,s),2.65-2.74(1H,m),3.20-3.29(3H,m),3.32-3.40(1H,m),3.75(3H,s),5.20(1H,dd),5.28(1H,d),5.50(1H,d),6.56-6.62(2H,m),7.12(1H,t),7.18(1H,t),7.40-7.46(2H,m),7.66(1H,s),8.25-8.36(3H,m),8.50(1H,d),9.35(1H,s),11.92(1H,s)；ES(m/z):M+H ⁺ 558.2。

Example 25: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -2- (2-dimethylaminoethyl-methylamino) -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-25)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (35mg, 0.3mmol in 0.4mL THF) was added dropwise to N under protection ⁴ - [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (140mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (77mg, 47%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.35(2H,br),2.77(3H,s),2.84-2.93(2H,m),3.82(3H,s),5.21(1H,dd),5.32(1H,d),5.57(1H,d),6.57(1H,m),6.92(1H,t),7.10(1H,s),7.18(1H,t),7.42-7.47(2H,m),8.29(1H,d),8.37(1H,s),8.50(1H,s),8.59(1H,d),8.63(1H,s),10.00(1H,s),11.20(1H,s)；ES(m/z):M+H ⁺ 546.2。

Example 26: n- {5- { [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- (2-dimethylaminoethyl-methylamino) -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-26)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47mg, 0.4mmol in 0.5mL THF) was added dropwise to N under protection ⁴ - [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl]-N ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (192mg, 0.4 mmol) and DIPEA (78mg, 0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (112mg, 50%) with MeOH (5-25% MeOH by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.24-2.32(2H,m),2.77(3H,s),2.86-2.92(2H,m),3.86(3H,s),3.97(3H,s),5.22(1H,dd),5.28(1H,d),5.39(1H,d),6.55(1H,m),6.82(1H,s),7.25-7.38(3H,m),7.47(1H,m),7.62(1H,s),8.38-8.45(3H,m),9.57(1H,s),10.15(1H,s)；ES(m/z):M+H ⁺ 560.2。

Example 27: n- {5- { [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-27)

At 10 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47mg, 0.4mmol in 0.5mL THF) was added dropwise to 4-methoxy-N' - [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl under protection]-6- (4-methylpiperidin-1-yl) benzene-1,3-diamine (182mg, 0.4 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). The resulting mixture was stirred at this temperature for 30min, allowed to warm to room temperature for 5h, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (102.7mg, 48%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.25(3H,s),2.57-2.65(4H,m),2.98(4H,s),3.74(3H,s),5.18(1H,dd),5.20(1H,d),5.48(1H,d),6.60(1H,m),6.92(1H,s),7.12(1H,t),7.23(1H,s),7.48-7.52(2H,m),8.12(1H,s),8.59(1H,s),8.78(1H,s),9.15(1H,s),9.54(1H,s),11.90(1H,s)；ES(m/z):M+H ⁺ 535.2。

Example 28: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene-mide (I-28)

At N ₂ Under protection, cis-2,4-pentadienoic acid (1.47g, 15mmol), N ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1,2,4-triamine (4.46g, 10mmol), triethylamine (1.52g, 15mmol) and anhydrous DMF (15 mL) were added to a reaction flask, stirred and the temperature of the mixture was reduced to 0 ℃, EDCI (2.88g, 15mmol) was added in portions, after the addition was completed, stirring was continued at 0 ℃ for 30 minutes, the reaction was allowed to warm to room temperature for 8h, and tlc detection (DCM/MeOH = volume ratio 20/1,2-3 drops of 30% ammonia) confirmed complete reaction of the raw polyarylamine. Ice water was added to the reaction and stirred, and saturated aqueous sodium carbonate was adjusted to pH about 10, filtered through a Buchner funnel, washed with 30mL of distilled water, 5mL of diethyl ether, and dried under vacuum to give an off-white solid (3.31g, 63%). ¹ H NMR(DMSO-d6)δ:2.23(s,6H),2.32(t,J＝5.8Hz,2H),2.72(s,3H),2.89(s,2H),3.86(s,3H),3.92(s,3H),5.49(d,J＝10.0Hz,1H),5.67(d,J＝16.9Hz,1H),6.27(d,J＝15.0Hz,1H),6.64(dt,J＝17.0,10.5Hz,1H),7.04(s,1H),7.15(t,J＝7.5Hz,1H),7.26–7.19(m,3H),7.53(d,J＝8.1Hz,1H),7.91(s,1H),8.25(d,J＝8.1Hz,1H),8.32(s,1H),8.67(s,1H),9.16(s,1H),10.17(s,1H)；ES(m/z):M+H ⁺ 526.2。

Example 29: n- {5- { [ 5-cyano-4- (1-cyclopropylindol-3-yl) pyrimidin-2-yl ] amino } -2- (2-dimethylaminoethyl-methylamino) -4-methoxyphenyl } -cis-2,4-pentadiene-amide (I-29)

At N ₂ Under protection, cis-2,4-pentadienoic acid (1.47g, 15mmol), N ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methyl-N ⁴ - [4- (1-Cyclopropylindol-3-yl) pyrimidin-2-yl]Benzene-1,2,4-triamine (4.72g, 10mmol), triethylamine (1.52g, 15mmol) and anhydrous DMF (15 mL) were added to a reaction flask, stirred and the temperature of the mixture was decreased to 0 ℃, EDCI (2.88g, 15mmol) was added in portions, after the addition was completed, stirring was continued at 0 ℃ for 30 minutes, the reaction was warmed to room temperature for 10h, and complete reaction of the raw material polyarylamine was confirmed by tlc assay (DCM/MeOH = volume ratio 20/1,2-3 drops of 30% aqueous ammonia). Ice water was added to the reaction and stirred, and the pH was adjusted to about 10 with saturated aqueous sodium carbonate, filtered through a Buchner funnel, washed with 30mL of distilled water, 8mL of ether, and dried under vacuum to give an off-white solid (2.76g, 50%). ¹ H NMR(DMSO-d6)δ:0.67-0.72(m,2H),0.89-0.92(m,2H),2.25(6H,s),2.32(2H,t),2.75(3H,s),2.98(2H,t),4.12(3H,s),5.26(1H,dd),5.37(1H,d),5.55(1H,d),6.60(1H,m),6.86(1H,s),7.29(1H,d),7.32-7.37(2H,m),7.45-7.51(2H,m),7.78(1H,s),8.20-8.27(1H,m),8.48(1H,d),9.11(1H,s),9.89(1H,s),10.92(1H,s)；ES(m/z):M+H ⁺ 552.4。

Example 30: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [4- (1-methylindol-3-yl) -5-isopropoxycarbonylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-30)

In N ₂ Under protection, cis-2,4-pentadienoic acid (1.47g, 15mmol), N ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) -5-isopropoxycarbonylpyrimidin-2-yl]Benzene-1,2,4-triamine (5.32g, 10mmol), triethylamine (1.52g, 15mmol) and anhydrous DMF (15 mL) were added to a reaction flask, the mixture was stirred, the temperature of the mixture was lowered to 0 ℃, EDCI (2.88g, 15mmol) was added in portions, after completion of the addition, stirring was continued at 0 ℃ for 30 minutes, the reaction was allowed to proceed to room temperature for 12h, and the completion of the reaction of the raw material polyarylamine was confirmed by TLC detection (DCM/MeOH = volume ratio 20/1,2. About.3 drops of 30% aqueous ammonia). Ice water was added to the reaction and stirred, and the pH was adjusted to about 10 with saturated aqueous sodium carbonate, filtered through a Buchner funnel, washed with 30mL of distilled water, 5mL of diethyl ether, and dried under vacuum to give an off-white solid (3.36g, 55%). ¹ H NMR(DMSO-d6)δ:1.35(6H,d),2.24(6H,s),2.28(2H,t),2.76(3H,s),2.98(2H,t),3.95(3H,s),4.05(3H,s),5.23-5.27(2H,m),5.35(1H,d),5.45(1H,d),6.58(1H,m),6.84(1H,s),7.24(1H,d),7.32-7.38(2H,m),7.44-7.50(2H,m),7.78(1H,s),8.20-8.26(1H,m),8.48(1H,d),9.05(1H,s),9.88(1H,s),11.04(1H,s)；ES(m/z):M+H ⁺ 612.3。

Example 31: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- [ methyl- (2-morpholin-4-ylethyl) amino ] phenyl } -cis-2,4-pentadiene amide (I-31)

At 20 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.2mL CH ₂ Cl ₂ In) dropwise addition to N ⁴ - { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -5-methoxy-N ¹ -methyl-N ¹ - (2-morpholin-4-ylethyl) benzene-1,2,4-triamine (102mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (4 mL) in solution. The resulting mixture was stirred at this temperature for an additional 5h. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying and film spinningThe organic solvent was removed by evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (58.9 mg, 50%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.28-2.37(4H,m),2.45(2H,t),2.74(3H,s),3.15(2H,t),3.52-3.63(4H,m),3.78(3H,s),5.18(1H,dd),5.28(1H,d),5.44(1H,d),6.55(1H,m),7.11(1H,s),7.16(1H,t),7.29-7.40(1H,m),7.52(1H,m),8.28(1H,s),8.40-8.46(2H,m),8.69(1H,s),8.89(1H,d),9.00(1H,s),9.36(1H,s)；ES(m/z):M+H ⁺ 589.2。

Example 32: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- [ methyl- [2- (4-methylpiperazin-1-ylethyl) amino ] phenyl } -cis-2,4-pentadiene amide (I-32)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.2mL CH ₂ Cl ₂ In) dropwise addition to N ⁴ - { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -5-methoxy-N ¹ -methyl-N ¹ - [2- (4-Methylpiperazin-1-ylethyl) benzene-1,2,4-triamine (105mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (4 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then saturated NaHCO is added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (61.4 mg, 51%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.31(3H,s),2.37-2.61(10H,m),2.68(3H,s),3.21(2H,t),3.89(3H,s),5.21(1H,dd),5.29(1H,d),5.42(1H,d),6.55(1H,m),6.74(1H,s),6.95(1H,t),7.25(1H,t),7.40-7.45(2H,m),8.50(1H,s),8.61(2H,t),8.97(1H,s),9.24(1H,s),9.45(1H,s)；ES(m/z):M+H ⁺ 602.2。

Example 33: n- { 4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- (4-methylpiperazin-1-yl) phenyl } -cis-2,4-pentadiene amide (I-33)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47mg, 0.4mmol in 0.5mL THF) was added dropwise to 4-methoxy-N' - [4- (1-methylindol-3-yl) pyrimidin-2-yl chloride with protection]-6- (4-methylpiperidin-1-yl) benzene-1,3-diamine (177mg, 0.4 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (115.2mg, 55%) with MeOH (MeOH 5-25% by volume). ¹ H NMR(DMSO-d6)δ:2.28(3H,s),2.54-2.62(4H,m),2.85-2.92(4H,m),3.88(3H,s),3.95(3H,s),5.27(1H,dd),5.34(1H,d),5.49(1H,d),6.63(1H,m),6.85(1H,s),7.15-7.26(3H,m),7.46(1H,m),7.58(1H,d),7.92(1H,s),8.34(1H,d),8.40(1H,d),8.58(1H,s),8.88(1H,s),9.14(1H,s)；ES(m/z):M+H ⁺ 524.2。

Example 34: n- {5- { [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-34)

At 10 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) was added under protection ₂ Cl ₂ Middle) is added dropwise to N- [ 5-chloro-4-(1-methylindol-3-yl) pyrimidin-2-yl]-4- [ 3-Dimethylaminoazetidin-1-yl) -6-methoxybenzene-1,3-diamine (191mg, 0.4 mmol) and DIPEA (78mg, 0.6 mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 5 hours. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (111.6 mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.19(6H,s),3.05-3.12(1H,m),3.54-3.61(2H,m),3.77(3H,s),3.94(3H,s),4.05(2H,t),5.22(1H,dd),5.29(1H,d),5.45(1H,d),6.54-6.60(2H,m),7.15(1H,t),7.27(1H,t),7.46-7.53(3H,m),8.20-8.28(3H,m),8.56(1H,s),9.27(1H,s)；ES(m/z):M+H ⁺ 558.2。

Example 35: n- {2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene-amide (I-35)

At 20 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL CH ₂ Cl ₂ In (b)) dropwise addition to 4- [ 3-dimethylaminoazetidin-1-yl) -6-methoxy-N- [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1,3-diamine (92mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (5 mL) in solution. The resulting mixture was stirred at this temperature for a further 5 hours. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ Using MeOH (the volume content of MeOH is 5-25%) as eluent, concentrating the obtained solution to obtain the target product(51.6mg，48％)。 ¹ H NMR(DMSO-d6)δ:2.10(6H,s),2.34(3H,s),3.05-3.14(1H,m),3.55(2H,t),3.87(3H,s),3.96(3H,s),4.05(2H,t),5.21(1H,dd),5.28(1H,d),5.42(1H,d),6.30(1H,s),6.51(1H,m),7.17(1H,t),7.32(1H,t),7.47-7.52(2H,m),7.70(1H,s),7.89(1H,s),8.01(1H,s),8.19(1H,s),8.44(1H,d),9.35(1H,s)；ES(m/z):M+H ⁺ 538.2。

Example 36: n- {2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-36)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) ₂ Cl ₂ In (b)) dropwise addition to 4- [ 3-dimethylaminoazetidin-1-yl) -6-methoxy-N- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1,3-diamine (177mg, 0.4mmol) and DIPEA (78mg, 0.6mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (121.5mg, 58%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),3.12(1H,t),3.50(2H,t),3.82(3H,s),3.88(3H,s),3.93(2H,t),5.17(1H,dd),5.24(1H,d),5.42(1H,d),6.55-6.61(2H,m),7.23(1H,d),7.27-7.32(2H,m),7.48(1H,m),7.60(1H,d),7.78(1H,s),8.10(1H,s),8.27(1H,d),8.44(2H,d),9.42(1H,s)；ES(m/z):M+H ⁺ 524.2。

Example 37: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-37)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) ₂ Cl ₂ In (b) is added dropwise to N- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl]-4- [ 3-Dimethylaminoazetidin-1-yl) -6-methoxybenzene-1,3-diamine (198mg, 0.4 mmol) and DIPEA (78mg, 0.6 mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (119.7mg, 55%) with MeOH (MeOH, 5 to 25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.15(6H,s),3.06-2.15(1H,m),3.61(2H,t),3.79(3H,s),3.99(3H,s),5.25(1H,dd),5.32(1H,d),5.42(1H,d),6.51(1H,s),6.62(1H,m),7.13(1H,t),7.22(1H,t),7.45-7.51(2H,m),7.62(1H,s),8.25(1H,s),8.32-8.38(1H,m),8.40(1H,s),8.52(1H,d),9.26(1H,s),11.90(1H,s)；ES(m/z):M+H ⁺ 544.2。

Example 38: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-38)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to N- { 5-cyano-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) -6-methoxybenzene-1,3-diamine (188mg, 0.4 mmol) and DIPEA (79mg, 0.6 mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then adding saturated NaHCO ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (132mg, 60%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.92(1H,dq),2.01-2.07(1H,m),2.25(6H,s),2.82-2.90(1H,m),3.25-3.42(4H,m),3.69(3H,s),5.17(1H,dd),5.25(1H,d),5.42(1H,d),6.50(1H,m),6.62(1H,s),7.15(1H,t),7.34-7.41(2H,m),7.52(1H,s),8.38(1H,d),8.67(1H,s),8.82(1H,d),8.96(2H,s),9.43(1H,s)；ES(m/z):M+H ⁺ 550.2。

Example 39: n- {5- { [ 5-Isopropoxycarbonyl-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-39)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (55mg, 0.5mmol in 0.5mL THF) was added dropwise to N with protection ⁴ - { 5-Isopropoxycarbonyl-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-5-methoxybenzene-1,2,4-triamine (259mg, 0.5mmol) and DIPEA (78mg, 0.6mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (146.7mg, 49%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.35(6H,d),2.23(6H,s),2.27(2H,dd),2.67(3H,d),3.75-2.82(2H,m),3.84(3H,s),5.22-5.27(3H,m),5.45(1H,d),6.57(1H,m),6.77(1H,s),6.92(1H,d),7.25(1H,s),7.41(1H,m),7.64(1H,s),8.58(2H,dd),8.69(1H,s),9.12(1H,s),9.45(1H,s),10.68(1H,s)；ES(m/z):M+H ⁺ 599.3。

Example 40: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -cis-2,4-pentadienamide (I-40)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) ₂ Cl ₂ Middle) was added dropwise to N- { 5-cyano-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -4- [ 3-dimethylaminoazetidin-1-yl) -6-methoxybenzene-1,3-diamine (182mg, 0.4 mmol) and DIPEA (78mg, 0.6 mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (96.5mg, 45%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.21(6H,s),3.05-3.12(1H,m),3.62(2H,t),3.74(3H,s),4.05(2H,s),5.21(1H,dd),5.28(1H,d),5.50(1H,d),6.37(1H,s),6.50(1H,s),7.17(1H,br),7.34(1H,s),7.45-7.49(2H,m),7.99(1H,br),8.76(1H,s),8.90(1H,br),9.02(1H,s),9.30(1H,s),9.74(1H,s)；ES(m/z):M+H ⁺ 536.2。

Example 41: n- {2- (3aR, 6aR) -5-Methylhexahydropyrrolo [3,4-b ] pyrrol-1-yl } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene-amide (I-41)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to 4- { (3aR, 6aR) -5-methylhexahydropyrrolo [3,4-b under protection]Pyrrol-1 (2H) -yl } -6-methoxy-N- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1,3-diamine (94mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (55mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.72-1.85(2H,m),2.15-2.23(1H,m),2.27(3H,s),2.30-2.36(1H,m),2.77(1H,d),2.81(1H,d),2.83-2.94(2H,m),3.25(1H,t),3.60-3.69(1H,m),3.89(3H,s),4.17(3H,s),5.19(1H,dd),5.30(1H,d),5.55(1H,d),6.52(1H,m),6.86(1H,s),7.26(1H,d),7.25-7.32(2H,m),7.40-7.46(2H,m),7.72(1H,s),8.05-8.11(1H,m),8.35(1H,d),9.15(1H,s),9.49(1H,s),9.91(1H,s)；ES(m/z):M+H ⁺ 550.2。

Example 42: n- {2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxy-5- { [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadienamide (I-42)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methyl-N ⁴ - {4- (4,5,6,7-Tetrahydropyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,2,4-triamine (87mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (5 mL). Stirring the resulting mixture at 0 deg.CThe mixture was stirred for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (49.6 mg, 48%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.62-1.71(2H,m),1.89-1.95(2H,m),2.24(6H,s),2.30(2H,t),2.75(3H,s),2.88(2H,t),3.14(2H,t),3.82(3H,s),4.13(2H,t),5.21(1H,dd),5.29(1H,d),5.40(1H,d),6.58(1H,m),6.95-7.01(2H,m),7.51(1H,m),7.84(1H,s),8.15(1H,s),8.39(1H,d),8.92(1H,s),10.84(1H,s)；ES(m/z):M+H ⁺ 517.4。

Example 43: n- {2- (3aR, 6aR) -5-methylhexahydropyrrolo [3,4-b ] pyrrol-1-yl } -4-methoxy-5- { [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-43)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4- { (3aR, 6 aR) -5-methylhexahydropyrrolo [3,4-b ] with protection]Pyrrol-1 (2H) -yl } -6-methoxy-N- [4- (4,5,6,7-tetrahydropyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl]Benzene-1,3-diamine (92mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (MeOH 5-25% by volume) as eluent,the resulting solution was concentrated to obtain the objective product (50.9mg, 47%). ¹ H NMR(DMSO-d6)δ:1.85-1.97(4H,m),2,05-2.10(2H,m),2.20(1H,s),2.27-2.36(1H,m),2.42(3H,s),2.70-2.96(4H,m),3.20-3.28(3H,m),3.64(1H,br),3.89(3H,s),4.21(2H,t),5.24(1H,dd),5.30(1H,d),5.55(1H,d),6.52(1H,m),6.89(1H,s),7.12(1H,d),7.40-7.47(2H,m),8.11(1H,s),8.38(1H,d),9.45(1H,s),10.01(1H,s)；ES(m/z):M+H ⁺ 541.4。

Example 44: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-44)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (22mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4- { (3R) -3-dimethylaminopyrrolidin-1-yl } -6-methoxy-N- [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] under protection]Pyridin-3-yl) pyrimidin-2-yl]Benzene-1,3-diamine (90mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (52.9 mg, 50%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.70-1.80(3H,m),1.90-1.98(2H,m),2.01-2.08(1H,m),2.20(6H,s),2.67-2.74(1H,m),3.00-3.07(2H,m),3.15-3.23(3H,m),3.32-3.39(1H,m),3.89(3H,s),4.16(2H,t),5.22(1H,dd),5.30(1H,d),5.60(1H,d),6.55(1H,m),6.61(1H,s),6.99(1H,d),7.67(1H,m),7.80(1H,s),8.14(2H,d),8.35(1H,d),9.36(1H,s)；ES(m/z):M+H ⁺ 529.4。

Example 45: n- { 4-methoxy-2- [ 1-methyl-1,2,3,6-tetrahydropyridin-4-yl ] -5- { [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadienamide (I-45)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4-methoxy-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -N' - {4- (4,5,6,7-tetrahydropyrazolo [1,5-a) with protection]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (86mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (58.4 mg, 57%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.79-1.86(2H,m),1.92-1.98(2H,m),2.27(3H,s),2.33-2.39(2H,m),2.50-2.57(2H,m),2.94-2.98(2H,m),3.20(2H,t),3.92(3H,s),4.17(2H,t),5.22(1H,dd),5.30(1H,d),5.47(1H,d),5.72(1H,m),6.68(1H,m),6.90(1H,s),7.23(1H,d),7.53(1H,m),7.89(1H,s),8.18(1H,s),8.35-8.42(2H,m),9.99(1H,s)；ES(m/z):M+H ⁺ 512.2。

Example 46: n- {2- (3-dimethylamino-azetidin-1-yl) -4-methoxy-5- { [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-46)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in0.3mL of THF) was added dropwise to 4- (3-dimethylaminoazetidin-1-yl) -6-methoxy-N- {4- (4,5,6,7-tetrahydropyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (87mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (53.6mg, 52%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.75-1.82(2H,m),1.92-1.97(2H,m),2.20(6H,s),2.99-3.10(3H,m),3.54(2H,t),3.80(3H,s),3.95(2H,t),4.14(2H,t),5.24(1H,dd),5.32(1H,d),5.54(1H,d),6.55-6.60(2H,m),6.97(1H,d),7.48(1H,m),7.77(1H,s),7.92(1H,s),8.12(1H,s),8.30(1H,d),9.42(1H,s)；ES(m/z):M+H ⁺ 515.4。

Example 47: n- { 4-methoxy-2- (5-methyl-2,5-diazaspiro [3,4] oct-2-yl) -5- { [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-47)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4-methoxy-6- (5-methyl-2,5-diazaspiro [3,4] under protection]Oct-2-yl) -N' - {4- (4,5,6,7-tetrahydropyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (92mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 m)L) after, mgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (50mg, 46%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.65-1.72(2H,m),1.75-1.82(2H,m),1.87-1.98(2H,m),2.10-2016(2H,m),2.38(3H,s),2.67(2H,t),3.12(2H,t),3.64(2H,d),3.87(3H,s),3.98(2H,d),4.15(2H,t),5.24(1H,dd),5.30(1H,d),5.56(1H,d),6.55-6.60(2H,m),6.98(1H,d),7.42-7.49(1H,m),7.75(1H,s),7.88(1H,s),8.12(1H,s),8.29(1H,d),9.51(1H,s)；ES(m/z):M+H ⁺ 541.4。

Example 48: n- { 4-methoxy-2- [ 1-methyl-1,2,3,6-tetrahydropyridin-4-yl ] -5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-48)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to a solution of 4-methoxy-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -N' - {4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (88mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL) with protection. The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (60.4 mg, 58%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.25(3H,s),2.35-2.41(2H,m),2.54-2.58(2H,m),2.97-3.03(2H,m),3.90(3H,s),4.04(3H,s),5.20(1H,dd),5.27(1H,d),5.50(1H,d),5.78(1H,m),6.52-6.58(1H,m),6.89(1H,s),7.21-7.29(3H,m),7.45(1H,m),7.54-7.58(1H,m),7.92(1H,s),8.32-8.37(2H,m),8.45(1H,s),8.58(1H,s),9.81(1H,s)；ES(m/z):M+H ⁺ 521.2。

Example 49: n- { 4-methoxy-2- { 5-methyl-2,5-diazaspiro [3,4] oct-2-yl } -5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-49)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4-methoxy-6- (5-methyl-2,5-diazaspiro [3,4] under protection]Oct-2-yl) -N' - {4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (94mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 5 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (56mg, 51%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.68-1.74(2H,m),2.00-2.07(2H,m),2.35(3H,s),2.68(2H,t),3.62(2H,d),3.87(3H,s),3.99(3H,s),5.20(1H,dd),5.31(1H,d),5.57(1H,d),6.56-6.61(2H,m),7.15(1H,d),7.20-7.28(2H,m),7.40-7.46(1H,m),7.55(1H,d),7.78(1H,s),7.98(1H,s),8.45(1H,d),8.50-8.56(2H,m),9.87(1H,s)；ES(m/z):M+H ⁺ 550.2。

Example 50: n- {2- [ (3S) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-50)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4- [ (3S) -3-dimethylaminopyrrolidin-1-yl chloride with protection]-6-methoxy-N' - {4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (92mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (53.8mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.74-1.78(1H,m),2.10(1H,s),2.19(6H,s),2.70-2.74(1H,m),3.20(1H,s),3.28(2H,d),3.40-3.45(1H,m),3.87(3H,s),3.95(3H,s),5.20(1H,dd),5.27(1H,d),5.46(1H,d),6.58-6.61(1H,m),6.67(1H,s),7.17-7.22(3H,m),7.40-7.45(1H,m),7.56(1H,d),7.79(1H,s),8.20(1H,s),8.31(1H,d),8.40(1H,d),8.51(1H,s),9.87(1H,s)；ES(m/z):M+H ⁺ 538.4。

Example 51: n- { 4-methoxy-2- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadienamide (I-51)

At-10 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.5mL CH ₂ Cl ₂ Middle) was added dropwise to 4-methoxy-6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -N' - { 4-pyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,3-diamine (86mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in CH ₂ Cl ₂ (6 mL) in solution. The resulting mixture was stirred at-10 ℃ for 1h, and the mixture was allowed to warm to room temperature and stirred for 4h. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (47.7mg, 47%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.27(3H,s),2.38(2H,s),2.54(2H,d),3.00(2H,d),3.72(3H,s),5.11(1H,dd),5.20(1H,d),5.45(1H,d),5.71(1H,m),6.58(1H,m),6.84(1H,s),7.12(1H,t),7.36(1H,d),7.45-7.50(2H,m),8.15(1H,s),8.27(1H,s),8.42(1H,d),8.61(1H,d),8.80-8.85(2H,m),9.44(1H,s)；ES(m/z):M+H ⁺ 508.2。

Example 52: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadienamide (I-52)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.4mL CH ₂ Cl ₂ Middle) was added dropwise to 4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) -6-methoxy-N- { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1,3-diamine (89mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (MeOH at 5-25 vol%) as eluent, and the resulting solution was concentrated to obtain the desired product (56.7 mg, 54%). ¹ H NMR(DMSO-d6)δ:1.73-1.79(1H,m),2.01-2.09(1H,m),2.17(6H,s),2.67-2.72(1H,m),3.19-3.25(3H,m),3.37-3.42(1H,m),3.89(3H,s),5.25(1H,dd),5.32(1H,d),5.48(1H,d),6.57(1H,m),6.70(1H,s),7.12(1H,dd),7.25(1H,d),7.40-7.45(2H,m),7.90(1H,s),8.11(1H,s),8.35(1H,d),8.50(1H,d),8.70(1H,s),8.81(1H,d),9.55(1H,s)；ES(m/z):M+H ⁺ 525.2。

Example 53: n- {2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxy-5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -phenyl } -cis-2,4-pentadiene amide (I-53)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (35mg, 0.3mmol, in 0.4mL CH) ₂ Cl ₂ In (b) was added dropwise to 4- (3-dimethylaminoazetidin-1-yl) -6-methoxy-N- { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1,3-diamine (129mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (92mg, 60%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.18(6H,s),3.06-3.12(1H,m),3.56-3.62(2H,m),3.89(3H,s),4.14(2H,t),5.17(1H,dd),5.28(1H,d),5.50(1H,d),6.50-6.55(2H,m),7.17(1H,td),7.28(1H,d),7.44-7.48(2H,m),7.81(1H,s),8.13(1H,s),8.36(1H,d),8.56(1H,br),8.81(1H,s),8.96(1H,d),9.49(1H,s)；ES(m/z):M+H ⁺ 511.2。

Example 54: n- {2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxy-5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-54)

At 0 ℃ and N ₂ Under protection, cis-2,4 is mixedPentadienoyl chloride (23mg, 0.2mmol, in 0.4mL THF) was added dropwise to N ¹ - (2-dimethylaminoethyl) -5-methoxy-N ¹ -methyl-N ⁴ - { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1,2,4-triamine (86mg, 0.2 mmol) and DIPEA (78mg, 0.6 mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (66.7mg, 65%) with MeOH (MeOH, 5 to 25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.32(2H,t),2.71(3H,s),2.90(2H,t),3.82(3H,s),5.15(1H,dd),5.24(1H,d),5.42(1H,d),6.50(1H,m),6.91(1H,s),7.12(1H,d),7.22(1H,d),7.30-7.35(1H,m),7.41-7.45(1H,m),8.13(1H,s),8.32(1H,d),8.47(1H,d),8.79-8.84(2H,m),8.90(1H,s),10.22(1H,br)；ES(m/z):M+H ⁺ 513.2。

Example 55: n- {2- { (3aR, 6aR) -5-Methylhexahydropyrrolo [3,4-b ] pyrrol-1 (2H) -yl } -5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-55)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4- { (3aR, 6 aR) -5-methylhexahydropyrrolo [3,4-b ] with protection]Pyrrole-1 (2H) -yl } -6-methoxy-N- { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1,3-diamine (91mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (54mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.70-1.76(1H,m),1.94-2.05(1H,m),2.10(3H,s),2.23(1H,d),2.41-2.48(1H,m),2.81(1H,s),3.12-3.20(1H,m),3.35-3.42(2H,m),3.79(3H,s),4.24-4.30(1H,m),5.25(1H,dd),5.33(1H,d),5.48(1H,d),6.50-6.56(1H,m),6.72(1H,s),7.11(1H,td),7.25(1H,d),7.35-7.40(2H,m),8.02(1H,s),8.11(1H,d),8.35(1H,d),8.47(1H,d),8.75-8.81(2H,m),9.56(1H,s)；ES(m/z):M+H ⁺ 537.2。

Example 56: n- { 4-methoxy-2- (5-methyl-2,5-diazaspiro [3,4] oct-2-yl) -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadienamide (I-56)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL THF) was added dropwise to 4-methoxy-6- (5-methyl-2,5-diazaspiro [3,4] under protection]Oct-2-yl) -N' - { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1,3-diamine (91mg, 0.2 mmol) and DIPEA (39mg, 0.3 mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (59mg, 55%) with MeOH (5-25% MeOH by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.66-1.71(2H,m),2.02-2.07(2H,m),2.30(3H,s),2.61(2H,t),3.68(2H,d),3.80(3H,s),3.97(2H,d),5.18(1H,dd),5.25(1H,d),5.50(1H,d),6.51-6.57(2H,m),7.12(1H,td),7.25(1H,d),7.45-7.49(2H,m),7.76(1H,s),7.97(1H,s),8.32(1H,d),8.55(1H,d),8.72(1H,s),8.84(1H,d),9.47(1H,s)；ES(m/z):M+H ⁺ 537.2。

Example 57: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-57)

At-10 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to 4- [ (3R) -3-dimethylaminopyrrolidin-1-yl chloride with protection]-N- {4- (1-methylindol-3-yl) pyrimidin-2-yl } -6-methoxybenzene-1,3-diamine (89mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (3 mL). The mixture was stirred at-10 ℃ for 30min, allowed to warm to room temperature for 4h, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (54.5mg, 52%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.96-2.00(1H,m),2.24(1H,d),2.90(1H,s),3.11(4H,d),3.92(3H,s),5.16(1H,dd),5.24(1H,d),5.40(1H,d),6.54-6.59(1H,m),6.82(1H,s),7.14(1H,d),7.23-7.28(1H,m),7.41-7.46(2H,m),7.71(1H,s),8.20(1H,s),8.34(1H,d),8.45(1H,s),8.81(1H,s),8.97(1H,s),9.85(1H,s)；ES(m/z):M+H ⁺ 524.2。

Example 58: n- {2- [ 3-dimethylamino-azetidin-1-yl ] -5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-58)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.4mL CH ₂ Cl ₂ In) is added dropwise to 4- [ 3-dimethylaminoazetidin-1-yl) -N- [4- (1H-indol-3-yl) pyrimidin-2-yl]-6-methoxy-benzene-1,3-diamine (86mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 4 hours. Then saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (52mg, 51%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.05(6H,d),3.10(1H,s),3.54(2H,t),3.87(3H,s),3.92(2H,t),5.15(1H,dd),5.28(1H,d),5.44(1H,d),6.33(1H,s),6.57(1H,m),7.16(2H,dt),7.23(1H,t),7.40-7.46(2H,m),7.84(1H,s),7.97(1H,s),8.20(1H,d),8.31(1H,d),8.45(1H,d),9.52(1H,s),11.81(1H,s)；ES(m/z):M+H ⁺ 510.2。

Example 59: n- {2- (2-dimethylaminoethyl-methylamino) -5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxyphenyl } -cis-2,4-pentadiene amide (I-59)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 3mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -N ⁴ - [4- (1H-indol-3-yl) pyrimidin-2-yl]-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (86mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (5 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (56mg, 55%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.17(6H,s),2.24-2.30(2H,m),2.61(3H,s),2.80-2.86(2H,m),3.87(3H,s),5.14(1H,dd),5.22(1H,d),5.56(1H,d),6.50-6.55(1H,m),6.82(1H,s),7.02(1H,d),7.12-7.16(1H,m),7.35(1H,dd),7.47(1H,m),7.61(1H,s),8.16(1H,d),8.32(1H,d),8.66(1H,s),9.80(1H,s),9.95(1H,s),10.32(1H,s)；ES(m/z):M+H ⁺ 512.2。

Example 60: n- { 4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ methyl- (2-methylaminoethyl) amino ] phenyl } -cis-2,4-pentadiene amide (I-60)

At 0 ℃ and N ₂ Under protection, N- [2- [ [ 5-methoxy-4- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino acid]Amino-2- (cis-2,4-pentadienoylamino) phenyl]-methylamino radical]Ethyl-N-methylcarbamic acid tert-butyl ester (122mg, 0.2mmol) and TFA (1 mL) 6mL CH was added ₂ Cl ₂ Then, the mixture was stirred at room temperature for 4 hours and concentrated in vacuo. Then adding 10% MeOH/CH to the residue ₂ Cl ₂ (volume content) and saturated NaHCO ₃ Washing (4 mL), washing the organic phase with water (3 mL), and adding MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (61.4 mg, 60%) with MeOH (MeOH at 5-25% by volume) as eluent.

The target product obtained in example 60 was analyzed by nuclear magnetic resonance, and the results were obtained ¹ H NMR(DMSO-d6)δ:2.30(3H,s),2.52-2.58(2H,m),2.70(3H,s),2.82-2.86(2H,m),3.81(3H,s),3.92(3H,s),5.17(1H,dd),5.26(1H,d),5.40(1H,d),6.52-6.57(1H,m),7.01(1H,s),7.16(1H,t),7.24-7.28(2H,m),7.42(1H,m),7.55(1H,d),7.92(1H,s),8.34(1H,d),8.42(1H,d),8.80(1H,s),9.31(1H,s),10.75(1H,s)；ES(m/z):M+H ⁺ 512.2。

Example 61: n- {2- (2-dimethylaminoethyl-methylamino) -5- [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadiene-amide (I-61)

At-10 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47mg, 0.4mmol in 0.5mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -5-trifluoromethoxybenzene-1,2,4-triamine (195mg, 0.4 mmol) and DIPEA (78mg, 0.6 mmol) in THF (5 mL). The mixture was stirred at 0 ℃ for 1h, warmed to room temperature for 4h, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (122.5mg, 54%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.34(2H,t),2.71(3H,s),2.89(2H,t),5.11(1H,dd),5.20(1H,d),5.42(1H,d),6.49(1H,m),6.90(1H,s),7.11(1H,d),7.25(1H,d),7.30-7.35(1H,m),7.47(1H,m),8.20(1H,s),8.37(1H,d),8.48(1H,d),8.79-8.83(2H,m),8.88(1H,s),10.12(1H,br)； ¹⁹ F NMR:-57.0(3F,s)；ES(m/z):M+H ⁺ 567.2。

Example 62: n- {5- [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-62)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to N under protection ⁴ - { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-5-trifluoromethoxybenzene-1,2,4-triamine (104mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (5 mL). The resulting mixture was reacted at room temperature for 4h and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (68.5mg, 57%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.21(6H,s),2.30(2H,t),2.72(3H,s),3.85-2.92(2H,m),5.12(1H,dd),5.23(1H,d),5.40(1H,d),6.52(1H,m),6.87(1H,s),7.11(1H,td),7.20-7.28(1H,m),7.41-7.46(2H,m),8.37(1H,s),8.44(1H,d),8.55(1H,d),8.92(1H,s),9.45(1H,s),10.27(1H,s)； ¹⁹ F NMR:-57.8(3F,s)；ES(m/z):M+H ⁺ 601.2。

Example 63: n- {2- [ 2-dimethylaminoethyl-methylamino ] -5- [ 5-methyl-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadienamide (I-63)

At 15 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.4mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - { 5-methyl-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -5-trifluoromethoxybenzene-1,2,4-triamine (100mg, 0.5 mmol) and DIPEA (39mg, 0.3 mmol) in THF (5 mL). Mixing the obtained mixtureThe mixture was reacted at room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (58mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.22(6H,s),2.29(2H,t),2.35(3H,s),2.70(3H,s),3.82-2.88(2H,m),5.14(1H,dd),5.23(1H,d),5.41(1H,d),6.53-6.58(1H,m),6.82(1H,s),7.15(1H,td),7.28-7.32(1H,m),7.40-7.45(2H,m),8.47(1H,s),8.56(1H,d),8.79(1H,d),9.00(1H,s),9.45(1H,s),10.17(1H,s)； ¹⁹ F NMR:-58.8(3F,s)；ES(m/z):M+H ⁺ 581.2。

Example 64: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 2-dimethylaminoethyl-methylamino ] -4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-64)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (35mg, 0.3mmol in 0.4mL THF) was added dropwise to N under protection ⁴ - { 5-cyano-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-5-trifluoromethoxybenzene-1,2,4-triamine (154mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ /MeOH (MeOH 5-25 vol.%) as eluent, and dissolvingThe solution was concentrated to obtain the objective product (106.6mg, 60%). ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.25(2H,dd),2.61(3H,d),3.75-2.80(2H,m),5.12(1H,dd),5.20(1H,d),5.55(1H,d),6.60(1H,m),6.70(1H,s),6.95(1H,d),7.16(1H,s),7.42(1H,m),7.68(1H,s),8.54(2H,dd),8.66(1H,s),9.12(1H,s),9.26(1H,s),10.45(1H,s)； ¹⁹ F NMR:-58.9(3F,s)；ES(m/z):M+H ⁺ 592.2。

Example 65: n- { 4-Difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (I-65)

At 20 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (47mg, 0.4mmol, in 0.5mL CH) ₂ Cl ₂ In (1) dropwise addition to 5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -benzene-1,2,4-triamine (188mg, 0.4 mmol) and DIPEA (78mg, 0.6mmol) in CH ₂ Cl ₂ (6 mL) in solution. After the resulting mixture was reacted at this temperature for 4 hours, saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (131.8mg, 60%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.23(6H,s),2.34(2H,t),2.70(3H,s),2.95(2H,t),5.15(1H,dd),5.26(1H,d),5.39(1H,d),6.52(1H,m),6.90(1H,s),7.11(1H,d),7.25(1H,d),7.30-7.35(1H,m),7.45-7.49(1H,m),8.21(1H,s),8.36(1H,d),8.49(1H,d),8.77-8.82(2H,m),8.88(1H,s),10.26(1H,br)； ¹⁹ F NMR:-80.0(2F,d)；ES(m/z):M+H ⁺ 549.2。

Example 66: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] phenyl } -cis-2,4-pentadiene amide (I-66)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to N under protection ⁴ - { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methylbenzene-1,2,4-triamine (101mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 4h, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (58mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.21(6H,s),2.31(2H,t),2.68(3H,s),3.80-2.85(2H,m),5.14(1H,dd),5.25(1H,d),5.46(1H,d),6.60(1H,m),6.82(1H,s),7.15(1H,td),7.28-7.34(1H,m),7.47-7.52(2H,m),8.44(1H,s),8.51(1H,d),8.57(1H,d),8.98(1H,s),9.26(1H,s),10.37(1H,s)； ¹⁹ F NMR:-80.1(2F,d)；ES(m/z):M+H ⁺ 583.2。

Example 67: n- { 4-Difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] -5- { [ 5-methyl-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadienamide (I-67)

At 0 ℃ and N ₂ Under the protection, cis-2,4-pentadienoyl chloride (38mg, 0.33mmol, in 0.4mL CH) ₂ Cl ₂ In) dropwise addition to N ⁴ - { 5-chloro-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methylbenzene-1,2,4-triamine (159mg, 0.33mmol) and DIPEA (65mg, 0.5mmol) in CH ₂ Cl ₂ (6 mL) in solution. Stirring the obtained mixture at 0 ℃ for reaction for 30min, raising the temperature to room temperature for reaction for 4h, and then adding saturated NaHCO ₃ The reaction was quenched with a small amount of methanol (3-5 drops) and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (MeOH 5-25% by volume) as eluent, and the resulting solution was concentrated to obtain the desired product (104mg, 56%). ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.27(2H,t),2.32(3H,s),2.75(3H,s),3.80-2.86(2H,m),5.12(1H,dd),5.25(1H,d),5.46(1H,d),6.58(1H,m),6.86(1H,s),7.11(1H,td),7.27-7.32(1H,m),7.42-7.46(2H,m),8.40(1H,s),8.55(1H,d),8.70(1H,d),8.96(1H,s),9.30(1H,s),10.11(1H,s)； ¹⁹ F NMR:-80.5(2F,d)；ES(m/z):M+H ⁺ 563.2。

Example 68: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] phenyl } -cis-2,4-pentadiene amide (I-68)

At 25 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.4mL THF) was added dropwise to N under protection ⁴ - { 5-cyano-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } -5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methylbenzene-1,2,4-triamine (99mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (6 mL). The resulting mixture was reacted at room temperature for 4h and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. Passing the obtained crude product throughPurifying by silica gel column chromatography with CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (52.8mg, 46%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.21(6H,s),2.27(2H,dd),2.60(3H,d),3.70-2.76(2H,m),5.15(1H,dd),5.24(1H,d),5.45(1H,d),6.52(1H,m),6.72(1H,s),6.98(1H,d),7.16(1H,s),7.46(1H,m),7.67(1H,s),8.55(2H,dd),8.62(1H,s),9.10(1H,s),9.25(1H,s),10.45(1H,s)； ¹⁹ F NMR:-80.8(2F,d)；ES(m/z):M+H ⁺ 574.2。

Example 69: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-69)

At 20 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (55mg, 0.5mmol in 0.6mL THF) was added dropwise to N with protection ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-trifluoromethoxybenzene-1,2,4-triamine (250mg, 0.5 mmol) and DIPEA (78mg, 0.6mmol) in THF (80 mL). The resulting mixture was stirred at 20 ℃ for 4h and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (10 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (168mg, 58%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.19(6H,s),2.25(2H,t),2.71(3H,s),2.98(2H,t),3.84(3H,s),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.52-6.56(1H,m),6.80(1H,s),7.18(1H,d),7.25-7.28(2H,m),7.41(1H,m),7.49(1H,m),7.70(1H,s),8.12(1H,m),8.45(1H,d),8.96(1H,s),9.88(1H,s),10.79(1H,s)； ¹⁹ F NMR:-57.1(3F,s)；ES(m/z):M+H ⁺ 580.2。

Example 70: n- {5- [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-70)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.4mL CH ₂ Cl ₂ In) dropwise addition to N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-trifluoromethoxybenzene-1,2,4-triamine (107mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (6 mL) in solution. Stirring the obtained mixture at 0 ℃ for reaction for 30min, raising the temperature to room temperature for reaction for 4h, and then adding saturated NaHCO ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (67.5mg, 55%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.38(2H,t),2.74(3H,s),2.95(2H,t),3.78(3H,s),5.22(1H,dd),5.29(1H,d),5.45(1H,d),6.57(1H,m),7.17-7.20(2H,m),7.40-7.46(2H,m),8.21(1H,d),8.46(1H,s),8.55(1H,s),8.68(1H,s),8.90(1H,s),9.57(1H,s)； ¹⁹ F NMR:-57.0(3F,s)；ES(m/z):M+H ⁺ 614.2。

Example 71: n- {2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-71)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (47mg, 0.4mmol in 0.5mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-trifluoromethoxybenzene-1,2,4-triamine (205mg, 0.4 mmol) and DIPEA (79mg, 0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (10 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (118.8mg, 50%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.18(6H,s),2.33(2H,t),2.40(3H,s),2.75(3H,s),2.91(2H,t),3.75(3H,s),5.14(1H,dd),5.28(1H,d),5.47(1H,d),6.55-6.60(1H,m),6.78(1H,s),7.13-7.20(2H,m),7.35(1H,d),7.44-7.49(1H,m),8.20(1H,d),8.41(1H,s),8.55(1H,s),8.68(1H,s),8.92(1H,s),9.51(1H,s)； ¹⁹ F NMR:-57.3(3F,s)；ES(m/z):M+H ⁺ 594.2。

Example 72: n- {5- [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-72)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.4mL THF) was added dropwise to N under protection ⁴ - [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl]-N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-5-trifluoromethoxybenzene-1,2,4-triamine (105mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ Quenching reaction between (4 mL) and a small amount of methanol (3-5 drops), and carrying out organic reactionThe phases were washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (48.4 mg, 40%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.18(6H,s),2.34(2H,t),2.72(3H,s),2.90(2H,t),3.75(3H,s),5.21(1H,dd),5.27(1H,d),5.44(1H,d),6.52-6.56(1H,m),6.91(1H,s),7.12-7.20(2H,m),7.44-7.48(2H,m),8.20(1H,d),8.46(1H,s),8.52(1H,s),8.61(1H,s),8.86(1H,s),9.77(1H,s)； ¹⁹ F NMR:-57.0(3F,s)；ES(m/z):M+H ⁺ 605.2。

Example 73: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] aminophenyl } -cis-2,4-pentadiene amide (I-73)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (58mg, 0.5mmol in 0.6mL THF) was added dropwise to 5-difluoromethoxy-N with protection ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1,2,4-triamine (241mg, 0.5 mmol) and DIPEA (79mg, 0.6 mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (10 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (168.6 mg, 60%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.19(6H,s),2.24(2H,t),2.70(3H,s),2.91(2H,t),3.77(3H,s),5.18(1H,dd),5.31(1H,d),5.48(1H,d),6.54(1H,m),6.85(1H,s),7.20(1H,d),7.26-7.31(2H,m),7.35-7.38(1H,m),7.45-7.49(1H,m),7.78(1H,s),8.05-8.08(1H,m),8.45(1H,d),8.99(1H,s),9.81(1H,s),10.78(1H,s)； ¹⁹ F NMR:-79.2(2F,d)；ES(m/z):M+H ⁺ 562.2。

Example 74: n- {5- [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -cis-2,4-pentadiene amide (I-74)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (35mg, 0.3mmol, in 0.4mL CH) ₂ Cl ₂ In (1) dropwise addition to 5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1,2,4-triamine (155mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in CH ₂ Cl ₂ (8 mL) in solution. Stirring the obtained mixture at 0 ℃ for reaction for 30min, raising the temperature to room temperature for reaction for 4h, and then adding saturated NaHCO ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (80.5mg, 45%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.38(2H,t),2.80(3H,s),2.93(2H,t),3.87(3H,s),5.14(1H,dd),5.25(1H,d),5.44(1H,d),6.55-6.59(1H,m),6.83(1H,s),7.15-7.21(2H,m),7.45-7.49(2H,m),8.26(1H,d),8.47(1H,s),8.54(1H,s),8.69(1H,s),8.91(1H,s),9.64(1H,s)； ¹⁹ F NMR:-80.0(2F,d)；ES(m/z):M+H ⁺ 596.2。

Example 75: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] aminophenyl } -cis-2,4-pentadiene amide (I-75)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (12mg, 0.1mmol in 0.3mL THF) was added dropwise to 5-difluoromethoxy-N under protection ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1,2,4-triamine (50mg, 0.1mmol) and DIPEA (20mg, 0.15mmol) in THF (10 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 5h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ The reaction was quenched with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (37.4 mg, 65%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.22(6H,s),2.30(2H,t),2.38(3H,s),2.75(3H,s),2.92(2H,t),3.76(3H,s),5.24(1H,dd),5.31(1H,d),5.43(1H,d),6.55-6.60(1H,m),6.87(1H,s),7.14-7.20(2H,m),7.44-7.49(2H,m),8.20(1H,d),8.47(1H,s),8.56(1H,s),8.69(1H,s),8.89(1H,s),9.61(1H,s)； ¹⁹ F NMR:-80.1(2F,d)；ES(m/z):M+H ⁺ 576.2。

Example 76: n- {5- [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -cis-2,4-pentadiene amide (I-76)

At 20 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to N under protection ⁴ - [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methylbenzene-1,2,4-triamine (101mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (6 mL). The resulting mixture was reacted at room temperature for 4h and then concentrated in vacuo. Then dissolving the residueIs solved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (56.4 mg, 48%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.18(6H,s),2.30(2H,t),2.73(3H,s),2.91(2H,t),3.75(3H,s),5.17(1H,dd),5.27(1H,d),5.48(1H,d),6.55-6.59(1H,m),6.91(1H,s),7.14-7.20(2H,m),7.44-7.49(2H,m),8.23(1H,d),8.40(1H,s),8.51(1H,s),8.67(1H,s),8.80(1H,s),9.71(1H,s)； ¹⁹ F NMR:-80.0(2F,d)；ES(m/z):M+H ⁺ 587.2。

Example 77: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadiene-mide (I-77)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (53mg, 0.45mmol in 0.6mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -N ⁴ - [4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ -methyl-5-trifluoromethoxybenzene-1,2,4-triamine (219mg, 0.45mmol) and DIPEA (79mg, 0.6mmol) in THF (7 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 5 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (10 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (114.6 mg, 45%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.19(6H,s),2.30(2H,t),2.66(3H,s),2.90(2H,t),5.17(1H,dd),5.25(1H,d),5.50(1H,d),6.55-6.69(1H,m),6.99(1H,s),7.14(1H,d),7.27(1H,d),7.30-7.35(1H,m),7.47-7.52(1H,m),8.22(1H,s),8.38(1H,d),8.51(1H,d),8.78-8.83(2H,m),8.95(1H,s),10.15(1H,br)； ¹⁹ F NMR:-58.7(3F,s)；ES(m/z):M+H ⁺ 566.2。

Example 78: n- {5- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-78)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -N ⁴ - [4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ -methyl-5-trifluoromethoxybenzene-1,2,4-triamine (104mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (5 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (15 mL), and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (MeOH 5-25% by volume) as eluent, and the resulting solution was concentrated to obtain the desired product (60mg, 50%). ¹ H NMR(DMSO-d6)δ:2.21(6H,s),2.32(2H,br),2.70(3H,s),2.84-2.89(2H,m),5.17(1H,dd),5.25(1H,d),5.44(1H,d),6.53-6.57(1H,m),6.91(1H,s),7.09(1H,s),7.22(1H,t),7.44-7.48(2H,m),8.30(1H,d),8.41(1H,s),8.49(1H,s),8.55(1H,d),8.95(1H,s),10.74(1H,s),11.99(1H,s)； ¹⁹ F NMR:-58.1(3F,s)；ES(m/z):M+H ⁺ 600.2。

Example 79: n- {2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-79)

At 0 ℃ and N ₂ Under protection, cis-2,4-pentadienoyl chloride (35mg, 0.3mmol, in 0.5mL CH) ₂ Cl ₂ In) dropwise addition to N ¹ - (2-dimethylaminoethyl) -N ⁴ - [4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ -methyl-5-trifluoromethoxybenzene-1,2,4-triamine (150mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in CH ₂ Cl ₂ (8 mL) in solution. The resulting mixture was reacted at room temperature for 4h and then saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (78.3mg, 45%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.23(6H,s),2.35(2H,t),2.45(3H,s),2.78(3H,s),2.94(2H,t),5.18(1H,dd),5.27(1H,d),5.40(1H,d),6.53-6.58(1H,m),6.87(1H,s),7.14-7.20(2H,m),7.42-7.46(2H,m),8.23(1H,d),8.45(1H,s),8.50(1H,s),8.65(1H,s),8.88(1H,s),9.59(1H,s)； ¹⁹ F NMR:-57.9(3F,s)；ES(m/z):M+H ⁺ 580.2。

Example 80: n- {5- [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (I-80)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (35mg, 0.3mmol in 0.4mL THF) was added dropwise to N under protection ⁴ - [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-5-trifluoromethoxybenzene-1,2,4-triamine (153mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in THF (6 mL). Mixing the obtained mixture withStirring at 0 deg.C for 30min, heating to room temperature, reacting for 4 hr, and vacuum concentrating. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (76.2mg, 43%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.38(2H,t),2.70(3H,s),2.82(2H,t),5.16(1H,dd),5.29(1H,d),5.45(1H,d),6.55-6.59(1H,m),6.91(1H,s),7.12-7.20(2H,m),7.44-7.48(2H,m),8.25(1H,d),8.47(1H,s),8.55(1H,s),8.65(1H,s),8.91(1H,s),9.64(1H,s)； ¹⁹ F NMR:-58.5(3F,s)；ES(m/z):M+H ⁺ 591.2。

Example 81: n- { 4-Difluoromethoxy-5- [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) phenyl } -cis-2,4-pentadiene amide (I-81)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.4mL THF) was added dropwise to 5-difluoromethoxy-N with protection ¹ - (2-dimethylaminoethyl) -N ⁴ - [4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ -methylbenzene-1,2,4-triamine (94mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (65.8mg, 60%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.23(6H,s),2.31(2H,t),2.70(3H,s),2.94(2H,t),5.19(1H,dd),5.25(1H,d),5.45(1H,d),6.55-6.58(1H,m),6.97(1H,s),7.11(1H,d),7.20(1H,d),7.30-7.33(1H,m),7.41-7.45(1H,m),8.17(1H,s),8.36(1H,d),8.47(1H,d),8.78-8.84(2H,m),8.91(1H,s),10.22(1H,br)； ¹⁹ F NMR:-79.4(2F,d)；ES(m/z):M+H ⁺ 548.2。

Example 82: n- {5- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -cis-2,4-pentadiene amide (I-82)

At 10 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (35mg, 0.3mmol, in 0.4mL CH, under protection ₂ Cl ₂ In) dropwise addition to N ⁴ - [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl]-5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methylbenzene-1,2,4-triamine (151mg, 0.3mmol) and DIPEA (59mg, 0.45mmol) in CH ₂ Cl ₂ (7 mL) in solution. Stirring the obtained mixture at 10 deg.C for reaction for 30min, heating to room temperature for reaction for 4h, and adding saturated NaHCO ₃ The reaction was quenched with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO was added ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (83.8mg, 48%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ HNMR(DMSO-d6)δ:2.21(6H,s),2.32(2H,br),2.65(3H,s),2.88-2.93(2H,m),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55-6.59(1H,m),6.96(1H,s),7.12(1H,s),7.19(1H,t),7.40-7.45(2H,m),8.20(1H,d),8.34(1H,s),8.44(1H,s),8.48(1H,d),8.61(1H,s),10.27(1H,s),11.91(1H,s)； ¹⁹ F NMR:-80.5(2F,d)；ES(m/z):M+H ⁺ 582.2。

Example 83: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1H-indol-3-yl) pyrimidin-2-yl ] aminophenyl } -cis-2,4-pentadiene amide (I-83)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to 5-difluoromethoxy-N with protection ¹ - (2-dimethylaminoethyl) -N ⁴ - [4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ -methylbenzene-1,2,4-triamine (96mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL) and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (47.2mg, 42%) with MeOH (MeOH at 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.20(6H,s),2.32(2H,t),2.38(3H,s),2.71(3H,s),2.95(2H,t),5.21(1H,dd),5.30(1H,d),5.45(1H,d),6.55-6.59(1H,m),6.77(1H,s),7.14-7.22(2H,m),7.34(1H,d),7.44-7.48(1H,m),8.21(1H,d),8.42(1H,s),8.49(1H,s),8.71(1H,s),8.90(1H,s),9.75(1H,s)； ¹⁹ F NMR:-80.6(2F,d)；ES(m/z):M+H ⁺ 562.2。

Example 84: n- {5- [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -cis-2,4-pentadiene amide (I-84)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.4mL CH) was added under protection ₂ Cl ₂ In) dropwise addition to N ⁴ - [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl]-N ¹ - (2-dimethylaminoethyl)Yl) -5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (99mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (6 mL) in solution. The mixture is stirred and reacted for 30 minutes at the temperature of 0 ℃, and then is heated to room temperature for reaction for 4 hours, and then saturated NaHCO is added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to obtain the desired product (52.7 mg, 46%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:2.22(6H,s),2.38(2H,t),2.67(3H,s),2.90(2H,t),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55-6.59(1H,m),6.86(1H,s),7.16-7.23(2H,m),7.45-7.48(2H,m),8.25(1H,d),8.47(1H,s),8.51(1H,s),8.75(1H,s),8.97(1H,s),9.69(1H,s)； ¹⁹ F NMR:-79.7(2F,d)；ES(m/z):M+H ⁺ 573.2。

Example 85: n- {2- [ 2-dimethylaminoethyl-methylamino ] -5- [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadienamide (I-85)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol in 0.3mL THF) was added dropwise to N under protection ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - {4- (4,5,6,7-Tetrahydropyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } -5-trifluoromethoxybenzene-1,2,4-triamine (98mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in THF (5 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH ₂ Cl ₂ (8 mL), and saturated NaHCO was added ₃ (4 mL) and a small amount of methanol (3-5 drops), and the organic phase is washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product obtained was purified by silica gel column chromatographyBy CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (65mg, 57%) with MeOH (MeOH 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.70-1.77(2H,m),1.93-1.97(2H,m),2.25(6H,s),2.31(2H,t),2.74(3H,s),2.88(2H,t),3.11(2H,t),4.10(2H,t),5.19(1H,dd),5.25(1H,d),5.50(1H,d),6.55-6.59(1H,m),6.90(1H,s),6.99-7.05(1H,m),7.44-7.49(1H,m),7.91(1H,s),8.20(1H,s),8.37(1H,d),8.94(1H,s),10.34(1H,s)； ¹⁹ F NMR:-59.1(3F,s)；ES(m/z):M+H ⁺ 571.2。

Example 86: n- { 4-Difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] -5- [4- (4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] aminophenyl } -cis-2,4-pentadienamide (I-86)

At 0 ℃ and N ₂ Cis-2,4-pentadienoyl chloride (23mg, 0.2mmol, in 0.3mL CH) was added under protection ₂ Cl ₂ In (1) dropwise addition to 5-difluoromethoxy-N ¹ - (2-dimethylaminoethyl) -N ¹ -methyl-N ⁴ - {4- (4,5,6,7-Tetrahydropyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-yl } benzene-1,2,4-triamine (95mg, 0.2mmol) and DIPEA (39mg, 0.3mmol) in CH ₂ Cl ₂ (6 mL) in solution. The mixture is stirred and reacted for 30 minutes at the temperature of 0 ℃, then the temperature is raised to room temperature for reaction for 4 hours, and saturated NaHCO is added ₃ The reaction was quenched (4 mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4 mL) and MgSO ₄ Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH ₂ Cl ₂ The resulting solution was concentrated to give the desired product (60.8mg, 55%) with MeOH (MeOH, 5-25% by volume) as eluent. ¹ H NMR(DMSO-d6)δ:1.67-1.74(2H,m),1.88-1.95(2H,m),2.27(6H,s),2.34(2H,t),2.72(3H,s),2.91(2H,t),3.06(2H,t),4.10(2H,t),5.19(1H,dd),5.26(1H,d),5.45(1H,d),6.54-6.58(1H,m),6.86(1H,s),6.99-7.13(1H,m),7.44-7.49(1H,m),7.91(1H,s),8.20(1H,s),8.39(1H,d),8.99(1H,s),10.29(1H,s)； ¹⁹ F NMR:-80.0(2F,d)；ES(m/z):M+H ⁺ 553.2。

Example 87: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene-namide methanesulfonate (I-87)

The method comprises the following steps: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl } -cis-2,4-pentadiene amide (example 28,105mg,0.2 mmol) was dissolved in ethanol (6 mL) and ethyl acetate (2 mL), and dissolved completely with stirring, to which was slowly added dropwise a solution of methanesulfonic acid (19mg, 0.2 mmol) in ethyl acetate (1 mL). The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at room temperature overnight to give the polymorphic target product (105.7mg, 85%). ¹ HNMR(DMSO-d6)δ:2.72(3H,s),2.93(3H,s),3.11(6H,s),3.56(3H,t),3.90-4.00(7H,m),5.21(1H,dd),5.27(1H,d),5.38(1H,d),6.52-6.56(1H,m),7.09(1H,t),7.21(1H,t),7.24(1H,s),7.40-7.45(3H,m),8.10-8.18(3H,m),8.55(1H,s),9.29(1H,s),9.72(1H,s),9.98(1H,s)。

The method 2 comprises the following steps: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene-mide (example 28,105mg,0.2 mmol) was dissolved in acetone (5 mL) and water (0.5 mL) at room temperature, stirred until completely dissolved, and a solution of methanesulfonic acid (19mg, 0.2 mmol) in acetone (0.5 mL) was added dropwise. The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at room temperature overnight to give the polymorphic form of the desired product (112mg, 90%).

The method 3 comprises the following steps: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene-mide (example 28,105mg,0.2 mmol) was dissolved in acetonitrile (5 mL) at room temperature, stirred until completely dissolved, and a solution of methanesulfonic acid (19mg, 0.2 mmol) in acetonitrile (1 mL) was slowly added dropwise thereto. The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at room temperature overnight to give the polymorphic form of the desired product (102mg, 82%).

Example 88: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadiene-namide methanesulfonate (I-88)

N- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino-4-trifluoromethoxyphenyl } -cis-2,4-pentadiene amide (example 69,116mg,0.2 mmol) was dissolved in ethanol (6 mL) and ethyl acetate (2 mL), stirred until completely dissolved, and a solution of methanesulfonic acid (19mg, 0.2 mmol) in ethyl acetate (1 mL) was slowly added dropwise thereto. The resulting mixture was stirred for 2h, filtered to give a solid compound, and dried under vacuum at room temperature overnight to give the polymorphic target product (121.6 mg, 90%). ¹ H NMR(DMSO-d6)δ:2.71(3H,s),2.90(3H,s),3.00(6H,s),3.58(3H,t),3.87-4.01(4H,m),5.17(1H,dd),5.24(1H,d),5.43(1H,d),6.55-6.59(1H,m),7.10(1H,t),7.21(1H,t),7.31(1H,s),7.42-7.46(3H,m),8.12-8.18(3H,m),8.57(1H,s),9.31(1H,s),9.67(1H,s),9.79(1H,s)； ¹⁹ F NMR:-58.5(3F,s)。

Example 89: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] aminophenyl } -cis-2,4-pentadiene amide methanesulfonate (I-89)

N- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Aminophenyl } -cis-2,4-pentadiene amide (example 73,112mg,0.2 mmol) was dissolved in acetone (5 mL), stirred until completely dissolved, and a solution of methanesulfonic acid (19mg, 0.2 mmol) in acetone (1 mL) was slowly added dropwise thereto. The resulting mixture was stirred for 2 hoursIn time, the solid compound was filtered and dried under vacuum at room temperature overnight to give the polymorphic target product (114mg, 87%). ¹ H NMR(DMSO-d6)δ:2.67(3H,s),2.85(3H,s),3.02(6H,s),3.58(3H,t),3.85-4.01(4H,m),5.23(1H,dd),5.30(1H,d),5.51(1H,d),6.54-6.59(1H,m),7.18(1H,t),7.29(1H,t),7.35(1H,s),7.45-7.49(3H,m),8.12-8.19(3H,m),8.58(1H,s),9.32(1H,s),9.68(1H,s),9.81(1H,s)； ¹⁹ F NMR:-80.0(2F,d)。

Example 90: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-cyclopropylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene-amide methanesulfonate (I-90)

N- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-cyclopropylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadienamide (example 29, 110mg,0.2 mmol) was dissolved in ethanol (5 mL) and ethyl acetate (2 mL) at room temperature, stirred to complete dissolution, and to this was slowly added dropwise a solution of methanesulfonic acid (19mg, 0.2 mmol) in ethyl acetate (1 mL). The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried overnight under vacuum at room temperature to give the polymorphic target product (116.6mg, 90%).

Example 91: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) -4-isopropoxycarbonylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide methanesulfonate (I-91)

N- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) -4-isopropoxycarbonylpyrimidin-2-yl ] amino } phenyl } -cis-2,4-pentadiene amide (example 30,122.4mg,0.2 mmol) was dissolved in ethanol (6 mL) and ethyl acetate (2 mL) at room temperature, stirred to complete dissolution, and a solution of methanesulfonic acid (19mg, 0.2 mmol) in ethyl acetate (1 mL) was slowly added dropwise thereto. The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at room temperature overnight to give the polymorphic target product (113.2mg, 80%).

Biological Properties

Test 1-L858R/T790M EGFR (double mutant) cell phosphorylation test: seeding cells of the human Lung cell line NCI-H1975. Mu.L in growth medium in a Corning Black clear-bottomed 384 well plate, 5% CO at 37% ₂ The culture was carried out overnight. Using sonic dosing, 100% serially diluted compounds in DMSO were added to the cells. The plates were incubated for an additional 2 hours and after gentle mixing of the medium, 40. Mu.L of lysis buffer was added to each well. Greiner black high binding 384-well plates were covered with capture antibody and then blocked with 3% BSA. The blocking solution was then removed and 15 μ L of the lysate was transferred to Greiner black high binding 384 well plates and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of detection antibody was added and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of fluorescent peroxidase substrate was added and incubated for 1 hour. mu.L of stop solution was added to the plate and fluorescence was read in an Envision microplate detector using an excitation wavelength of 352nm and an emission wavelength of 460 nm. The appropriate fitted curve was obtained based on the data using Origin et al software and the IC determined by calculating the concentration of compound required to obtain a 50% effect ₅₀ The results are shown in Table 1.

Test 2-Exon19 deletion EGFR (activating single mutant) cell phosphorylation test: human lung cell line PC9 (Exon 19 deleted EGFR) according to R&D Systems DuoSet IC Human Phospho-EGF R ELISA to perform the measurement of endogenous p-EGFR cell phosphorylation assays in cell lysates. 40 μ L of cells were seeded in the growth medium in Corning black clear bottom 384 well plates at 37 ℃ in 5% CO ₂ The culture was carried out overnight. Dosing with sonic waves, compounds serially diluted in 100% dmso were added to the cells. The plates were incubated for an additional 2 hours and after gentle mixing of the media, 40. Mu.L of lysis buffer was added to each well. Greiner black high binding 384 well plates were covered with capture antibody and then blocked with 3% BSA. Then go toRemove the blocking solution and transfer 15. Mu.L of the lysate to Greiner black high binding capacity 384 well plates for 2 hours of culture. After gentle mixing and washing of the plates with PBS, 20 μ L of detection antibody was added and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of fluorescent peroxidase substrate was added and incubated for 1 hour. mu.L of stop solution was added to the plate and fluorescence was read in an Envision microplate detector using an excitation wavelength of 352nm and an emission wavelength of 460 nm. The appropriate fitted curve was obtained based on the data using Origin et al software and the IC determined by calculating the concentration of compound required to obtain a 50% effect ₅₀ The results are shown in Table 1.

Test 3-wild type EGFR cell phosphorylation test: human colon cell line LoVo according to R&D Systems DuoSet IC Human Phospho-EGF R ELISA to perform the measurement of endogenous p-EGFR cell phosphorylation assays in cell lysates. 40 μ L of cells were seeded in the growth medium in Corning black clear bottom 384-well plates, 5% CO at 37% ₂ The culture was carried out overnight. Dosing with sonic waves, compounds serially diluted in 100% dmso were added to the cells. The plates were incubated for 2 hours and after gentle mixing of the media, 40. Mu.L of lysis buffer was added to each well. Greiner black high binding 384-well plates were covered with capture antibody and then blocked with 3% BSA. The blocking solution was then removed and 15 μ L of the lysate was transferred to Greiner black high binding 384 well plates and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of detection antibody was added and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of fluorescent peroxidase substrate was added and incubated for 1 hour. mu.L of stop solution was added to the plate and fluorescence was read in an Envision microplate detector using an excitation wavelength of 352nm and an emission wavelength of 460 nm. The appropriate fitted curve was obtained based on the data using Origin et al software and the IC determined by calculating the concentration of compound required to obtain a 50% effect ₅₀ The results are shown in Table 1.

The test data (μ M) for 9 examples of the invention are shown in the table below. Although the detection data is expressed by a certain number of significant figures, it should not be considered as a number indicating that the data has been determined to be exactly a significant figure.

TABLE 1 biological Property test results

Test results show that the compounds shown in the table have effects on activating mutation, double mutation and wild type mutation, and have good selectivity and good application prospects.

Through stability tests, the half-life periods of the compounds shown in the table are over 60 hours, so that the dosage of the medicine can be well reduced, the time interval of medicine use is enlarged, and the medicine has lower toxicity.

The compounds disclosed in the present invention can be used alone or in combination with other agents for the treatment of various cancers, and are not limited to non-small cell lung cancer, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, and the like.

Claims

1. An N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof:

wherein A is selected from substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted hydropyrazolopyridyl, substituted or unsubstituted indolyl; the substituents in the substituted pyrazolopyridinyl, substituted hydropyrazolopyridinyl and substituted indolyl are respectively and independently selected from C1-C5 alkyl;

R ² is selected from alkoxy of C1 to C5 or fluoro alkoxy of C1 to C5;

wherein R is ⁴ Is selected from C1-C3 alkyl; r is ⁵ And R ⁶ Each independently selected from hydrogen or C1-C3 alkyl and not simultaneously hydrogen, or R ⁵ And R ⁶ Connecting to form a ring; n is an integer of 2 to 5;

2. The N- [5- (pyrimidin-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadienamide derivative of claim 1, wherein a is selected from 4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-cyclopropyl-1H-indol-3-yl or pyrazolo [1,5-a ] pyridin-3-yl.

3. N- [5- (pyrimidin-2-ylamino) -2,4-disubstituted phenyl according to claim 1]-cis-2,4-pentadiene amide derivative, wherein said R is ¹ Selected from hydrogen, chloro, methyl, cyano or isopropyloxycarbonyl;

the R is ² Selected from methoxy, difluoromethoxy or trifluoromethoxy.

4. N- [5- (pyrimidin-2-ylamino) -2,4-disubstituted phenyl according to claim 1]-cis-2,4-pentadiene amide derivative, wherein said R is ³ Selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino)Ethyl radical](methyl) amino, [2- (methylamino) ethyl](methyl) amino, 5-methyl-2,5-diazaspiro [3,4]Oct-2-yl, (3aR, 6aR) -5-methylhexahydropyrrolo [3,4-b]Pyrrol-1 (2H) -yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4- [2- (dimethylamino) -1-oxoethyl]Piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl) ethyl]Amino, methyl [2- (morpholin-4-yl) ethyl ] ethyl]Amino or 4- [ (2S) -2-aminopropionyl group]Piperazin-1-yl.

5. The N- [5- (pyrimidin-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative of claim 1, wherein the derivative is one or more of compounds represented by formulas (I-1) to (I-91):

6. use of the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative according to any one of claims 1 to 5 in the preparation of an epidermal growth factor receptor inhibitor medicament.

7. Use of the N- [5- (pyrimidine-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadiene amide derivative according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and/or prevention of cancer.

8. The use of claim 7, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, mesothelioma, and complications thereof.

9. The use of claim 7, wherein the cancer is a non-small cell cancer.

10. A pharmaceutical composition comprising the N- [5- (pyrimidin-2-amino) -2,4-disubstituted phenyl ] -cis-2,4-pentadienamide derivative of any one of claims 1 to 5.