CN107793413A

CN107793413A - Pyrimidine heterocyclic compound and its preparation method and application

Info

Publication number: CN107793413A
Application number: CN201610803436.3A
Authority: CN
Inventors: 田红旗; 黄功超; 程瑛
Original assignee: BINJIANG PHARMA Inc
Current assignee: KECHOW PHARMA Inc
Priority date: 2016-09-05
Filing date: 2016-09-05
Publication date: 2018-03-13
Anticipated expiration: 2036-09-05
Also published as: CN107793413B

Abstract

The present invention relates to the compound of formula (I) and its pharmaceutically acceptable salt, prodrug and solvate, this kind of compound can be used for cancer and inflammation in treatment mammal.The invention also discloses the preparation method of formula (I) compound and include the pharmaceutical composition of the compound.

Description

Pyrimidine heterocyclic compound and preparation method and application thereof

Technical Field

The present invention relates to certain fluoroheterocyclic compounds and pharmaceutically acceptable salts thereof, which are useful for the treatment and prevention of diseases or conditions mediated by certain variant forms of epidermal growth factor receptor (e.g., L858R activation mutant, Exon19 deletion activation mutant, and T790M resistance mutant). Such compounds and their salts are useful in the treatment or prevention of many different cancers. The invention is also directed to pharmaceutical compositions comprising the compounds and salts thereof, to intermediates in the preparation of the compounds, and to methods of using the compounds and salts thereof to treat various forms of EGFR-mediated diseases.

Background

EGFR is a member of the erbB receptor family of transmembrane protein tyrosine kinases. When bound to a growth factor ligand, such as Epidermal Growth Factor (EGF), the receptor may homodimerize with additional EGFR molecules or heterodimerize with another family member, such as erbB2(HER2), erbB3(HER3), or erbB4(HER 4).

Homodimerization and/or heterodimerization of erbB receptors results in phosphorylation of key tyrosine residues in the intracellular domain and in stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many human cancers, including lung, head and neck, and breast cancers.

Thus, the erbB family represents a reasonable target for the development of anticancer drugs, and many agents targeting EGFR or erbB2 are now clinically available, including gefitinib (IRESSA)^TM) Erlotinib (TARCEVA)^TM) Lapatinib (TYKERB)^TM,TYVERB^TM). A detailed discussion of erbB receptor signaling and its involvement in tumorigenesis is provided in New England Journal of medicine (2008) stage 358, 1160-74 and Bi deg.C chemical and biological Research communication (2004) Vol.319, 1-11.

Activating mutations of EGFR in non-small cell lung cancer (NSCLC) reported in 2004 (Science [2004] stage 304, 1497-500 and New England Journal of medicine [2004] stage 350, 2129-39) were associated with response to gefitinib treatment. The most common EGFR activating mutations (L858R and del 746_ a750) result in increased affinity for small molecule tyrosine kinase inhibitors (such as gefitinib and erlotinib) and decreased affinity for adenosine monophosphate (ATP) relative to wild-type (WT) EGFR. Finally, acquired resistance to gefitinib or erlotinib treatment, such as the mutation at gatekeeper residue T790M, which is reported to be detected in 50% of clinically resistant patients, is not considered to sterically hinder gefitinib or erlotinib binding to EGFR, but only alters the affinity for ATP to levels comparable to WT EGFR.

Given the importance of such mutations in the resistance of existing therapies targeting EGFR. Drugs that can inhibit EGFR including a mutation in the gatekeeping gene are considered to be particularly useful in the treatment of cancer.

There remains a need for compounds that can exhibit advantageous potency properties for WT EGFR, and/or selectivity with respect to other enzyme receptors, which make these compounds particularly promising for development as therapeutic agents, relative to activating mutant forms of EGFR (e.g., L858R EGFR mutant, or del e746_ a750 mutant or Exon19 deletion EGFR mutant) and/or resistant mutant forms of EGFR (e.g., T790M EGFR mutant). In this regard, there is a need for compounds that exhibit high inhibition of certain activating or resistant mutant forms of EGFR while exhibiting relatively low inhibition of WT EGFR. Due to the reduced toxicology associated with inhibition of wild-type EGFR, it is expected that such compounds may be more suitable for use as therapeutic agents, particularly for cancer treatment. Such toxicology is known to manifest as rashes and/or diarrhea in humans.

The applicant has found that one or more fluoro-heterocyclic compounds have high potency relative to several EGFR mutant forms, while showing relatively low inhibition of WTEGFR. The compounds of the invention may also exhibit advantageous physical properties (e.g., higher aqueous solubility, permeability, and/or lower plasma protein binding) and/or advantageous toxicity profiles (e.g., reduced tendency to hERG block) and/or advantageous metabolic profiles compared to other known EGFR/EGFR mutant inhibitors. Thus, such compounds are particularly useful in the treatment of disease conditions that involve EGFR and/or activating mutations of EGFR and/or resistance mutations of EGFR, for example, in the treatment of cancer.

Disclosure of Invention

One aspect of the present invention provides compounds of formula (I) and pharmaceutically acceptable salts, prodrugs and solvates thereof,

wherein,

R¹selected from: hydrogen, deuterium, halogen, unsubstituted or substituted C1-6 alkyl, -NR6R₇Nitro, cyano, -OR⁶、-C(O)OR⁶、-C(O)R⁶、-C(O)NR⁶R⁷、-S(O)_t-R⁶、-S(O)₂-NR⁶R⁷；

R²Selected from: hydrogen, halogen, C_1-6Alkyl, halogen substituted C_1-6Alkyl, -S (O)_t-R⁶、-OR¹³；

R³Selected from: hydrogen, halogen, unsubstituted or substituted C_1-6Alkyl, unsubstituted OR substituted aromatic OR non-aromatic heterocyclyl, unsubstituted OR substituted heterocycloalkyl, -OR⁶、-NR⁶R⁷、-C(O)R⁶、-S(O)_t-R⁶；

R⁴And R⁵Independently selected from: hydrogen, unsubstituted or substituted C_1-6Alkyl, -C (O) R⁶、-S(O)_t-R⁶(ii) a Or, R⁴And R³Together with the nitrogen atom to which they are attached and the phenyl ring form a substituted or unsubstituted aromatic or non-aromatic heterocyclic group;

t is 0, 1, 2;

R⁶and R⁷Independently selected from: hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted C_1-6An alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic or non-aromatic heterocyclic group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted amino group, a halogen;

R¹³selected from halogen substituted C_1-6An alkyl group;

g is selected from the following groups:

x is selected from carbon, nitrogen (CH, N);

R⁸selected from: hydrogen, deuterium, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, -C (O) R⁶、-S(O)_t-R6；

R⁹Selected from: hydrogen, halogen, substituted OR unsubstituted alkyl, -OR⁶、-S(O)_t-R⁶。

Preferably, R⁸Selected from: hydrogen, deuterium, substituted or unsubstituted C_1-3Alkyl, substituted or unsubstituted C_3-5Cycloalkyl, -S (O)₂-R⁶，R⁶Selected from: substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-6Cycloalkyl groups of (a); more preferably, R⁸Selected from: hydrogen, halogen substituted or unsubstituted C_1-3Alkyl (e.g., methyl, ethyl, isopropyl, n-propyl), -S (O)₂-R⁶，R⁶Selected from: substituted or unsubstituted C_1-3Alkyl, substituted or unsubstituted cyclopropyl; further preferably, R⁸Selected from: -CH₃、-CH₂CF₃Cyclopropane, isopropyl, methylsulfonyl;

preferably, R⁹Selected from: hydrogen, halogen, substituted or unsubstituted C_1-6Alkyl, -OR of⁶、-S(O)₂-R⁶，R⁶Is substituted or unsubstituted C_1-6Alkyl groups of (a); more preferably, R⁹Selected from: hydrogen, halogen substituted or unsubstituted C_1-3Alkyl (e.g., methyl, ethyl, isopropyl, n-propyl); further preferably, R⁹Selected from: hydrogen, -CH₃、-CF₃、-CH₂CF₃；

In one embodiment of the invention, R⁹Is hydrogen;

more preferably, G is selected from:the compounds of formula (I) herein have the general formula:

in a preferred embodiment of the invention, G isR⁸Selected from: -CH₃、-CH₂CF₃Cyclopropane, isopropyl, methylsulfonyl; preferably selected from: -CH₃、-CH₂CF₃。

In a preferred embodiment of the invention, in said compound, R³Selected from: -C (O) R⁶、-S(O)-R⁶、-S(O)₂-R⁶(ii) a Or, R⁴And R³Together with the nitrogen atom to which they are attached and the phenyl ring form a substituted or unsubstituted aromatic or non-aromatic heterocyclic group;

preferably, R⁶Selected from: c_1-3Alkyl, halogen substituted C_1-3Alkyl group of (i), (ii), (iii), (iv) and (iv)₂)_PNR¹⁰R¹¹、-NR₁₂(CH₂)_PNR¹⁰R¹¹、-NR¹⁰R¹¹Wherein p is selected from an integer of 1 to 6, R¹⁰、R¹¹、R¹²Independently selected from H, C_1-3Alkyl groups of (a); more preferably, R⁶Selected from: -CH₃、-CF₃、-CH₂F、-CHF₂、-N(CH₃)CH₂CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-N(CH₃)₂；

Preferably, R⁷Selected from: H. c_1-3Alkyl, halogen substituted C_1-3Alkyl groups of (a);

in a preferred embodiment of the invention, said combinationIn which R is³Selected from: -C (O) NR⁶R⁷、-SOR⁶、-SO₂R⁶，R²Selected from: hydrogen, deuterium, halogen, -OR¹³Halogen-substituted C_1-6Alkyl, -S (O)_t-R⁶。

In another preferred embodiment of the present invention, in the compound, R³Selected from: c_1-3Alkyl, -OR of¹³、-SR⁶，R²Selected from: hydrogen, deuterium, halogen substituted C_1-6Alkyl, -S (O)_t-R⁶。

Preferably, R¹Selected from: hydrogen, deuterium, halogen, fluorine substituted or unsubstituted C_1-3Alkyl, nitro, cyano; further preferably, R¹Selected from: hydrogen, deuterium, halogen, cyano, methyl, trifluoromethyl; even more preferably, R¹Selected from: hydrogen, chloro, cyano, trifluoromethyl; most preferably, R¹Selected from: hydrogen, chlorine;

in another preferred embodiment of the invention, R⁴And R⁵Independently selected from: hydrogen, unsubstituted or substituted C_1-3Alkyl, -C (O) R⁶、-S(O)₂-R⁶，R⁶Selected from: hydrogen, substituted or unsubstituted C_1-3Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted C_1-3An alkenyl group; more preferably, R⁴And R⁵Independently selected from: hydrogen, methyl, -C (O) R⁶、-S(O)₂-R⁶，R⁶Selected from: vinyl, methylvinyl, 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl, cyclopropyl;

in one embodiment of the invention, R⁴Is hydrogen, R⁵Selected from: acryloyl, 3- (dimethylamino) propionyl, cyclopropaneformyl;

in another preferred embodiment of the invention, R⁴And R³Together with the nitrogen atom to which they are attached and the benzene ring formA substituted or unsubstituted aromatic or non-aromatic heterocyclic group, said compound having the structure of the formula:

n is 1 or 2;

R⁶selected from: hydrogen, substituted or unsubstituted C_1-6Alkyl groups of (a); preferably selected from: hydrogen, substituted or unsubstituted C_1-3Alkyl groups of (a);

in a preferred embodiment of the invention, R⁶Is 2- (dimethylamino) ethyl;

preferably, the compound has the structure of formula II-1;

in some preferred embodiments of the invention, the compound of formula i is selected from:

the above groups, in addition to oxygen and halogen, may be linked to each other to form a cycloalkyl or heterocycloalkyl group, which may be optionally substituted by substituents selected from: -ORa, -NRaRb, C optionally substituted by-ORa_1-5An alkyl group;

ra and Rb may be the same or different and are each independently selected from hydrogen and C_1-5An alkyl group which may be optionally substituted with one to three substituents selected from: hydroxy, C_1-5Alkoxy, halogen, amino.

Another aspect of the invention provides a process for the preparation of a compound of formula (I), preferably, such as:

wherein R is¹,R²,R³,R⁴As defined above. The base is organic base including triethylamine, pyridine, diisopropylethylamine, etc. or inorganic base including potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, etc.

Yet another aspect of the present invention provides pharmaceutical compositions comprising a compound of formula (I) or pharmaceutically acceptable salts, prodrugs and solvates thereof.

In a further aspect of the present invention, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug and solvate thereof, and a pharmaceutical composition thereof for the manufacture of a medicament for preventing and/or treating tumors, acute and chronic inflammatory diseases, inflammatory bowel diseases, skin diseases, diabetes, ocular diseases, diseases associated with angiogenesis or revascularization in mammals, and diseases associated with chronic pain.

A further aspect of the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug and solvate thereof, and pharmaceutical compositions thereof, in the manufacture of a medicament for the treatment and/or prevention of a disorder or disease mediated by activated or resistant mutant forms of EGRF, preferably ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelogenous leukemia, multiple myeloma or mesothelioma.

The compound of the invention has better physical and chemical properties and safe toxicity parameters, and can be used for treating cancer and inflammation of mammals.

Detailed Description

The present invention is defined throughout the disclosure with the following terms, if not otherwise indicated:

the term "prodrug" refers to any derivative that can be converted in vivo to the corresponding active drug compound. In one embodiment, when a compound of the present invention contains a hydroxyl group, a prodrug thereof may be an ester thereof with a suitable acid, including, for example, lactic acid, citric acid, ascorbic acid, and the like.

The term "pharmaceutically acceptable salt", unless otherwise specified, includes salts of acidic groups (such as, but not limited to, potassium, sodium, magnesium, calcium, and the like) or salts of basic groups (such as, but not limited to, sulfate, hydrochloride, phosphate, nitrate, carbonate, and the like) that may be present in the compounds of the invention.

The term "solvate" refers to a complex molecular compound formed by solute molecules or ions attracting adjacent solvent molecules in solution through intermolecular forces such as coulomb forces, van der waals forces, charge transfer forces, hydrogen bonding, and the like. In one embodiment, the solvent is water, i.e. the compound of the invention forms a hydrate.

The alkyl, alkenyl, alkynyl, cycloalkyl moieties may each independently be optionally substituted with one or more groups selected from: hydroxyl, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, mercapto.

Saturated or unsaturated hydrocarbon radicals, such as alkyl, alkanediyl or alkenyl, including combinations with heteroatoms, such as alkoxy, can each be linear or branched, respectively.

Depending on the substituents, the compounds of the formula (I) may, depending on the substituents, be present as optical isomers or as mixtures of isomers of different composition, which mixtures, if appropriate, may be separated off in a customary manner. The present invention provides pure isomers and isomer mixtures, processes for their preparation and their use, as well as compositions comprising them. For the sake of simplicity, this is referred to hereinafter as the compound of the formula (I), which refers both to the pure optical isomers and, where appropriate, to mixtures of isomers in different proportions.

Synthesis of

Suitable solvents commonly used in organic reactions can be used in the following steps of the preparation process of the present invention, such as, but not limited to: aliphatic and aromatic, optionally hydrocarbon or halogenated hydrocarbon (e.g., pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, volatile oil, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene), aliphatic and aromatic, optionally alcohol (e.g., methanol, ethanol, propanol, isopropanol, t-butanol, ethylene glycol, etc.), ether (e.g., diethyl ether and dibutyl ether, ethylene glycol dimethyl ether and diglyme, tetrahydrofuran and dioxane, etc.), ester (e.g., methyl acetate or ethyl acetate, etc.), nitrile (e.g., acetonitrile or propionitrile, etc.), ketone (e.g., acetone, butanone, etc.), amide (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.), and dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide and N, N-dimethylpropylene urea (DMPU) and the like.

Synthesis examples:

example 1: synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) aniline

Step 1: synthesis of methyl 5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzoate:

the compound 3- (2-chloropyrimidin-4-yl) -1-methylindole (2.4g,9.85mmol) and methyl 4-amino-5-methoxy-2-nitrobenzoate (2.67g,11.82mmol) were charged into a reaction flask, followed by addition of 1, 4-dioxane (20mL), addition of p-toluenesulfonic acid (2.03g,11.82mmol) with stirring, heating to 85 ℃ for reaction for 48 hours, after completion of the reaction, cooling to room temperature to precipitate a solid, filtration, washing of the cake with acetonitrile, and drying to give a yellow solid (4.0g, yield: 93.7%).¹H NMR(400MHz,CDCl₃):δ9.66(s,1H),8.44(d,J＝4Hz,1H),8.21-8.19(m,1H), 8.17(s,1H),7.94(s,1H),7.44-7.41(m,2H),7.28(s,1H),7.17(s,1H),4.06(s,3H),3.95(s,3H),3.93(s,3H).

Step 2: synthesis of 5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzoic acid:

mixing the compound 5-methoxy-4- ((4- (1-methyl-1H-indole)-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzoic acid methyl ester (1.0g,2.3mmol) was added to a reaction flask, then methanol (10mL) was added to dissolve, sodium hydroxide (1M,4.62mL,4.62mmol) was added with stirring, heated to 75 ℃ to react for 8 hours, after the reaction was complete, cooled to room temperature, pH adjusted to 4 with 10% hydrochloric acid, filtered, the filter cake was washed with methanol and dried to give a yellow solid (0.86g, yield: 88.9%).¹H NMR(400MHz,DMSO-d6):δ9.10(s,1H),8.46-8.43(m,4H),7.57-7.55(d,J＝8Hz,1H),7.41-7.39(m,2H),7.32-7.28(m,1H),7.22-7.19(m,1H),4.07(s,3H),3.90(s,3H).

And step 3: synthesis of N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzamide:

the compound 5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzoic acid (850mg,2.03mmol) was added to a reaction flask, after DCM (10mL) was added and dissolved, HOBT (411mg,3.04mmol) and EDCI (583mg,3.04mmol) were added, and after 30 minutes of reaction N was added¹,N¹-dimethylethane-1, 2-diamine (310mg,3.04mmol), stirred at room temperature for reaction for 1 hour, after completion of the reaction, the reaction solution was diluted with saturated brine, extracted with dichloromethane, the organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, and concentrated to give a crude product which was used directly in the next step (900mg, yield: 88.27%).¹H NMR(400MHz,MeOD-d4):δ9.74(s,1H),8.38(m,1H),8.24(m,2H),7.48(s,1H),7.29-7.25(m,3H),7.15(s,1H),4.11(s,3H),3.92(s,3H),3.80(t,2H),2.96(s,3H),2.87(t,2H),2.51(s,6H).

And 4, step 4: synthesis of 2-amino-N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide:

the compound N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzamide (500mg,0.99mmol), iron powder (305mg,5.46mmol) and ammonium chloride (425mg,7.94mmol) were added to a reaction flask, followed by EtOH/H₂O-4/1 (10mL) solution, and reflux reaction for 2 reactionsAfter a lapse of time, the reaction mixture was cooled, filtered, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (400mg, yield: 85.07%).¹H NMR(400MHz,CDCl₃)δ8.47(d,J＝8.8Hz,1H),8.34(d,J＝4.8Hz,1H),8.24(m,2H),7.78(s,1H),7.37(m,2H),7.05(d,J＝4.8Hz,1H),6.73(s,1H),4.11(s,3H),4.08(s,3H),3.87(m,2H),3.10(s,3H),2.70(s,2H),2.60(s,2H),2.38(s,6H)。

And 5: synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) aniline

A solution of acryloyl chloride (73mg,0.80mmol) in dichloromethane was added dropwise to a stirred mixture of 2-amino-N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide (380mg,0.80mmol) and DIPEA (114mg,0.88mmol) in dichloromethane (2mL) cooled in an ice-water bath. After the reaction for 1.5 hours, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (250mg, yield: 59.05%).¹H NMR(400MHz,CDCl₃)δ9.60(s,1H),9.27(s,1H),8.77(s,1H),8.40(d,J＝5.3Hz,1H),8.10(d,J＝7.4Hz,1H),7.88(s,1H),7.38(s,1H),7.28(d,J＝3.0Hz,2H),7.23(d,J＝5.3Hz,1H),6.95(s,1H),6.40(s,2H),5.74(d,J＝9.4Hz,1H),3.95(d,J＝8.9Hz,6H),3.86–3.74(m,2H),3.14(s,3H),2.91(m,2H),2.59(s,6H).MS(ESI)m/z 528.62[M+H].

Example 2: synthesis of N- (2- (dimethylamino) ethyl) -2- (3- (dimethylamino) propionylamino) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide

The compound 2-propene prepared in example 1 was usedamide-N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) aniline (200mg,0.38mmol) was added to a reaction flask, then ethanol (5mL) was added to dissolve it, 30% dimethylamine ethanol solution (2mL) was added with stirring, the reaction was stirred at room temperature for 30 minutes, and after completion of the TLC detection reaction, concentration and TLC purification gave the title compound as an off-white solid (100mg, yield: 46.06%).¹H NMR(400MHz,CDCl₃)δ10.27(s,1H),9.16(s,1H),8.39(d,J＝5.3Hz,2H),8.21(s,1H),7.80(s,1H),7.42–7.37(m,1H),7.31(dd,J＝8.9,5.2Hz,2H),7.17(d,J＝5.3Hz,1H),6.77(s,1H),3.94(s,3H),3.87(s,3H),3.10(s,3H),2.81(m,6H),2.55(s,6H),2.04(m,8H).MS(ESI)m/z573.32[M+H].

Example 3: synthesis of N- (5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (2,2, 2-trifluoroacetyl) -4- (trifluoromethoxy) phenyl) acrylamide:

step 1: synthesis of 2,2, 2-trifluoro-1- (4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) oxy) -2-nitro-5- (trifluoromethoxy) phenyl) ethanone:

the compounds 3- (2-chloropyrimidin-4-yl) -1-methylindole (1.5g,6.16mmol) and 1- (4-amino-2-nitro-5- (trifluoromethoxy) phenyl) -2,2, 2-trifluoroacetone (1.96g,6.16mmol) were added to a reaction flask, followed by 2-pentanol (100mL), p-toluenesulphonic acid monohydrate (1.27g,7.39mmol) was added with stirring, heated to 105 ℃ for 2.5 hours, after completion of the reaction, cooled to room temperature to precipitate a solid, filtered, the filter cake was washed with acetonitrile, and dried to give a yellow solid (2.3g, yield: 71%).¹H NMR(400MHz,CDCl₃):δ9.46(s,1H),8.56(d,1H),8.17(m,1H),7.59(m,1H),7.56(s,1H),7.50(s,1H),7.42-7.41(m,2H),7.19(s,1H),3.69(s,3H).

Step 2: synthesis of 1- (2-amino-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) phenyl) -2,2, 2-trifluoroacetone:

the compound 2,2, 2-trifluoro-1- (4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) oxy) -2-nitro-5- (trifluoromethoxy) phenyl) ethanone (500mg,0.95mmol), iron powder (293mg,5.23mmol) and ammonium chloride (407mg,7.61mmol) were added to a reaction flask, followed by EtOH/H₂O-4/1 (5mL) solution was refluxed for 2 hours, cooled, filtered, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give the objective compound (400mg, yield: 85%).¹H NMR(400MHz,CDCl₃):δ8.53(s,1H),8.32(d,1H),8.17(m,1H),7.59(m,1H),7.42-7.41(m,2H),7.24(d,1H),7.19(s,1H),6.99(s,1H),5.77(s,1H),4.57(br s,2H),3.69(s,3H).

And step 3: synthesis of N- (5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (2,2, 2-trifluoroacetyl) -4- (trifluoromethoxy) phenyl) acrylamide:

a solution of acryloyl chloride (19mg,0.20mmol) in dichloromethane was added dropwise to a stirred mixture of 1- (2-amino-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) phenyl) -2,2, 2-trifluoroacetone (100mg,0.20mmol) and DIPEA (65mg,0.50mmol) in dichloromethane (2mL) cooled in an ice-water bath. After 1.5 hours of the reaction, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (55mg, yield: 50%).¹HNMR(400MHz,CDCl₃):δ9.07(s,1H),8.81(s,1H),8.58(d,1H),8.17(m,1H),7.59(m,1H),7.42-7.41(m,2H),7.24(d,1H),7.22(s,1H),7.19(s,1H),6.95(s,1H,),6.48(m,1H),6.01(m,1H),5.51(m,1H),3.69(s,3H).MS(ESI)m/z 550.42[M+H].

Example 4 Synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) benzamide:

step 1: synthesis of methyl 4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitro-5- (trifluoromethoxy) benzoate:

the compound 3- (2-chloropyrimidin-4-yl) -1-methylindole (500mg,2.05mmol) and methyl 4-amino-2-nitro-5- (trifluoromethoxy) benzoate (575mg,2.05mmol) were charged into a reaction flask, followed by addition of 2-pentanol (10mL), addition of p-toluenesulfonic acid monohydrate (424mg,2.46mmol) under stirring, heating to 105 ℃ for reaction for 2.5 hours, after completion of the reaction, cooling to room temperature, precipitation of a solid, filtration, washing of the filter cake with acetonitrile, and drying to give a yellow solid (650mg, yield: 65%).¹H NMR(400MHz,CDCl₃):δ9.46(s,1H),8.43(d,1H),8.17(m,1H),7.61(s,1H),7.59(m,1H),7.56(s,1H),7.42-7.41(m,2H),7.24(d,1H),7.19(s,1H),3.98(s,3H),3.69(s,3H).

Step 2: synthesis of 4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitro-5- (trifluoromethoxy) benzoic acid:

methyl 4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitro-5- (trifluoromethoxy) benzoate (600mg,1.23mmol) was added to a reaction flask, THF/MeOH ═ 4/1(10mL) was added, then an aqueous solution of 1M lithium hydroxide (2.46mL,2.46mmol) was added, and the mixture was stirred at room temperature for 4 hours, after completion of the reaction, pH was adjusted to 3 to 4 with 1M hydrochloric acid, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (580mg, yield: 99.5%). MS (ESI) M/z 474.10[ M + H ]

And step 3: synthesis of N- (2- (dimethylamino) ethyl) -4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitro-5- (trifluoromethoxy) benzamide:

the compound 4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitro-5- (trifluoromethoxy) benzoic acid (200mg, 0.42mmol) was added to a reaction flask,DMF (5mL) was added and the mixture was dissolved, followed by addition of HOBT (86mg,0.63mmol) and EDCI (121mg,0.63mmol), reaction for 30 minutes, and addition of N¹,N¹-dimethylethane-1, 2-diamine (56mg,0.63mmol), stirred at room temperature for reaction for 1 hour, after completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give the objective compound (180mg, yield: 78.4%).¹H NMR(400MHz,CDCl₃):δ9.46(s,1H),8.43(d,1H),8.17(m,1H),8.03(s,1H),7.63(s,1H),7.59(m,2H),7.42-7.41(m,2H),7.24(d,1H),7.19(s,1H),3.69(s,3H),3.59(m,2H),2.57(m,2H),2.26(s,6H).

And 4, step 4: synthesis of 2-amino-N- (2- (dimethylamino) ethyl) -4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) benzamide:

the compound N- (2- (dimethylamino) ethyl) -4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitro-5- (trifluoromethoxy) benzamide (160mg,0.29mmol) was added to a reaction flask and EtOH/H was added₂O-4/1 (5mL), followed by Fe (91mg,1.62mmol) and NH₄Cl (126mg,2.36 mmol). After the reaction was completed, it was cooled to room temperature, filtered, washed with ethanol, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (130mg, yield: 86.0%). MS (ESI) M/z 514.51[ M + H ]]

And 5: synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) benzamide:

a solution of acryloyl chloride (18mg, 0.19mmol) in dichloromethane was added dropwise to a stirred mixture of 2-amino-N- (2- (dimethylamino) ethyl) -4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) benzamide (100mg, 0.19mmol) and DIPEA (31mg, 0.23mmol) in dichloromethane (2mL) cooled in an ice-water bath. After 1.5 hours of reaction, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined and anhydrousDried over sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (55mg, yield: 49.7%).¹H NMR(400MHz,CDCl₃):δ10.12(s,1H),9.46(s,1H),8.43(d,1H),8.17(m,1H),8.03(s,1H),7.59(m,1H),7.42-7.41(m,2H),7.31(s,1H),7.24(d,1H),7.19(s,1H),7.02(s,1H),6.48(m,1H),6.01(m,1H),5.51(m,1H),3.69(s,3H),3.59(m,2H),2.57(m,2H),2.26(s,6H).MS(ESI)m/z:568.56[M+H].

Example 5 Synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide:

the compound 3- (2-chloropyrimidin-4-yl) -1-methylindole (1.0g, 4.1mmol) and methyl 4-amino-5-methoxy-2-nitrobenzoate (928mg,4.1mmol) were charged into a reaction flask, followed by addition of 2-pentanol (10mL), addition of p-toluenesulfonic acid monohydrate (848mg,4.92mmol) with stirring, reaction to 105 ℃ for 2.5 hours, after completion of the reaction, cooling to room temperature, precipitation of a solid, filtration, cake washing with acetonitrile, and drying to give a yellow solid (1.5g, yield: 84.3%).¹H NMR(CDCl₃):δ9.46(s,1H),8.43(d,1H),8.17(m,1H),7.61(s,1H),7.59(m,1H),7.56(s,1H),7.42-7.41(m,2H),7.24(d,1H),7.19(s,1H),3.98(s,3H),3.83(s,3H),3.69(s,3H).

the compound methyl 5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzoate (1.0g,2.31mmol) was added to a reaction flask, THF/MeOH-4/1 (20mL) was added, followed by 1M lithium hydroxideAfter completion of the reaction, the pH of the resulting solution was adjusted to 3 to 4 with 1M hydrochloric acid, the solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the objective compound (900mg, yield: 93.0%).¹H NMR(400MHz,DMSO-d6):δ9.10(s,1H),8.46-8.43(m,4H),7.57-7.55(d,J＝8Hz,1H),7.41-7.39(m,2H),7.32-7.28(m,1H),7.22-7.19(m,1H),4.07(s,3H),3.90(s,3H).

And step 3: synthesis of N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzamide:

the compound 5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzoic acid (200mg,0.48mmol) was added to a reaction flask, after dissolution in DMF (5mL), HOBT (97mg,0.72mmol) and EDCI (138mg,0.72mmol) were added, and after 30 minutes of reaction N was added¹,N¹-dimethylethane-1, 2-diamine (63mg,0.72mmol), stirred at room temperature for reaction for 1 hour, after completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give the objective compound (160mg, yield: 68.5%).¹HNMR(400MHz,CDCl₃)：δ9.46(s,1H),8.43(d,1H),8.17(m,1H),8.03(s,1H),7.63(s,1H),7.59(m,2H),7.42-7.41(m,2H),7.24(d,1H),7.19(s,1H),3.83(s,3H),3.69(s,3H),3.59(m, 2H),2.57(m,2H),2.26(s,6H).

And 4, step 4: synthesis of 2-amino-N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide:

the compound N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzamide (150mg,0.31mmol) was added to a reaction flask and EtOH/H was added₂O-4/1 (5mL), followed by Fe (94mg,1.69mmol) and NH₄Cl (131mg,2.45 mmol). Heating to reflux for 4 hr, cooling to room temperature, filtering, washing with ethanol, drying with anhydrous sodium sulfate, and concentratingThe target compound (120mg, yield: 85.2%). MS (ESI) M/z 460.54[ M + H ]].

And 5: synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide:

a solution of acryloyl chloride (22mg, 0.24mmol) in dichloromethane was added dropwise to a stirred mixture of 2-amino-N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide (110mg, 0.24mmol) and DIPEA (38mg, 0.29mmol) in dichloromethane (2mL) cooled in an ice-water bath. After the reaction for 1.5 hours, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (40mg, yield: 35.4%).¹H NMR(400MHz,CDCl₃):δ10.12(s,1H),9.46(s,1H),8.43(d,1H),8.17(m,1H),8.03(s,1H),7.59(m,1H),7.42-7.41(m,2H),7.31(s,1H),7.24(d,1H),7.19(s,1H),7.02(s,1H),6.48(m,1H),6.01(m,1H),5.51(m,1H),3.83(s,3H),3.69(s,3H),3.59(m,2H),2.57(m,2H),2.26(s,6H).MS(ESI):m/z 514.59[M+H].

Example 6: synthesis of N- (2- (2,2, 2-trifluoroacetyl) -5- ((4- (1- (2,2, 2-trifluoroethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) acrylamide:

step 1: synthesis of 1- (2,2, 2-trifluoroethyl) -1H-indole

Compound 1H-indole (5.0g, 42.68mmol) was charged to a reaction flask, acetonitrile: DMF ═ 3:2(100mL) was added, and Cs was then added₂CO₃(16.69g,51.22mmol) and 2,2, 2-trifluoroethyl trifluoromethanesulfonate (11.89g,51.22mmol) under nitrogen at room temperature overnight, and after completion of the reaction, the mixture was filteredThe solid was removed, the reaction solution was added to water, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give the objective product (6.5g, yield: 76.5%).¹H NMR(400MHz,CDCl₃):δ7.59-7.55(m,2H),7.42(t,1H),7.33(d,1H),7.04(t,1H),6.41(d,1H),4.37(m,2H).

Step 2: synthesis of 3- (2-chloropyrimidin-4-yl) -1- (2,2, 2-trifluoroethyl) -1H-indole:

the compound 2, 4-dichloropyrimidine (3.5g,23.49mmol) was added to a reaction flask, ethylene glycol dimethyl ether (30mL) was added to dissolve the compound, after dissolution, ferric trichloride (3.81g,23.49mmol) and 1-methylindole (5.15g,25.84mmol) were added, and the mixture was heated to 60 ℃ and stirred for reaction overnight. After the completion of the reaction, the reaction mixture was cooled to room temperature, water (100mL) was added to precipitate a large amount of solid, which was filtered, and the filter cake was washed with methanol and dried to obtain a purple solid (5.5g, yield: 75.1%).¹H NMR(400MHz,CDCl₃):δ9.15(d,1H),8.17(m,1H),7.72(d,1H),7.59(m,1H),7.42-7.39(m,2H),7.19(s,1H),4.37(m,2H).

And step 3: synthesis of 2,2, 2-trifluoro-1- (2-nitro-4- ((4- (1- (2,2, 2-trifluoroethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) phenyl) ethanone:

the compounds 3- (2-chloropyrimidin-4-yl) -1- (2,2, 2-trifluoroethyl) -1H-indole (500mg, 1.60mmol) and 1- (4-amino-2-nitro-5- (trifluoromethoxy) phenyl) -2,2, 2-trifluoroacetone (510mg,1.60mmol) were added to a reaction flask, then 2-pentanol (10mL) was added, p-toluenesulphonic acid monohydrate (332mg,1.92mmol) was added under stirring, heated to 105 ℃ for 2.5 hours, after completion of the reaction, cooled to room temperature, a solid precipitated, filtered, the filter cake was washed with acetonitrile, and dried to give a yellow solid (750mg, yield: 78.8%).¹H NMR(400MHz,CDCl₃):δ9.47(s,1H),8.43(d,1H),8.17(m,1H),7.59(m,1H),7.56(s,1H),7.50(s,1H),7.42-7.39(m,2H),7.24(d,1H),7.19(s,1H),4.37(m,2H).

And 4, step 4: synthesis of 1- (2-amino-4- ((4- (1- (2,2, 2-trifluoroethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) phenyl) -2,2, 2-trifluoroacetone:

the compound 2,2, 2-trifluoro-1- (2-nitro-4- ((4- (1- (2,2, 2-trifluoroethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) phenyl) ethanone (300mg,0.51mmol) was added to a reaction flask, EtOH: H was added₂O4: 1(5mL), followed by Fe (156mg,2.78mmol) and NH₄Cl (217mg,4.04 mmol). After the reaction was completed, it was cooled to room temperature, filtered, washed with ethanol, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (260mg, yield: 91.3%). MS (ESI) M/z 564.38[ M + H ]]

And 5: synthesis of N- (2- (2,2, 2-trifluoroacetyl) -5- ((4- (1- (2,2, 2-trifluoroethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) acrylamide:

a solution of acryloyl chloride (24mg, 0.27mmol) in dichloromethane was added dropwise to a stirred mixture of 1- (2-amino-4- ((4- (1- (2,2, 2-trifluoroethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (trifluoromethoxy) phenyl) -2,2, 2-trifluoroacetone (150mg,0.27mmol) and DIPEA (42mg,0.32mmol) in dichloromethane (2mL) cooled in an ice-water bath. After the reaction for 1.5 hours, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (100mg, yield: 60.8%).¹H NMR(400MHz,CDCl₃):10.12(s,1H),9.47(s,1H),8.43(d,1H),8.17(m,1H),7.59(m,1H),7.56(s,1H),7.50(s,1H),7.42-7.39(m,2H),7.24(d,1H),7.22(s,1H),6.95(s,1H),6.48(m,1H),6.01(m,1H),5.52(m,1H),4.37(m,2H).MS(ESI):m/z:618.42[M+H]

Example 7: synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) benzamide

Step 1: synthesis of 3-iodopyrazolo [1,5-a ] pyridine:

the compound pyrazolo [1,5-a]Pyridine (5.0g,42.32mmol) was added to a reaction flask, acetonitrile (20mL) was added to dissolve the pyridine, and then NIS (10.47g,46.56mmol) was added in portions, and the mixture was stirred under reflux for 1 hour. The reaction mixture was poured into water and extracted twice with MTBE and the organic phase was washed with 2N NaOH and 15% Na in that order₂S₂O₃The solution was washed with water, saturated brine and dried over anhydrous sodium sulfate, and concentrated to give the objective compound (8.7g, yield: 84.23%).¹H-NMR(400MHz,CDCl₃):δ8.46(d,1H),7.96(s,1H),7.48(d,1H),7.22-7.17(m,1H),6.80(td,1H)；

Step 2: synthesis of 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine:

the compound 3-iodopyrazolo [1, 5-a)]Pyridine (8.5g,34.83mmol) and 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (9.72g,52.25mmol) were added to a reaction flask, then anhydrous tetrahydrofuran (60mL) was added, cooled with an ice-water bath, a tetrahydrofuran solution of isopropyl magnesium chloride (1.5M,23.22mL,34.83mmol) was added dropwise under nitrogen protection, reacted for 2 hours under ice-water bath cooling, after completion of the reaction, the reaction was quenched, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give a white solid (7.5g, yield: 88.2%).¹H-NMR(400MHz,CDCl₃):δ8.51(dt,1H),8.23(s,1H),7.96(dt,1H,),7.21(m,1H),6.81(td,1H),1.36(s,12H)；

And step 3: synthesis of 3- (2-chloropyrimidin-4-yl) pyrazolo [1,5-a ] pyridine:

the compound 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a]Pyridine (7g,28.68mmol) and 2, 4-dichloropyrimidine (5.13g,34.41mmol) were added to a reaction flask, ethylene glycol dimethyl ether (120mL) was added, followed by bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (Pd)(Amhos)Cl₂) (1.31g,1.85mmol) and sodium carbonate (2M,31.55mL,63.10mmol), replacing nitrogen, heating to 80 ℃ under nitrogen atmosphere for four hours, cooling to room temperature after completion of the reaction, diluting with water, extracting twice with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain the objective compound (4g, yield: 60.47%).¹H-NMR(400MHz,CDCl₃)δ8.92(s,1H),8.91-8.85(m,1H),8.61(d,1H),8.49(m,1H),7.95(d,1H),7.65(m,1H),7.19(m,1H).

And 4, step 4: synthesis of methyl 5-methoxy-2-nitro-4- ((4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) benzoate:

the compound 3- (2-chloropyrimidin-4-yl) pyrazolo [1,5-a]Pyridine (500mg, 2.17mmol) and methyl 4-amino-5-methoxy-2-nitrobenzoate (490mg,2.17mmol) were added to a reaction flask, followed by 2-pentanol (5mL), p-toluenesulphonic acid monohydrate (498mg, 2.60mmol) with stirring, heated to 105 ℃ for 2.5 hours, after completion of the reaction, cooled to room temperature, solid precipitated, filtered, the filter cake was washed with acetonitrile and dried to give a yellow solid (650mg, yield: 71.3%).¹H NMR(400MHz,CDCl₃):δ9.46(s,1H),8.60(d,1H),8.43(m,1H),7.81(s,1H),7.61(s,1H),7.56(s,1H),7.45(m,1H),7.24(d,1H),7.01-6.65(m,2H),3.98(s,3H),3.83(s,3H).

And 5: synthesis of 5-methoxy-2-nitro-4- ((4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) benzoic acid:

the compound methyl 5-methoxy-2-nitro-4- ((4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) benzoate (500mg,1.19mmol) was charged in a reaction flask, THF/MeOH (4/1) (10mL) was added, then 1M aqueous solution of lithium hydroxide (2.38mL, 2.38mmol) was added, and the mixture was stirred at room temperature for 4 hours, after completion of the reaction, pH was adjusted to 3 to 4 with 1M hydrochloric acid, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (470mg, yield: 97.2%).

Step 6: synthesis of N- (2- (dimethylamino) ethyl) -5-methoxy-2-nitro-4- ((4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) benzamide:

mixing the compound 5-methoxy-2-nitro-4- ((4- (pyrazolo [1, 5-a))]Pyridin-3-yl) pyrimidin-2-yl) amino) benzoic acid (400mg, 0.98mmol) was added to a reaction flask, DMF (5mL) was added and dissolved, HOBT (200mg,1.48mmol) and EDCI (284mg,1.48mmol) were added, and N was added after 30 minutes of reaction¹,N¹-dimethylethane-1, 2-diamine (131mg, 1.48mmol), stirred at room temperature for reaction for 1 hour, after completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give the objective compound (350mg, yield: 74.6%).¹H NMR(400MHz,CDCl₃):δ9.46(s,1H),8.43(d,1H),8.17(m,1H),8.03(s,1H),7.63(s,1H),7.59(m,2H),7.42-7.41(m,2H),7.24(d,1H),7.19(s,1H),3.83(s,3H),3.69(s,3H),3.59(m,2H),2.57(m,2H),2.26(s,6H).

And 7: synthesis of 2-amino-N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) benzamide:

mixing the compound N- (2- (dimethylamino) ethyl) -5-methoxy-2-nitro-4- ((4- (pyrazolo [1, 5-a))]Pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (300mg, 0.63mmol) was added to the reaction flask and EtOH/H was added₂O-4/1 (5mL), followed by Fe (193mg, 3.46mmol) and NH₄Cl (270mg, 5.04 mmol). After the reaction was completed, it was cooled to room temperature, filtered, washed with ethanol, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (200mg, yield: 71.4%). MS (ESI) M/z 447.5[ M + H ]].

And 8: synthesis of 2-acrylamido-N- (2- (dimethylamino) ethyl) -5-methoxy-4- ((4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) benzamide:

a solution of acryloyl chloride (37mg, 0.43mmol) in methylene chloride was added dropwise to 2-amino-N- (2- (dimethylamino) ethyl) -5-methoxy-4-carboxylic acid cooled in an ice-water bath((4- (pyrazolo [1, 5-a))]Pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (150mg, 0.34mmol) and DIPEA (65mg, 0.51mmol) in a stirred mixture of dichloromethane (3 mL). After the reaction for 1.5 hours, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (80mg, yield: 47.5%).¹H NMR(400Hz,CDCl₃):δ11.94(s,1H),10.12(s,1H),9.47(s,1H),8.43(d,1H),8.24(d,1H),7.91(s,1H),7.56(d,1H),7.50(s,1H),7.27-7.21(m,2H),7.15(t,1H),7.05(s,1H),6.44(dd,1H),6.28(dd,1H),5.77(dd,1H),3.93(m,3H),3.86(s,3H),2.89(t,2H),2.72(s,3H),2.29(t,2H),2.21(s,6H).MS(ES+):m/z:501.55[M+1].

Example 8: synthesis of N- (4-methoxy-5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) -2- (trifluoromethyl) phenyl) acrylamide:

step 1: synthesis of 4-methoxy-1-nitro-2- (trifluoromethyl) benzene:

4-chloro-1-nitro-2- (trifluoromethyl) benzene (250mg,1.11mmol) was dissolved in anhydrous methanol (5mL) and a sodium block (38mg,1.67mmol) was added at room temperature. After the sodium cake was reacted, the reaction solution was refluxed for 6 hours. After the reaction was completed, it was cooled to room temperature. Water (20mL) was added and the mixture was extracted with methylene chloride (20 mL. times.3). The organic phases were combined, washed with saturated brine (40mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate ═ 20:1) to give a yellow oil (180mg, yield: 81.4%).¹H NMR(400MHz,CDCl₃)δ8.01(d,J＝9.2Hz,1H),7.10(dd,J＝3.2Hz,J2＝9.2H,1H),7.26(d,J＝12.0Hz,1H),3.93(s,3H).

Step 2: synthesis of 4-methoxy-2- (trifluoromethyl) aniline

4-methoxy-1-nitro-2- (trifluoromethyl) benzene (9.0g,40.7mmol) was dissolved in ethyl acetate (50mL) and methanol (100mL), 10% palladium on carbon (1.2g, 50% water) was added, hydrogen balloon was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oil (7.7g, 99.0%) which was used in the next step.

And step 3: synthesis of N- (4-methoxy-2- (trifluoromethyl) phenyl) acetamide

4-methoxy-2- (trifluoromethyl) aniline (4.8g,25.1mmol) was dissolved in dichloromethane (10mL) and triethylamine (5.0g,50.0mmol) and acetic anhydride (5.0g,50.0mmol) were added. The reaction solution was stirred at room temperature overnight. After completion of the reaction, water (100mL) was added and the mixture was extracted with methylene chloride (100 mL. times.3). The organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a gray solid. The gray solid was washed with a mixture of petroleum ether and ethyl acetate (20: 1) to give a white solid (5.4g, yield: 92.3%).¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝9.2Hz,1H),7.21(br,1H),7.10(d,J＝2.4Hz,1H),7.05(d,J＝2.8Hz,1H),7.03(d,J＝2.4Hz,1H),3.81(s,3H),2.17(s,3H).

And 4, step 4: synthesis of N- (4-methoxy-5-nitro-2- (trifluoromethyl) phenyl) acetamide

N- (4-methoxy-2- (trifluoromethyl) phenyl) acetamide (5.4g,23.2mmol) was dissolved in concentrated sulfuric acid (50mL) and placed in a chilled salt bath. Potassium nitrate (2.8g,27.8mmol) was dissolved in concentrated sulfuric acid (25mL) and slowly added dropwise to the reaction flask, maintaining the temperature below 0 ℃. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into crushed ice (300g) and extracted with ethyl acetate (200 mL. times.3). The organic phases were combined, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate 1:1) to give a white solid (5.1g, yield: 79.1%).¹H NMR(400MHz,DMSO-d6)δ9.64(s,1H),7.94(s,1H),7.53(s,1H),3.98(s,3H)，2.02(s,3H).

And 5: synthesis of N- (5-amino-4-methoxy-2- (trifluoromethyl) phenyl) acetamide

N- (4-methoxy-5-nitro-2- (trifluoromethyl) phenyl) acetamide (5.1g,18.35mmol) was dissolved in ethanol (100mL) and saturated ammonium chloride (50 mL). Zinc powder was added and the reaction solution was refluxed for 1.5 hours. After the reaction was completed, about half of the ethanol was removed by concentration under reduced pressure. The solid was filtered, washed with water, and then with a mixture of petroleum ether and ethyl acetate (1:1) to give a white solid (4.3g, yield: 84.2%).¹H NMR(400MHz,CDCl₃)δ7.35(s,1H),7.20(br,1H),6.89(s,1H),4.12(b,2H),3.84(s,3H),2.15(s,3H).

Step 6: synthesis of N- (4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (trifluoromethyl) phenyl) acetamide

N- (5-amino-4-methoxy-2- (trifluoromethyl) phenyl) acetamide (496mg,2.0mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (704mg,4.0mmol) were dissolved in 2-pentanol (10mL), followed by addition of p-toluenesulfonic acid monohydrate (688mg,4.0 mmol). The reaction mixture was stirred at 130 ℃ for 4 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, and saturated sodium bicarbonate (20mL) was added to the reaction mixture, followed by extraction with dichloromethane (100 mL. times.3). The organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent petroleum ether: ethyl acetate ═ 2:1) to give a yellow solid (113mg, yield: 12.4%).¹H NMR(400MHz,MeOD/CDCl₃)δ8.88(s,1H),8.25(d,J＝5.6Hz,1H),8.18(m,2H),7.51(s,1H),7.40(m 1H),7.29(m,2H),7.20(m,1H),7.11(s,1H)，3.96(s,3H),3.88(s,3H),2.14(s,3H).

And 7: 6-methoxy-N¹Synthesis of- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (trifluoromethyl) benzene-1, 3-diamine

N- (4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (trifluoromethyl) phenyl) acetamide (91mg,0.2mmol) was dissolved in concentrated hydrochloric acid. The reaction solution is heated to 110 ℃ in a sealed tube and stirred for 5 hoursThen (c) is performed. After the reaction was completed, the reaction mixture was cooled to room temperature, and a 1N aqueous sodium hydroxide solution was added thereto until the pH was 8. It was extracted with dichloromethane (10 mL. times.3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate 1:1) to give a yellow oil (48mg, yield: 58.1%).¹H NMR(400MHz,CDCl₃)δ8.47(m,1H),8.32(m,1H),7.93(br,1H),7.80(s,1H),7.38(m,1H),7.30(m,2H),7.07(d,J＝5.2Hz,1H),6.90(s,1H),3.95(br,2H),3.88(s,6H).

And 8: synthesis of N- (4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amine) -2- (trifluoromethyl) benzene) acetyl

6-methoxy-N1- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (trifluoromethyl) benzene-1, 3-diamine (28mg, 0.068mmol) was dissolved in anhydrous tetrahydrofuran (2mL) and diisopropylethylamine (13mg,0.1mmol) was added. Acryloyl chloride (7mg, 0.078mmol) was added at-40 ℃. The reaction solution was slowly warmed to room temperature and stirred for 1 hour. After completion of the reaction, water (5mL) was added, and the mixture was extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent methanol: dichloromethane ═ 1:1) to give a yellow solid (18mg, yield: 56.6%).¹H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.60(s,1H),8.34(m,3H),8.12(s,1H)，7.50(m,1H),7.31(d,J＝5.2Hz,2H),7.23(m,3H),6.48(m,1H),6.20(dd,J1＝1.0Hz,J2＝8.4Hz,1H),5.72(m,1H)，3.97(s,3H),3.84(s,3H).¹³C NMR(100MHz,DMSO-d6)δ33.51,56.92,108.18,109.09,110.97,112.60,119.94,121.80,121.86,122.66,122.87,125.58,125.64,127.27,128.69,131.72,133.22,134.01,138.11,146.34,157.83,159.45,162.53,164.84.MS(ESI):m/z 468.17[M+H].

Example 9: synthesis of N- (2-fluoro-4-methoxy-5- (4- (1-methyl-1H-indol-3-yl) pyridin-2-ylamino) phenyl) acrylamide:

step 1: synthesis of 2, 4-difluoro-5-nitroaniline

2, 4-difluoroaniline (24.0g,186mmol) was dissolved in concentrated sulfuric acid (200mL) and nitric acid (11.7g,186mmol) was added slowly dropwise at 0 ℃ with the temperature maintained below 4 ℃ during the addition. Stirring in an ice water bath for half an hour. After the reaction was completed, the reaction solution was poured into ice water (1L), and sodium hydroxide was slowly added until the pH was 8. Extraction with ethyl acetate (1L × 3), combination of organic phases, washing of the organic phases with saturated brine (1L), drying over anhydrous sodium sulfate, concentration under reduced pressure, and separation and purification of the crude product by silica gel column chromatography (eluent petroleum ether: ethyl acetate ═ 10:1) gave a red solid (22.8g, yield: 70.4%).¹H NMR(400MHz,CDCl₃)δ7.49(m,1H),6.95(t,J＝10.0Hz,1H),3.89(s,1H)。

Step 2: synthesis of 4-fluoro-2-methoxy-5-nitroaniline

2, 4-difluoro-5-nitroaniline (3.48g,20mmol) was dissolved in anhydrous methanol (50mL), and sodium methoxide (1.30g,24mmol) was added at ordinary temperature and stirred for 48 hours. After completion of the reaction, water (100mL) was added and the mixture was extracted with methylene chloride (100 mL. times.3). The organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate ═ 6:1) to give a red solid (3.26g, yield: 87.6%).¹H NMR(400MHz,CDCl₃)δ7.38(d,J＝7.6Hz,1H),6.62(d,J＝12.4Hz,1H),3.92(s,3H),3.88(br,2H).MS(ESI)m/z:187.1[M+H].

And step 3: synthesis of N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine

4-fluoro-2-methoxy-5-nitroaniline (1.40g,7.52mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1.83g,7.52mmol) was dissolved in 2-pentanol (50mL) and p-toluenesulfonic acid monohydrate was addedCompound (1.55g,9.0 mmol). The reaction mixture was stirred at 105 ℃ for 3 hours, and after completion of the reaction, it was cooled to room temperature and filtered through a suction filter funnel. The solid was washed with 2-pentanol (50mL) and then with a mixed solvent of dichloromethane (50mL) and petroleum ether (50 mL). Then, it was dried in vacuo to give a yellow solid (2.80g, yield: 94.6%).¹H NMR(400MHz,MeOD/CDCl₃)δ9.82(br,1H),8.65(s,1H),8.48(s,1H),8.12(s,1H),7.57(d,J＝8.0Hz,1H),7.49(m,2H),7.28(m,1H),7.10(m,1H),5.72(s,1H),3.96(s,3H),3.88(s,3H).MS(ESI)m/z:394.1[M+H].

And 4, step 4: 4-fluoro-6-methoxy-N¹Synthesis of- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine

N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (796mg,2.0mmol) was then added 10% palladium on carbon catalyst (80mg) under a nitrogen atmosphere, then the nitrogen was replaced with hydrogen three times, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the palladium-carbon catalyst was filtered off, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent dichloromethane: methanol 20:1) to obtain a brown solid (582mg, yield: 80.2%).¹H NMR(400MHz,DMSO-d6)δ8.33(d,J＝6.8Hz,1H),8.21(d,J＝4.8Hz,1H),8.05(d,J＝10.0Hz,1H),7.91(s,1H),7.42(s,1H),7.32(d,J＝8.4Hz,1H),7.18(m,2H),6.99(d,J＝5.2Hz,1H),6.60(d,J＝12.0Hz,1H),3.94(br,2H)，3.81(s,3H)，3.75(s,3H).MS(ES+):m/z 364.2[M+H].

And 5: synthesis of N- (2-fluoro-4-methoxy-5- (4- (1-methyl-1H-indol-3-yl) pyridin-2-ylamino) phenyl) acrylamide

4-fluoro-6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (137mg, 0.377mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and diisopropylethylamine (97mg,0.75mmol) was added. Acryloyl chloride (40mg, 0.45mmol) was added at-5 ℃. The reaction solution was stirred at 5 ℃ for 2 hours. After completion of the reaction, water (0.5mL) was added, the reaction mixture was concentrated under reduced pressure, and the crude solid was washed with methylene chloride to give a yellow solid (87mg, yield: 55.3%).¹H NMR(400MHz,DMSO-d6)δ9.78(s,1H)，8.81(d,J＝8.8Hz,1H),8.44(s,1H),8.25(m,2H),7.81(s,1H),7.44(d,J＝8.0Hz,1H),7.17(m,3H),7.00(d,J＝12.0Hz,1H),6.57(m,1H)，6.25(d,J＝16.8Hz,1H),5.70(d,J＝12.0Hz,1H),3.86(s,6H).¹³C NMR(100MHz,DMSO-d6)δ33.29,56.69,99.67,99.92,107.85,110.71,112.89,117.05,117.72,117.88,121.33,121.79,122.36,125.16,125.79,126.81,132.10,133.86,138.07,157.89,160.12,162.18,163.71.MS(ESI)m/z:418.2[M+H].

Example 10: synthesis of N- (2- ((2- (methylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) phenyl) cyclopropanecarboxamide:

step 1: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴Synthesis of- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine:

n- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (393mg, 1.0mmol) was dissolved in dimethylacetamide (20mL), and N, N, N' -trimethylethylenediamine (122mg, 1.2mmol) and N, N-diisopropylethylamine (168mg, 1.3mmol) were added. The reaction solution was stirred at 85 ℃ for 5 hours. After the reaction was completed, it was cooled to room temperature, and 20mL of water was added. A solid precipitate appeared, which was then filtered, washed with water, and then dried in vacuo to give a yellow solid (421mg, yield: 88.5%).¹H NMR(400MHz,MeOD/CDCl₃)δ9.34(s,1H),8.24(d,J＝5.2Hz,1H),8.13(m,2H),7.60(s,1H),7.37(d,J＝5.2Hz,1H),7.22(m,2H),7.15(d,J＝5.2Hz,1H),6.72(s,1H),3.98(s,3H),3.86(s,3H),3.29(m,2H),2.85(s,3H),2.70(m,2H),2.35(s,6H).

Step 2: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴Synthesis of (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamineThe composition is as follows:

will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (666mg, 1.4mmol) was dissolved in ethanol (40mL), and iron powder (470mg,8.4mmol) and ammonium chloride (241mg,4.5mmol) were added. The reaction was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent dichloromethane: methanol 20:1) to give a brown oil (552mg, yield: 88.6%).¹H NMR(400MHz,CDCl₃)δ8.48(d,J＝8.8Hz,1H),8.29(d,J＝5.2Hz,1H),8.14(s,1H),7.74(s,1H),7.57(s,1H),7.29(m,3H),6.97(d,J＝5.2Hz,1H),6.70(s,1H),3.94(br,2H),3.83(s,3H),3.82(s,3H),2.96(m,2H),2.67(s,3H),2.41(m,2H),2.26(s,6H)。

And step 3: synthesis of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) cyclopropanecarboxamide:

will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (73mg,0.164mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and diisopropylethylamine (32mg,0.250mmol) was added. Acryloyl chloride (21mg,0.200mmol) was added at-10 ℃. The reaction solution was stirred at 10 ℃ for 1 hour. After completion of the reaction, water (0.5mL) was added, the reaction mixture was concentrated under reduced pressure, and the crude solid was washed with dichloromethane to give a yellow solid (62mg, yield: 73.6%).¹H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.72(s,1H),9.03(s,1H),8.34(d,J＝5.6Hz,1H)，8.04(d,J＝8.8Hz,1H),7.71(s,1H),7.37(d,J＝6.8Hz,1H),7.24(m,3H),7.17(d,J＝5.6Hz,1H),6.76(s,1H),3.95(s,3H),3.86(s,3H),3.47(s,1H),2.93(m,2H),2.69(s,3H),2.34(m,8H),1.22(m,2H),1.09(m,2H).¹³C NMR(100MHz,DMSO-d6)δ7.40,7.61,15.50,32.91,43.75,45.20,55.96,57.08,104.46,107.82,109.24,110.12,113.59,120.25,120.86,121.72,125.94,127.56,129.91,133.87,135.05,138.20,143.67,157.75,159.63,162.13,171.17.MS(ES+):m/z 513.8[M+H].

Example 11: synthesis of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) methacrylamide:

will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (50mg,0.337mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and diisopropylethylamine (56mg,0.438mmol) was added. Acryloyl chloride (42mg, 0.400mmol) was added at-10 ℃. The reaction solution was stirred at 10 ℃ for 1 hour. After completion of the reaction, water (0.5mL) was added, the reaction mixture was concentrated under reduced pressure, and the crude solid was washed with methylene chloride to give a yellow solid (124mg, yield: 71.6%).¹H NMR(400MHz,DMSO-d6)δ9.78(s,1H),9.74(s,1H),9.06(s,1H),8.36(d,J＝5.2Hz,1H),8.05(d,J＝8.4Hz,1H),7.73(s,1H),7.36(d,J＝8.8Hz,1H),7.23(m,3H),6.78(s,1H),5.87(s,3H),5.44(s,3H),3.95(s,3H),3.86(s,3H),2.99(m,2H),2.65(s,3H),2.31(m,2H),2.21(s,6H),2.11(s,3H).¹³C NMR(100MHz,DMSO-d6)δ18.94,32.97,44.58,45.13,54.97,56.12,57.14,76.79,77.11,77.43,104.35,107.89,109.50,110.02,113.58,119.19,120.23,120.89,121.75,125.93,133.96,135.04,138.22,141.44,144.19,157.84,159.54,162.08,165.67.MS(ESI)m/z:513.8[M+H].

Example 12: synthesis of 3- (dimethylamino) -N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) propionamide:

step 1: synthesis of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide:

a solution of acryloyl chloride (41mg, 0.45mmol) in methylene chloride was added dropwise to N cooled in an ice-water bath¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴A stirred mixture of (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (200mg, 0.45mmol) and DIPEA (70mg, 0.54mmol) in dichloromethane (5 mL). After the reaction for 1.5 hours, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (130mg, yield: 57.97%).¹H NMR(400MHz,CDCl₃):δ10.22(s,1H),9.14(s,1H),8.68(s,1H),8.33(d,1H),8.24(d,1H),7.91(s,1H),7.53(d,1H),7.27-7.20(m,2H),7.15(t,1H),7.04(s,1H),6.43(dd,1H),6.27(dd,1H),5.77(dd,1H),3.92(s,3H),3.86(s,3H),2.89(t,2H),2.72(s,3H),2.29(t,2H),2.21(s,6H).MS(ESI):m/z 500.42[M+H].

Step 2: synthesis of 3- (dimethylamino) -N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) propionamide:

the compound N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (100mg,0.20mmol) was added to a reaction flask, followed by addition of ethanol (5mL) for dissolution, addition of 30% dimethylamine ethanol solution (1mL) with stirring, reaction with stirring at room temperature for 30 minutes, concentration after completion of the TLC detection reaction, and TLC purification to give the objective compound as an off-white solid (80mg, yield: 73.38%).¹HNMR(400MHz,DMSO-d6)δ10.65(s,1H),10.07(s,1H),9.91(s,1H),8.58(s,2H),8.28(s,1H),7.56(d,J＝7.8Hz,1H),7.25(dt,J＝28.2,7.2Hz,3H),6.99(s,1H),3.92(s,3H),3.86(s,3H),3.23(m,4H),2.77(s,12H),2.65(m,4H).MS(ESI)m/z:545.33[M+H].

Example 13: synthesis of 2-acrylamido-5-methoxy-N, N-dimethyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) aniline:

step 1: synthesis of 2-amino-5-methoxy-N, N-dimethyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide:

2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzoic acid (117mg,0.300mmol) and dimethylamine hydrochloride (41mg, 0.500mmol) were dissolved in DMF (3mL) and diisopropylethylamine (129mg,1.0mmol) and HATU (171mg,0.450mmol) were added. The reaction mixture was stirred at room temperature overnight, and after completion of the reaction, the mixture was diluted with methylene chloride (20mL), water (20mL) was added, and the mixture was extracted with methylene chloride (20 mL. times.3). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent dichloromethane: methanol 40: 1) to give a yellow solid (110mg, 88.1%).¹H NMR(400MHz,CDCl₃)δ8.45(d,J＝6.8Hz,1H),8.29(d,J＝5.6Hz,1H),8.20(s,1H),7.98(s,1H),7.85(s,1H),7.80(s,1H),7.36(m,1H),7.28(m,2H)，7.05(d,J＝5.2Hz,1H)，6.67(s,1H),3.85(s,3H),3.82(s,3H),3.07(s,6H).MS(ESI)m/z 417.10[M+H].

Step 2: synthesis of 2-acrylamido-5-methoxy-N, N-dimethyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) aniline:

2-amino-5-methoxy-N, N-dimethyl-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzamide (29) (100mg, 0.240mmol) was dissolved in anhydrous tetrahydrofuran (5mL) and diisopropylethylamine (46mg, 0.360mmol) was added. Acryloyl chloride (24mg, 0.270mmol) was added at-10 ℃. Stirred at-10 ℃ for 1 hour. After completion of the reaction, water (5mL) was added and the mixture was extracted with methylene chloride (10 mL. times.3). Combining the organic phases, saturating the organic phaseWashed with brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent dichloromethane: methanol 40: 1) to give a yellow solid (38m, yield: 33.7%).¹H NMR(400MHz,DMSO-d6)δ9.57(m,2H),8.78(s,1H),8.33(d,J＝5.2Hz,1H),8.03(d,J＝8.4Hz,1H),7.85(s,1H),7.33(d,J＝6.0Hz,1H),7.22(m,3H),6.70(s,1H),6.30(m,2H),5.71(d,J＝10.0Hz,1H),3.89(s,3H),3.81(s,3H),3.05(s,6H).MS(ESI)m/z:471.10[M+H].

Example 14: synthesis of methyl 2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzoate:

step 1: synthesis of methyl 2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzoate:

the compound methyl 5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrobenzoate (500mg,1.15mmol), iron powder (354mg,6.34mmol) and ammonium chloride (494mg,9.23mmol) were added to a reaction flask, followed by EtOH/H₂O-4/1 (10mL) solution was refluxed for 2 hours, cooled, filtered through celite, washed with dichloromethane, the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give the objective compound (400mg, yield: 85.95%). 1H NMR (400MHz, CDCl3) δ 8.47(d, J ═ 9.2Hz,1H),8.33(d, J ═ 5.2Hz,1H),8.23(s,1H),7.97(M,2H),7.31(M,5H),7.04(d, J ═ 5.2Hz,1H),3.84(M,9H) ms (esi) M/z 471.10[ M + H471.10 [ M + esi ]].

Step 2: synthesis of methyl 2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzoate:

methyl 2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) benzoate (30) (28mg,0.070mmol) was dissolved in THF (5mL) and diisopropylethylamine (9mg, 0.10mmol) was added. Acryloyl chloride (10mg, 0.080mmol) was added at-10 ℃. The reaction solution was stirred at-10 ℃ for 1 hour. After completion of the reaction, water (5mL) was added and the mixture was extracted with methylene chloride (10 mL. times.3). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent dichloromethane: methanol ═ 100:1) to give a yellow solid (21mg, yield: 65.6%). 1H NMR (400MHz, DMSO-d6) δ 11.48(s,1H),10.09(s,1H),9.04(s,1H),8.40(d, J ═ 5.2Hz,1H),8.05(M,2H),7.44(s,1H),7.36(M,1H),7.25(M,3H),6.40(M,2H),5.77(M,1H),3.94(s,3H),3.91(s,3H),3.89(s,3H). ms (esi) M/z 458.11[ M + H ].

Example 15: synthesis of 1- (6-methoxy-7- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one:

step 1: synthesis of 6-methoxy-3, 4-dihydroquinolin-2 (1H) -one:

the compound 6-hydroxy-3, 4-dihydroquinolin-2 (1H) -one (2.0g, 12.26mmol), K₂CO₃(2.5g, 18.38mmol) in a three-necked flask, adding 15mL of DMF, heating to 42 ℃ for reaction for 1h, adding iodomethane (2.1g, 14.72mmol) dropwise under the condition of keeping out of the light, detecting the progress of the reaction by TLC spot plate, after 3h, moving to room temperature, adding 75mL of ice water, standing for 0.5h, and filtering to obtain a white solid (2.0g, 92.1% yield).¹H NMR(400MHz,CDCl₃)δ8.40(s,1H),6.72(t,J＝2.0Hz,3H),3.78(s,3H),2.96–2.91(m,2H),2.64–2.59(m,2H).

Step 2: synthesis of 6-methoxy-1, 2,3, 4-tetrahydroquinoline:

the compound 6-methoxy-3, 4-dihydroquinolin-2 (1H) -one (1.1g, 6.21mmol) is placed in a three-necked flask with 50mL of anhydrous THFAdding LiAlH in batches under ice bath condition₄(0.7g, 18.63mmol), heating and refluxing after the addition is finished, detecting the progress of the reaction by a TLC point plate, completing the reaction for about 2 hours, carrying out post-treatment, moving to an ice bath condition, dropwise adding 0.7g of water, stirring for 15 minutes, dropwise adding 15% sodium hydroxide solution (0.7g), stirring for 15 minutes, dropwise adding 2.1g of water, stirring for 0.5 hours, then adding anhydrous magnesium sulfate (0.7g), stirring for 0.5 hours, filtering, washing a filter cake with THF, drying a filtrate with anhydrous magnesium sulfate, and concentrating to obtain an oil (0.92g, yield 91.1%).¹H NMR(400MHz,CDCl₃)δ6.64–6.58(m,1H),6.48(d,J＝8.5Hz,0H),3.75(s,2H),3.30–3.25(m,1H),2.78(t,J＝6.5Hz,1H),2.00–1.91(m,1H).

And step 3: synthesis of 1- (6-methoxy-3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one:

the compound 6-methoxy-1, 2,3, 4-tetrahydroquinoline (0.9g, 5.54mmol) is put into a three-neck flask, DCM (10mL) is added, DIPEA (0.9g, 7.20mmol) is added under ice bath conditions, allylacyl chloride (0.6g, 6.65mmol) is added dropwise and the reaction is continued under ice bath conditions, the progress of the reaction is checked by TLC spot plate, about 3h reaction is completed, post-treatment is carried out, DCM (20mL) is added to dilute the reaction solution, the reaction solution is washed with saturated sodium bicarbonate solution (20mL), the organic phase is dried with anhydrous sodium sulfate and concentrated to obtain (1.12g, yield 93.3%).¹H NMR(400MHz,CDCl₃)δ6.77–6.66(m,1H),6.59–6.46(m,1H),6.43–6.36(m,1H),6.23–6.05(m,0H),5.63(dd,J＝10.0,2.2Hz,1H),3.84(t,J＝6.7Hz,2H),3.80(s,3H),2.68(t,J＝6.6Hz,2H),1.96(p,J＝6.6Hz,2H).

And 4, step 4: synthesis of 1- (6-methoxy-7-nitro-3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one:

adding TFA (18mL) into a compound 1- (6-methoxy-3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one (1.12g, 5.16mmol) under an ice bath condition, adding sodium nitrite (0.37g, 5.41mmol) in batches, moving to room temperature for continuous reaction after the addition is finished, after finishing the reaction for about 1.5H, performing after-treatment, adding ice water (200mL), extracting with DCM (30mL multiplied by 3), combining organic layers, drying with anhydrous magnesium sulfate, concentrating, and performing column chromatography separation and purification to obtain the compoundSolid (0.3g, yield: 22.2%).¹H NMR(400MHz,CDCl₃)δ6.89(s,1H),6.56–6.42(m,2H),5.77(dd,J＝7.7,4.4Hz,1H),5.34–5.20(m,1H),3.96(s,3H),3.86(t,J＝6.6Hz,2H),2.80(t,J＝6.5Hz,2H),2.05–1.96(m,2H).

And 5: synthesis of 1- (7-amino-6-methoxy-3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one:

the compound 1- (6-methoxy-7-nitro-3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one (0.3g, 1.14mmol), reduced iron powder (0.38g, 6.84mmol) and ammonium chloride (0.61g, 11.4mmol) were placed in a two-necked flask, ethanol (21mL) and water (7mL) were added, heated under reflux, the reaction progress was checked by TLC spot plate, after about 1.5H, post-treatment, filtration while hot, the cake was washed twice with ethanol, the filtrate was concentrated to remove ethanol, after which the aqueous layer was extracted with DCM (10 mL. times.3), the organic layers were combined, dried over anhydrous magnesium sulfate, and desolventized to give the product (0.23g, yield 88.5%).¹H NMR(400MHz,CDCl₃)δ6.86(s,1H),6.54–6.43(m,2H),5.75(dd,J＝7.7,4.4Hz,1H),5.32–5.24(m,1H),4.18(s,2H),3.94(s,3H),3.87(t,J＝6.6Hz,2H),2.80(t,J＝6.5Hz,2H),2.05–1.96(m,2H).

Step 6: synthesis of 1- (6-methoxy-7- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one:

the compound 1- (7-amino-6-methoxy-3, 4-dihydroquinolin-1 (2H) -yl) prop-2-en-1-one (0.22g, 0.95mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (0.19g, 0.79mmol) and p-chlorobenzoic acid (0.16g, 0.95mmol) were placed in a two-necked flask, 1, 4-dioxane (6mL) was added and heated to 90 ℃ to effect reaction, progress of reaction was checked by TLC plate, reaction was completed for about 5H, post-treatment was followed by cooling to room temperature, 25% ammonia (0.2mL) and water (0.97mL) were added to quench, desolvation and purification was performed by column chromatography to obtain the product (83mg, yield 24.0%).¹H NMR(400MHz,CDCl₃)δ8.68(s,1H),8.36(d,J＝5.3Hz,1H),8.24(d,J＝7.3Hz,1H),7.91(s,1H),7.74(s,1H),7.42(d,J＝7.6Hz,1H),7.33(dd,J＝16.3,7.4Hz,2H),7.14(d,J＝5.3Hz,1H),6.84–6.70(m,2H),6.40(dd,J＝16.8,2.0Hz,1H),5.58(d,J＝10.4Hz,1H),3.99–3.87(m,8H),2.74(t,J＝6.6Hz,2H),2.03(p,J＝6.6Hz,2H).MS(ESI)m/z 440.21[M+H].

Example 16: synthesis of 1- (5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) indol-1-yl) prop-2-en-1-one:

step 1: synthesis of 5-methoxyindole:

weighing 5-methoxy-1H-indole (0.4g, 2.72mmol), adding acetic acid (25mL) into a three-neck flask, adding sodium cyanoborohydride (0.51g, 8.16mmol) in batches, continuing the reaction at room temperature after the addition is finished, detecting the progress of the reaction by a TLC (thin layer chromatography) spot plate, finishing the reaction after about 2.5H, adding water (3mL) for quenching, adjusting the pH to 5-6 by using saturated sodium bicarbonate solution, extracting DCM (10mL multiplied by 4), combining organic layers, drying over anhydrous magnesium sulfate, and concentrating to obtain the target compound (0.35g, yield 86.3%).¹H NMR(400MHz,CDCl₃)δ6.78–6.75(m,1H),6.67(d,J＝8.4Hz,1H),6.61(dd,J＝8.4,2.5Hz,1H),3.75(s,3H),3.56(t,J＝8.2Hz,2H),3.36(s,2H),3.01(t,J＝8.2Hz,2H).

Step 2: synthesis of 1- (5-methoxyindol-1-yl) prop-2-en-1-one:

weighing 5-methoxyindole (0.35g, 2.35mmol), adding DCM (7mL) for dissolution, adding DIPEA (0.36g, 2.82mmol) under an ice bath condition, dropwise adding allyl chloride (0.23g, 2.59mmol), continuing to react under the ice bath condition after the addition is finished, detecting the reaction progress through a TLC point plate, after about 5h of reaction completion, carrying out post-treatment, adding DCM (20mL) for diluting the reaction solution, washing with a saturated sodium bicarbonate solution (20mL), extracting a sodium bicarbonate solution layer with DCM (10mL multiplied by 3), drying with anhydrous magnesium sulfate, concentrating, and purifying by column chromatography to obtain a target compound (0.28g, yield 58.7%).¹HNMR(400MHz,CDCl₃)δ8.23(d,J＝8.9Hz,1H),6.75(d,J＝8.2Hz,2H),6.62–6.44(m,2H),5.77(dd,J＝9.6,2.4Hz,1H),4.20–4.15(m,2H),3.79(s,3H),3.19(t,J＝8.3Hz,2H).

And step 3: synthesis of 1- (5-methoxy-6-nitroindol-1-yl) prop-2-en-1-one:

weighing 1- (5-methoxyindol-1-yl) prop-2-en-1-one (0.27g, 1.33mmol) in a two-neck flask, adding TFA (5mL) under ice bath conditions, adding sodium nitrite (0.097g, 1.40mmol) in batches, moving to room temperature for continuing the reaction, adding ice water (50mL) into the reaction solution after about 2h of reaction completion, precipitating a solid, standing for 1h, filtering, and drying a filter cake to obtain a product (0.25g, yield 75.8%).¹H NMR(400MHz,CDCl₃)δ8.77(s,1H),6.92(d,J＝10.0Hz,1H),6.54(d,J＝5.5Hz,2H),5.84(t,J＝6.0Hz,1H),4.24(t,J＝8.5Hz,2H),3.92(s,3H),3.28(t,J＝8.3Hz,2H).

And 4, step 4: synthesis of 1- (-amino-5-methoxyindol-1-yl) -2-en-1-one:

1- (5-methoxy-6-nitroindol-1-yl) prop-2-en-1-one (0.25g, 1.01mmol), reduced iron powder (0.34g, 6.06mmol) and ammonium chloride (0.54g, 10.1mmol) were weighed into a two-necked flask, ethanol (21mL) and water (7mL) were added and heated under reflux, the progress of the reaction was checked by TLC spotting, after-treatment was carried out for about 1h, filtration was carried out while hot, the cake was washed twice with ethanol, ethanol was removed by concentration, the aqueous layer was extracted with DCM (10 mL. times.3), dried over anhydrous magnesium sulfate and concentrated to give a solid (0.16g, yield 72.7%).¹H NMR(400MHz,DMSO)δ7.64(s,1H),6.73(d,J＝8.0Hz,2H),6.24(d,J＝16.1Hz,1H),5.76(t,J＝6.0Hz,1H),4.66(s,2H),4.14(t,J＝7.5Hz,2H),3.73(s,3H),3.02(t,J＝7.3Hz,2H).

And 5: synthesis of 1- (5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) indol-1-yl) prop-2-en-1-one:

1- (-amino-5-methoxyindol-1-yl) -2-en-1-one (0.16g, 0.73mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (0.15g, 0.61mmol) and p-chlorobenzoic acid (0.13g, 0.73mmol) were weighed outIn a two-necked flask, 1, 4-dioxane (6mL) was added and heated to 90 ℃ to react, the progress of the reaction was checked by TLC spot plate, after about 24 hours, the reaction was carried out, and after the completion of the post-treatment, the reaction was cooled to room temperature, 25% ammonia (0.15mL) and water (0.75mL) were added to quench, and the product was purified by column chromatography (117mg, yield 45.2%).¹H NMR(400MHz,CDCl₃)δ9.82(s,1H),9.07(s,1H),8.38(d,J＝5.3Hz,1H),8.06(d,J＝6.7Hz,1H),7.76(s,1H),7.39(d,J＝7.0Hz,1H),7.32–7.23(m,2H),7.20(d,J＝5.2Hz,1H),6.76(s,1H),6.66(dd,J＝16.7,10.1Hz,1H),6.53(d,J＝15.2Hz,1H),5.78(d,J＝9.0Hz,1H),4.21(t,J＝8.3Hz,2H),4.00(s,3H),3.89(s,3H),3.19(t,J＝8.2Hz,2H).MS(ESI)m/z:426.28[M+H].

Example 17: synthesis of N- (2- ((2- (dimethylamino) ethyl) sulfinyl) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide:

step 1: synthesis of N- (4- ((2- (dimethylamino) ethyl) thio) -2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine

NaH (60%, 2.03g,50.84mmol) was charged into a reaction flask, DMF (25mL) was added, a solution of 2- (dimethylamino) ethanethiol hydrochloride (3.60g,25.42mmol) in DMF (25mL) was added under nitrogen, the reaction mixture was stirred at room temperature for 45 minutes, then a solution of N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (2.0g,5.08mmol) in DMF (25mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water, filtered, and the filter cake was washed with water and dried in vacuo to give a yellow solid (2.2g, yield: 90.42%).

Step 2: 4- ((2- (dimethylamino) ethyl) thio) -6-methoxy-N¹Synthesis of- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine:

taking Fe powder (0.77g,12mmoL) and NH₄Cl (1.3g,24mmoL) in water (10mL) and ethanol (10mL) was added the compound N- (4- ((2- (dimethylamino) ethyl) thio) -2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (0.96g,2mmoL) in ethanol (20mL), refluxed in an oil bath at 80 ℃ for 2 hours, the reaction was completed (DCM: MeOH ═ 20:1), solids were removed by hot filtration, the filtrate was concentrated, water was added in 50mL, extracted with dichloromethane, dried over anhydrous sodium sulfate of the organic phase, and concentrated to give the product (0.5g, yield: 56%).¹H NMR(400MHz,DMSO-d6)δ8.45(d,J＝7.8Hz,1H),8.36(d,J＝4.6Hz,2H),7.92(s,1H),7.87(s,1H),7.55(d,J＝8.0Hz,1H),7.32–7.19(m,3H),7.02(s,1H),3.90(s,3H),3.84(s,3H),3.17(dd,J＝8.8,4.9Hz,3H),3.09(dd,J＝8.9,4.8Hz,2H),2.74(s,6H).

And step 3: synthesis of N- (2- ((2- (dimethylamino) ethyl) thio) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide:

taking a compound 4- ((2- (dimethylamino) ethyl) sulfenyl) -6-methoxyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (1.1g,2.45mmol) was dissolved in 20mL of dichloromethane, stirred in an ice-water bath for 10 minutes, diisopropylethylamine (613mg,4.9mmol) was added, a solution of acryloyl chloride (246mg,2.7mmol) in dichloromethane (2mL) was added, stirred in an ice-water bath for 2 hours, the reaction mixture was quenched (DCM: MeOH ═ 20:1), dichloromethane (100mL) was added, a solution of sodium bicarbonate (100mL) was added, the mixture was separated, dried over anhydrous sodium sulfate, the crude product was concentrated, and the crude product was purified by column chromatography (DCM: MeOH ═ 100:1) to obtain a product (600mg, yield 49%).¹H NMR(400MHz,CDCl₃)δ10.14(s,1H),9.77(s,1H),8.98(s,1H),8.42(d,J＝5.3Hz,1H),8.09(dd,J＝6.3,2.2Hz,1H),7.88(s,1H),7.42(dd,J＝6.5,2.3Hz,1H),7.35–7.23(m,3H),7.11(s,1H),6.51(dd,J＝16.9,1.8Hz,1H),6.39(dd,J＝16.9,10.0Hz,1H),5.78(dd,J＝10.0,1.7Hz,1H),4.01(s,3H),3.94(s,3H),2.89(t,J＝6.2Hz,2H),2.38(t,J＝6.2Hz,2H),2.29(s,6H).

And 4, step 4: synthesis of N- (2- ((2- (dimethylamino) ethyl) sulfinyl) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide

The compound N- (2- ((2- (dimethylamino) ethyl) thio) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (580mg,1.15mmol) was taken in dichloromethane (30mL), stirred in an ice-water bath for 10 minutes, 1mL of trifluoroacetic acid was added), a solution of 70% m-chloroperoxybenzoic acid (290mg,1.2mmol) in methylene chloride (2mL) was added, after stirring in an ice-water bath for 0.5 hour, the reaction was quenched (DCM: MeOH ═ 20:1), dichloromethane (100mL) was added to the reaction mixture, 100mL sodium bicarbonate solution was added, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, the concentrated crude product was purified by column chromatography (DCM: MeOH ═ 100:1 to 20:1) gave the product (300mg, yield: 47%).¹H NMR(400MHz,CDCl₃)δ10.43(s,1H),9.74(s,1H),8.84(s,1H),8.43(d,J＝5.3Hz,1H),8.13–8.06(m,1H),7.98(s,1H),7.41(dd,J＝6.6,2.3Hz,1H),7.35–7.24(m,3H),7.11(s,1H),6.47(dd,J＝17.0,1.2Hz,1H),6.28(dd,J＝17.0,10.3Hz,1H),5.80(dd,J＝10.3,1.0Hz,1H),3.97(d,J＝4.8Hz,6H),3.58–3.46(m,1H),3.03(dd,J＝7.8,5.3Hz,1H),2.60(dd,J＝11.8,6.5Hz,1H),2.49(dd,J＝8.9,5.7Hz,1H),2.32(s,6H).MS(HESI)m/z:519.22[M+H].

Example 18: synthesis of 3- (dimethylamino) -N- (2- ((2- (dimethylamino) ethyl) sulfinyl) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) propionamide:

the compound N- (2- ((2- (dimethylamino) ethyl) sulfinyl) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (50mg,0.096mmol) was taken in tetrahydrofuran (5mL), stirred in an ice-water bath for 10 minutes, dimethylamine-tetrahydrofuran solution (1M,2mL,2mmol) was added, stirred in an ice-water bath for 0.5 hour, the reaction was completed (DCM: MeOH 10:1), and the reaction mixture was stirredThe reaction was concentrated to give the crude product, which was purified on column (DCM: MeOH: 100:1 to 20:1) to give the product (12mg, 21% yield).¹H NMR(400MHz,CDCl₃)δ10.74(s,1H),9.37(s,1H),8.53(s,1H),8.43(s,1H),8.18(s,1H),7.94(s,1H),7.42(s,1H),7.28(s,2H),7.26–7.19(m,2H),3.99(s,3H),3.96(s,3H),3.31(dt,J＝13.5,6.9Hz,1H),3.11–3.01(m,1H),2.86(t,J＝6.4Hz,2H),2.76–2.69(m,1H),2.65(t,J＝6.6Hz,2H),2.52(dt,J＝13.5,6.9Hz,1H),2.40(d,J＝14.8Hz,6H),2.34(s,6H).MS(ESI)m/z:564.27[M+H].

Example 19: synthesis of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluoro-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide:

step 1: synthesis of N- (2, 4-difluoro-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine:

the compound 3- (2-chloropyrimidin-4-yl) -1-methylindole (300mg,1.23mmol) and methyl 4-amino-2-nitro-5- (trifluoromethoxy) benzoate (257mg,1.48mmol) were charged into a reaction flask, followed by addition of 1, 4-dioxane (10mL), addition of p-toluenesulfonic acid (254mg,1.48mmol) with stirring, heating to 85 ℃ for 10 hours, reaction completion, cooling to room temperature, precipitation of a solid, filtration, washing of the filter cake with acetonitrile, and drying to give a yellow solid (460mg, yield: 98.08%).¹H NMR(400MHz,CDCl₃)δ9.59(s,1H),8.32(d,J＝5.7Hz,1H),8.19(s,1H),8.10(d,J＝7.9Hz,1H),7.82(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.35-7.28(m,2H),7.18(d,J＝8.0Hz,1H),7.12(t,J＝10.1Hz,1H),3.94(s,3H).

Step 2: n is a radical of¹- (2- (dimethylamino) ethyl) -5-fluoro-N¹-methyl-N⁴Synthesis of- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine:

the compound N- (2, 4-difluoro-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (200mg,0.52mmol) was added to a reaction flask, followed by DMF (5mL) and N added with stirring¹,N¹,N²-trimethylethane-1, 2-diamine (53mg,0.52mmol), stirred at room temperature for reaction for 10 hours, after completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography gave the title compound (90mg, yield: 38.18%).¹H NMR(400MHz,CDCl₃)δ9.42(d,J＝8.7Hz,1H),8.39(d,J＝5.3Hz,1H),8.26–8.18(m,1H),8.09(s,1H),7.40(s,1H),7.32(m,2H),7.22(d,J＝5.4Hz,2H),7.01(d,J＝12.9Hz,1H),3.93(s,3H),3.39(m,2H),2.86(m,5H),2.50(s,6H).

And step 3: n is a radical of¹- (2- (dimethylamino) ethyl) -5-fluoro-N¹-methyl-N⁴Synthesis of- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine:

compound N¹- (2- (dimethylamino) ethyl) -5-fluoro-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (70mg,0.15mmol), iron powder (46mg,0.83mmol) and ammonium chloride (65mg,1.21mmol) were added to a reaction flask, followed by EtOH/H₂O-4/1 (8mL) solution was refluxed for 2 hours, cooled, filtered through a silica gel sheet, washed with dichloromethane, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (60mg, yield: 91.64%).¹H NMR(400MHz,MeOD)δ8.41(d,J＝8.1Hz,1H),8.22(d,J＝5.5Hz,1H),8.07(d,J＝2.9Hz,1H),7.56(d,J＝8.2Hz,1H),7.45(d,J＝8.1Hz,1H),7.32–7.23(m,2H),7.20–7.15(m,1H),7.02–6.97(m,1H),3.90(s,3H),3.12(t,J＝6.5Hz,2H),2.70(s,5H),2.49(s,6H).

And 4, step 4: synthesis of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-fluoro-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide:

a solution of acryloyl chloride (13mg,0.14mmol) in dichloromethane was added dropwise to ice waterCooled in bath N¹- (2- (dimethylamino) ethyl) -5-fluoro-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (60mg,0.14mmol) and DIPEA (20mg,15mmol) in a stirred mixture of dichloromethane (2 mL). After 30 minutes of the reaction, it was diluted with dichloromethane, washed with saturated sodium bicarbonate, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give the objective compound (25mg, yield: 37.05%).¹H NMR(400MHz,MeOD)δ8.54(d,J＝8.4Hz,1H),8.33(d,J＝8.0Hz,1H),8.29(d,J＝5.5Hz,1H),8.20(s,1H),7.47(d,J＝8.1Hz,1H),7.30–7.21(m,2H),7.18(t,J＝7.2Hz,1H),6.64–6.53(m,1H),6.49(dd,J＝16.9,1.9Hz,1H),6.28–6.09(m,1H),5.88(dd,J＝9.8,1.9Hz,1H),3.92(s,3H),3.40(t,J＝5.9Hz,2H),3.19(t,J＝5.9Hz,2H),2.81(s,6H),2.75(s,3H).MS(ESI)m/z:488.25[M+H].

Synthesis of methyl 4-amino-5-methoxy-2-nitrobenzoate:

concentrated sulfuric acid (20mL) was charged into a reaction flask, and the compound methyl 4-amino-3-methoxybenzoate (5.0g,27.6mmol) was added to the reaction mixture under ice bath conditions, after complete dissolution, potassium nitrate (3.35g,33.11mmol) was added in portions, and after reaction for 30 minutes in ice water bath, the reaction mixture was slowly poured into ice water, extracted with ethyl acetate, and the organic phase was washed successively with a saturated sodium bicarbonate solution, a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid (5.8g, yield: 93%).¹HNMR(400MHz,CDCl₃):7.12(1H,s),7.10(1H,s),4.37(2H,s),3.97(3H,s),3.88(3H,s)。

Example 20: cell viability assay

1. Cell: NCI-H1975, PC-9 and A431, all from the Shanghai cell Bank of Chinese academy of sciences.

2. Reagent: hyclone DMEM high-sugar medium, RPMI1640 medium, MEM medium, Tryple, MTT (5mg/mL), DMSO, DPBS.

3. The instrument comprises the following steps:37℃,5％CO₂incubator, UTRAO enzyme-linked immunosorbent assay (ELISA) reader, biological safety cabinet, cell counting plate, and ott optical microscope.

4. Experiment consumables: stock number of 96-well plate: 3599, 96-hole round bottom dispensing plate.

Activity testing of NCI-H1975 cells Experimental procedure:

1. plate paving: cells in logarithmic growth phase were digested with Tryple, terminated with fresh medium, counted, adjusted to 11111 cells/mL with fresh medium, 90 μ L per well, and the other edges filled with sterile DPBS.

2. At 37 ℃ with 5% CO₂Incubate in incubator for 24 hours to allow cells to fill about 50% of the bottom of the well.

3. The experimental group is prepared as follows: dissolving the drug in DMSO to prepare 20mmol/L stock solution, diluting with DMSO to prepare 2mmol/L, sequentially diluting 3 times and 8 concentration gradients to obtain 200 × compound gradient solution, adding 10 μ L gradient compound solution into 190 μ L RPMI1640 culture medium to obtain 10 × gradient compound solution, adding 10 μ L10 × compound solution into 90 μ L96-well cell culture plate, repeating three gradients, wherein the concentration gradients of the compound in the 96-well cell culture plate are 0.05080526nM, 1.524158nM, 4.572474nM, 13.717420nM, 41.152260nM, 123.456800nM, 370.370400nM, 1111.111000nM, 3333.333000nM and 10000.000000nM, each well is 100 μ L, and the final concentration of DMSO is 0.5%.

The control group, containing the same volume of solvent as the experimental group, was diluted with complete medium at 100. mu.L per well.

4. At 37 ℃ in 5% CO₂Incubate in incubator for 72 h.

After 5.72h, 20. mu.L of MTT solution (5mg/mL) was added to each well and incubation was continued for 4 h.

6. The culture was terminated and the culture medium in the wells was carefully aspirated.

7. And (3) zeroing the wells, adding 150 mu L of dimethyl sulfoxide (DMSO) into each well of the experimental group and the control group, oscillating at a medium speed for 10s in a microplate reader, fully dissolving crystals, and measuring the light absorption value at the position of 492 nm.

IC of all Compounds 1 to 14₅₀The values are shown in Table 1.

Activity testing of PC-9 cells Experimental procedure:

4. At 37 ℃ in 5% CO₂Incubate in incubator for 72 h.

After 5.72h, 20 μ of LMTT solution (5mg/mL) was added to each well and incubation continued for 4 h.

IC of all Compounds 1 to 14₅₀The values are shown in Table 1.

Activity test of a431 cells experimental procedure:

3. The experimental group was dosed. Dissolving the drug in DMSO to prepare 20mmol/L stock solution, diluting with DMSO to prepare 2mmol/L, sequentially diluting 3 times and 8 concentration gradients to obtain 200 × compound gradient solution, adding 10 μ L gradient compound solution into 190 μ L RPMI1640 culture medium to obtain 10 × gradient compound solution, adding 10 μ L10 × compound solution into 90 μ L96 well cell culture plate, repeating three gradients, wherein the concentration gradients of the compound in 96 well cell culture plate are 0.05080526nM, 1.524158nM, 4.572474nM, 13.717420nM, 41.152260nM, 123.456800nM, 370.370400nM, 1111.111000nM, 3333.333000nM and 10000.000000nM, each well is 100 μ L, and the final concentration of DMSO is 0.5%.

4. At 37 ℃ in 5% CO₂Incubate in incubator for 72 h.

7. And (3) zeroing a hole, adding 150 mu L of dimethyl sulfoxide (DMSO) into each hole of the experimental group and the control group, oscillating at a medium speed of a microplate reader for 10s, fully dissolving a crystal, and measuring the light absorption value at the wavelength of 492 nm.

IC of all Compounds 1 to 14₅₀The values are shown in Table 1:

TABLE 1 results of cell Activity assays for Compounds 1-14

- -means no detection.

Claims

1. A compound of formula (I) and pharmaceutically acceptable salts, prodrugs and solvates thereof,

wherein,

R¹selected from: hydrogen, deuterium, halogen, unsubstituted or substituted C_1-6Alkyl, -NR⁶R⁷Nitro, cyano, -OR⁶、-C(O)OR⁶、-C(O)R⁶、-C(O)NR⁶R⁷、-S(O)_t-R⁶、-S(O)₂-NR⁶R⁷；

t is 0, 1, 2;

R¹³selected from halogen substituted C_1-6An alkyl group;

g is selected from the following groups:

x is selected from CH and N;

R⁸selected from: hydrogen, deuterium, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, -C (O) R⁶、-S(O)_t-R⁶；

2. The compound of claim 1, and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein G is selected from the group consisting of:and/or the presence of a gas in the gas,

the R is⁸Selected from: hydrogen, halogen substituted or unsubstituted C_1-3Alkyl, -S (O)₂-R⁶(ii) a And/or the presence of a gas in the gas,

said R⁹Selected from: hydrogen, halogen substituted or unsubstituted C_1-3An alkyl group.

3. The compound of claim 1, wherein R is R, and pharmaceutically acceptable salts, prodrugs and solvates thereof³Selected from: -C (O) R⁶、-S(O)-R⁶、-S(O)₂-R⁶(ii) a Or, R⁴And R³Together with the nitrogen atom to which they are attached and the phenyl ring form a substituted or unsubstituted aromatic or non-aromatic heterocyclic group.

4. The compound of claim 3, wherein R is R, and pharmaceutically acceptable salts, prodrugs and solvates thereof⁶Selected from: c_1-3Alkyl, halogen substituted C_1-3Alkyl group of (i), (ii), (iii), (iv) and (iv)₂)_PNR¹⁰R¹¹、-NR₁₂(CH₂)_PNR¹⁰R¹¹、-NR¹⁰R¹¹Wherein p is selected from an integer of 1 to 6, R¹⁰、R¹¹、R¹²Independently selected from H, C_1-3Alkyl of R⁷Selected from: H. c_1-3Alkyl of (C)_1-3Alkyl, halogen substituted C_1-3Alkyl group of (1).

5. The compound of claim 4, wherein R is R, and pharmaceutically acceptable salts, prodrugs and solvates thereof⁶Selected from: -CH₃、-CF₃、-CH₂F、-CHF₂、-N(CH₃)CH₂CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-N(CH₃)₂。

6. The compound of claim 4, wherein R is R, and pharmaceutically acceptable salts, prodrugs and solvates thereof³is-C (O) NHR⁶R⁷、-SOR⁶、-SO₂R⁶，R²Is hydrogen, deuterium, halogen, -OR¹³Halogen-substituted C_1-6Alkyl, -S (O)_t-R⁶。

7. The compound of claim 4, wherein R is R, and pharmaceutically acceptable salts, prodrugs and solvates thereof³Is C_1-3Alkyl, -OR of¹³、-SR⁶，R²Is hydrogen, deuterium, halogen-substituted C_1-6Alkyl, -S (O)_t-R⁶。

8. The compound of claim 1, wherein R is R, and pharmaceutically acceptable salts, prodrugs and solvates thereof⁴And R³Together with the nitrogen atom to which they are attached and the phenyl ring form a substituted or unsubstituted aromatic or non-aromatic heterocyclic group, said compound having the general structure:

n is 1 or 2;

R⁶selected from: hydrogen, substituted or unsubstituted C_1-6Alkyl group of (1).

9. The compound of claim 1, and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein the compound is selected from the group consisting of:

10. a pharmaceutical composition comprising a compound of any one of claims 1-9 and pharmaceutically acceptable salts, prodrugs and solvates thereof.

11. Use of a compound according to any one of claims 1-9 and pharmaceutically acceptable salts, prodrugs and solvates thereof and a pharmaceutical composition according to claim 10 for the preparation of a medicament for the treatment and/or prevention of disorders or diseases mediated by EGRF in the form of activated or resistant mutants.

12. The use of claim 11, wherein the EGRF-mediated disorder or disease in the form of an activating or resistant mutant is ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelogenous leukemia, multiple myeloma, or mesothelioma.