CN105503827A

CN105503827A - EGFR (Epidermal growth factor receptor) inhibitor and preparation method and use thereof

Info

Publication number: CN105503827A
Application number: CN201510626680.2A
Authority: CN
Inventors: 孙兴义; 危明松; 崔媛媛; 仝朝龙; 张福军; 包如迪; 喻红平; 徐耀昌
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansen Biological Medicine Technology Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansen Biological Medicine Technology Co Ltd
Priority date: 2014-10-11
Filing date: 2015-09-28
Publication date: 2016-04-20
Anticipated expiration: 2035-09-28
Also published as: CN105503827B

Abstract

The present invention discloses an EGFR (Epidermal growth factor receptor) inhibitor and a preparation method and use thereof. In particular, the present invention relates to compounds of N-(5-((4-((2-(alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino)-phenyl) acryloyl amide analogs shown as a formula (I), wherein substituents of the formula (I) are as defined in the specification. The series of compounds can inhibit the activity of a L858R EGFR mutant, a T790MEGFR mutant and an exon 19 deletion activated mutant, can be used for treating diseases alone or partly actively mediated by an EGFR mutant, has broad application in medicines for prevention and treatment of cancer particularly non-small cell lung cancer, and is expected to be developed into a new generation EGFR inhibitor.

Description

EGFR inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to an EGFR inhibitor, namely an N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridine-3-yl) amino) pyrimidine-2-yl) amino) -phenyl) allylamide analogue, and preparation and application thereof.

Background

Egfr (epidermalgrowth factor receptor) is a member of the erbB receptor family of transmembrane protein tyrosine kinases. EGFR can form homodimers on cell membranes by binding to its ligand, e.g., Epidermal Growth Factor (EGF), or heterodimers with other receptors in the family, such as erbB2, erbB3, or erbB 4. The formation of these dimers can lead to phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in the cells. These intracellular signaling pathways play important roles in cell proliferation, survival, and resistance to apoptosis. Dysregulation of the EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and mutation, can promote cellular transformation to malignancy, and play an important role in proliferation, invasion, metastasis and angiogenesis of tumor cells. Therefore, EGFR is a rational target for anticancer drug development.

First generation small molecule EGFR inhibitors including gefitinib (Iressa)^TM) And erlotinib (Tarceva)^TM) They show better therapeutic effects in lung cancer treatment and have been used as first-line drugs for treating NSCLC (New England Journarof medicine (2008) Vol.358,1160-74, Biochemical research communications (2004) Vol.319,1-11) which is a non-small cell lung cancer accompanied by mutation of EGFR activation.

Activation of mutant EGFR (including L858R and exon 19 deletion mutation del E746_ A750) with decreased affinity for Adenosine Triphosphate (ATP) and increased affinity for small molecule inhibitors, relative to wild-type (WT) EGFR, results in increased sensitivity of tumor cells to first generation EGFR inhibitors such as gefitinib or erlotinib for targeted therapy purposes (Science [2004] stage 304, 1497-500; New England journal of medicene [2004] stage 350, 2129-39).

However, almost all NSCLC patients develop resistance to small molecule inhibitors after 10-12 months of treatment with first generation small molecule EGFR inhibitors. The drug resistance mechanism comprises EGFR secondary mutation, bypass activation and the like. In half of patients, the drug resistance is caused by the secondary mutation of the EGFR gatekeeper gene residue T790M, thereby reducing the affinity of the drug and the target point to generate drug resistance, and causing the recurrence or disease progression of the tumor.

In view of the importance and prevalence of such mutations in EGFR-targeted therapies for lung cancer, several drug development companies (fevered, BI, AZ, etc.) have attempted to develop second generation small molecule EGFR inhibitors to treat lung cancer patients with such resistance by inhibiting the EGFR t790M mutant, all with poor selectivity and failure. Even though afatinib has been FDA approved for the treatment of lung cancer, it is only used for first line treatment of patients with EGFR activating mutations; in patients with EGFR t790M mutation, however, the dose was limited due to severe skin and gastrointestinal toxicity caused by the stronger inhibitory effect of afatinib on wild-type EGFR, and no therapeutic effect was shown.

Therefore, there is a need for the development of third generation small molecule EGFR inhibitors that inhibit the EGFR t790M mutant with high selectivity and no or low activity against wild-type EGFR. Due to the high selectivity, the damage of skin and gastrointestinal tract caused by the inhibition of wild type EGFR can be greatly reduced, so as to treat the tumor with EGFRT790M secondary mutation resistance. In addition, it is also of interest to retain inhibitory activity against EGFR activating mutants (including L858REGFR, exon 19 deletion mutation del E746_ A750). Because of weak inhibition to wild EGFR, the third-generation EGFR inhibitor has better safety than the first-generation EGFR inhibitor, and is expected to be used as a first-line treatment to treat NSCLC accompanied with EGFR activating mutation and clear a small amount of possible EGFR 790T mutant strain of an initial treatment patient so as to delay the occurrence of drug resistance.

Lung cancer is a serious disease threatening human health, and death of lung cancer accounts for the first place of all malignant tumors. In China, the incidence rate of lung cancer is rising year by year, and the number of new cases is nearly 70 ten thousand every year. In europe and the united states, lung cancer cases with EGFR activating mutations account for about 10% of all NSCLC; in China, this proportion is as high as 30%. Thus, china has a larger market for EGFR targets.

Disclosure of Invention

In the process of research, the inventor finds that a class of N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridine-3-yl) amino) pyrimidine-2-yl) amino) -phenyl) acryloyl amide analogues with the structure shown in the formula (I) have the activity of inhibiting EGFR mutants, particularly L858REGFR mutants, T790MEGFR and exon 19 deletion activation mutants, and can be used for treating diseases which are mediated by the EGFR mutant activity alone or in part, for example, have wide application in medicaments for preventing and treating cancers, particularly non-small cell lung cancer.

In one aspect, the present invention provides a compound having the following formula (I): N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x, Y are each independently selected from CH or N, and X, Y is different;

R₁is selected from C_1-8Alkyl radical, C_3-8Cycloalkyl, optionally further substituted by one or more groups selected from fluoro, chloro, bromo, iodo, hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy, halogen substituted C_1-8Alkoxy radical, C_3-8Cycloalkyl or C_3-8Cycloalkoxy is substituted by a substituent;

R₂selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, C_1-8Alkoxy, trifluoromethyl, trifluoromethoxy, SO₂R₅、C(O)OR₅、C(O)R₆Or P (O) R₇R₈；

R₃Selected from the following structures:

R₄is selected from C_1-8Alkyl radical, C_3-8A cycloalkyl group;

R₅is selected from C_1-8Alkyl radical, C_3-8Cycloalkyl, halo-substituted C_1-8Alkyl, phenyl or p-methylphenyl;

R₆、R₇、R₈each independently selected from C_1-8Alkyl radical, C_3-8Cycloalkyl, halo-substituted C_1-8Alkyl radical, C_1-8Alkoxy, amino or di-C_1-8An alkylamino group.

As a still further preferred embodiment, said N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) allylamide analog, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R₃Selected from:X、Y、R₁、R₂、R₄、R₅、R₆、R₇、R₈as defined for the compounds of formula (I).

As a still further preferred embodiment, said N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R₁Is selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, optionally further substituted by one or more groups selected from fluoro, chloro, bromo, iodo, hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy, halogen substituted C_1-8Alkoxy radical, C_3-8Cycloalkyl or C_3-8Cycloalkoxy is substituted by a substituent; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined for the compounds of formula (I).

As a still further preferred embodiment, said N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amideAnalog, stereoisomer or pharmaceutically acceptable salt thereof, R₁Is selected from C_1-4Alkyl radical, C_3-6Cycloalkyl optionally further substituted with one or more substituents selected from fluoro, chloro, bromo, iodo or hydroxy; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined for the compounds of formula (I).

As a still further preferred embodiment, said N- (5- ((4- ((2- (alk-substituted-sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R₁Is selected from C_1-4Alkyl, optionally further substituted with one or more substituents selected from fluoro or hydroxy; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined for the compounds of formula (I).

As a still further preferred embodiment, said N- (5- ((4- ((2- (alk-substituted-sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R₁Selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined for the compounds of formula (I).

As a still further preferred embodiment, the aforementioned N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R₂Selected from hydrogen, fluorine, chlorine, cyano, C_1-8Alkoxy, difluoromethyl, trifluoromethyl or trifluoromethoxy; r₄Selected from isopropyl or cyclopropyl; x, Y, R₂、R₃、R₅、R₆、R₇、R₈As defined for the compounds of formula (I).

As a most preferred embodiment, the N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, stereoisomer, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

in another aspect, the present invention provides a method for preparing the aforementioned N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein, X₁、X₂Selected from fluorine, chlorine, bromine or iodine; x, Y, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined for the compounds of formula (I).

In a further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the aforementioned N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a further aspect, the invention provides an application of the N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridine-3-yl) amino) pyrimidine-2-yl) amino) -phenyl) acryloyl amide analogue, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in preparation of a therapeutic drug for treating diseases mediated by the activity of the L858REGFR mutant, the T790MEGFR mutant and the exon 19 deletion activation mutant.

As a further preferred embodiment, the aforementioned N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the use of the aforementioned pharmaceutical composition in the manufacture of a therapeutic medicament for the treatment of a disease mediated alone or in part by EGFR mutant activity.

As a still further preferred embodiment, the aforementioned N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloylamide analogue, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the use of the aforementioned pharmaceutical composition for the manufacture of a medicament for the treatment of cancer.

As a still further preferred embodiment, the cancer is selected from 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 cancer, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, Acute Myeloid Leukemia (AML), multiple myeloma, melanoma, or mesothelioma; preferably non-small cell lung cancer.

Detailed Description

Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

“C_1-8Alkyl "refers to straight-chain alkyl groups and branched-chain alkyl-containing groups comprising 1 to 8 carbon atoms, alkyl refers to a saturated aliphatic hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylpentyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C_3-8Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms, for example:

non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups that share a single carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-, di-or multi-spirocycloalkyl groups, non-limiting examples of which include:

"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, non-limiting examples of fused ring alkyl groups including:

"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. "C_1-8Alkoxy "means an alkyloxy group having 1 to 8 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.

"Cycloalkoxy" refers to and-O- (unsubstituted cycloalkyl), wherein cycloalkyl is as defined above. "C_3-8Cycloalkoxy "means a cycloalkyloxy group having 3 to 8 carbons, and non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

"halogen-substituted C_1-8Alkyl "refers to a 1-8C alkyl group optionally substituted on the hydrogen of the alkyl group by a fluorine, chlorine, bromine, iodine atom, e.g. diFluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.

“C(O)R₆"means R₅A substituted carbonyl group.

“P(O)R₇R₈"means R₇、R₈Substituted phosphoryl, R₇、R₈Optionally identical or different substituents.

' di C_1-8Alkylamino "refers to two C_1-8An alkyl-substituted amino group.

"THF" refers to tetrahydrofuran.

"DCM" refers to dichloromethane.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts () are given in parts per million (ppm). NMR was measured using a Brukeravence-400 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent1200Infinityseries Mass spectrometer. HPLC was carried out using an Agilent1200 DAD high pressure liquid chromatograph (SunfireC 18150X 4.6mm column) and a Waters2695-2996 high pressure liquid chromatograph (GiminiC 18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, and the solvent is a dry solvent, unless otherwise specified.

Preparation of intermediates

1. Intermediate 1: preparation of 4-fluoro-2-methoxy-5-nitroaniline

4-fluoro-2-methoxynitrobenzene (10g, 58.44mmol) was dissolved in methanol, 1g of palladium on carbon was added, hydrogen was substituted and reacted for three days under a hydrogen atmosphere. Filtering, collecting filtrate, and evaporating methanol to obtain oily crude product. To the crude product was added concentrated sulfuric acid at 0 ℃ to dissolve all the solids in the mixture, and potassium nitrate (5.91g) was added in portions. The reaction was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into ice water, NaHCO was added₃Adjusting the pH value to 6.0-8.0. The aqueous phase was extracted three times with dichloromethane and the organic phase was collected and dried. The organic solvent was distilled off, and the residue was purified by column chromatography to give 4-fluoro-2-methoxy-5-nitroaniline (4.0 g).

2. Intermediate 2: preparation of 4-fluoro-2-isopropoxy-5-nitroaniline

The preparation method of the 4-fluoro-2-isopropoxy-5-nitroaniline is the same as that of the intermediate 1.

3. Intermediate 3: preparation of 4-fluoro-2-ethoxy-5-nitroaniline

The preparation method of the 4-fluoro-2-ethoxy-5-nitroaniline is the same as the preparation of the intermediate 1.

4. Intermediate 4: preparation of 2- (difluoromethoxy) -4-fluoronitrobenzene

Dissolving 5-fluoro-2-nitrophenol (3.0g,19.1mmol) and potassium carbonate (5.28g,38.2mmol) in DMF, adding sodium monochlorodifluoroacetate (4.37g,28.6mmol), heating to 100 ℃ under nitrogen protection, stirring for 16 hours, concentrating the reaction solution, adding H2O (50mL) and methyl tert-butyl ether (50mL) to the residue, separating by extraction, washing the organic phase three times with water, drying over magnesium sulfate, filtering, concentrating the filtrate, and purifying the residue by flash silica gel column chromatography to obtain 2- (difluoromethoxy) -4-fluoronitrobenzene (3.0g, 75%).

5. Intermediate 5: preparation of 2- (difluoromethoxy) -4-fluoro-5-nitroaniline

2- (Difluoromethoxy) -4-fluoronitrobenzene (3.0g,14.5mmol) was dissolved in methanol (30mL), Pd/C (500mg) was added, the reaction was allowed to react at room temperature for 2 hours under a hydrogen atmosphere, the reaction was completed on a spot plate, the reaction solution was filtered through celite, and the filtrate was concentrated to give a crude product (1.7g, 66%). The crude product was carefully dissolved in concentrated sulfuric acid (5mL) while cooling on ice, after stirring to clear on ice, potassium nitrate (1.1g,9.5mmol) was added slowly in portions, the reaction was stirred for an additional 3 hours while cooling on ice, LCMS showed completion of the reaction, and the reaction was slowly quenched into saturated aqueous sodium carbonate (100 mL). After quenching was complete, the aqueous phase was extracted with methyl tert-butyl ether (3X20mL), the organic phase was dried over magnesium sulfate and filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography to give 2- (difluoromethoxy) -4-fluoro-5-nitroaniline (2.0g 90%).

6. Intermediate 6: preparation of 4-fluoro-1-nitro-2- (trifluoromethoxy) benzene

While cooling with ice water, 3-fluoro-trifluoromethoxybenzene (20g) was dissolved in 40 ml of concentrated sulfuric acid, potassium nitrate (28g) was added in portions with rapid stirring, and stirred at 0 ℃ for 3 hours at room temperature overnight, and the reaction solution was carefully introduced onto 1 kg of crushed ice, stirred for 30 minutes, extracted with ethyl acetate, dried over sodium sulfate, filtered, the filtrate was distilled off, and the residue was purified by column chromatography to obtain 12g of a pale yellow liquid.

7. Intermediate 7: preparation of 4-fluoro-2- (trifluoromethoxy) aniline

Dissolving crude 64-fluoro-1-nitro-2- (trifluoromethoxy) benzene (12g) as the intermediate prepared in the previous step in 100ml of absolute ethanol, adding stannous chloride dihydrate (25g) under the cooling of ice water, and stirring the reaction solution at room temperature overnight. Adding 1N sodium hydroxide aqueous solution to adjust pH value to about 12, filtering, extracting the filtrate with ethyl acetate, drying the extract with sodium sulfate, filtering, evaporating solvent, and purifying the residue by column chromatography to obtain light yellow oily liquid 4-fluoro-2- (trifluoromethoxy) aniline (4.78 g).

¹HNMR(400MHz,CDCl₃)6.94(d,J＝8.8Hz,1H),6.83(m,1H),6.76(dd,J＝5.4,8.8Hz,1H),3.87-3.59(2H)。

8. Intermediate 8: preparation of 4-fluoro-5-nitro-2- (trifluoromethoxy) aniline

4-fluoro-2- (trifluoromethoxy) aniline (2.5g) was dissolved in concentrated sulfuric acid (10ml) cooled in ice water, potassium nitrate (3g) was added thereto, and the mixture was stirred at room temperature for 3 hours, and the reaction mixture was added to ice water, and then 3N aqueous sodium hydroxide solution was added thereto to adjust the pH to about 10, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, filtration and evaporation of the solvent, and the residue was purified by column chromatography to give 4-fluoro-5-nitro-2- (trifluoromethoxy) aniline (1.79 g).

9. Intermediate 9: preparation of sodium cyclopropanesulfinate

Sodium sulfite (1.32g,1.1mmol) and sodium bicarbonate (1.6g,20.0mmol) were dissolved in pure water (15mL), and after stirring for 10 minutes at 55 ℃ for the reaction, cyclopropylsulfonyl chloride (1.4g,10.0mmol) was slowly added dropwise, and after stirring for 3 hours at 60 ℃ for the reaction, water was directly concentrated to dryness to give sodium cyclopropylsulfinate (4 g).

Preparation of the Compounds of examples

Example 1: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl) propenylamide

The first step is as follows: preparation of 2-isopropylmercapto-3-nitropyridine

Placing 2-fluoro-3-nitropyridine (500mg,3.52mmol) and potassium carbonate (973mg,7.04mmol) in a 100mL round-bottomed bottle, adding 15mL of DMF, adding isopropylmercaptan (0.36mL,3.87mmol) under stirring, reacting the mixture at room temperature for 1 hour, removing the reaction solvent after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain the product 2-isopropylmercapto-3-nitropyridine (660mg, yield 95%).

LC-MS：t＝4.31min,198.9(M+H⁺)；

¹HNMR(400MHz,CDCl₃)8.61(dd,J＝4.8，1.6Hz,1H),8.40(dd,J＝8.4,1.6Hz,1H),7.10(dd,J＝8.4,4.8Hz,1H),4.13-4.06(m,1H),1.35(d,J＝6.8Hz,6H)。

The second step is that: preparation of 2-isopropyl sulfuryl-3-nitropyridine

Placing 2-isopropylmercapto-3-nitropyridine (660mg,3.33mmol) and m-chloroperoxybenzoic acid (mCPBA) (85%, 2.2g and 9.99mmol) in a 100mL round-bottomed bottle, adding 15mL of dichloromethane, stirring the mixture at room temperature overnight, after the reaction is finished, removing the reaction solvent by rotation, sequentially using a saturated sodium sulfite solution, a saturated potassium carbonate solution and a saturated common salt solution to wash the crude product with water, extracting the crude product with dichloromethane, drying and drying by rotation, and performing column chromatography to obtain a product 2-isopropylsulfonyl-3-nitropyridine (700mg and 91% yield).

LC-MS:t＝3.39min,230.2(M+H⁺)；

¹HNMR(400MHz,CDCl₃)8.84(dd,J＝4.4,1.6Hz,1H),8.06(dd,J＝8.4,1.6Hz,1H),7.68(dd,J＝8.0,4.4Hz,1H),4.03-3.96(m,1H),1.36(d,J＝6.8Hz,6H)。

The third step: preparation of 2-isopropyl sulfuryl-3-aminopyridine

Placing 2-isopropyl sulfuryl-3-nitropyridine (700mg,2.18mmol) in a 100mL hydrogenation bottle, adding 15mL methanol, replacing with nitrogen, adding 100mg palladium/carbon (10%) in the bottle, replacing with hydrogen balloon, stirring overnight, filtering the solution after the reaction is finished, and performing rotary drying on the filtrate under reduced pressure to obtain the product (600mg, yield 90%). LC-MS (t 2.85min, 201.0) (M + H)⁺)。

The fourth step: preparation of 2, 5-dichloro-N- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidin-4-amine

Dissolving 2-isopropyl sulfuryl-3-aminopyridine (200mg,1.0mmol) in DMF (6mL), slowly adding NaH (44mg,1.1mmol) at 0 ℃, continuously stirring the reaction solution for half an hour at 0 ℃, dropping 2,5, 6-trichloropyrimidine (201mg,1.1mmol) into the reaction solution at 0 ℃, and naturally heating the mixture to room temperature and stirring overnight after dropping. After completion, 200mL of water was added and extracted with ethyl acetate (30 mL. times.3), the organic phases were combined and dried, the reaction solvent was removed by rotation, and the crude product was subjected to column chromatography to give the product (90mg, 26% yield).

LC-MS:t＝3.95min,346.9(M+H⁺)；

¹HNMR(400MHz,CDCl₃)10.48(s,1H),9.17(dd,J＝8.4,1.6Hz,1H),8.38(dd,J＝4.4,2.8Hz,1H),8.26(s,1H),7.55(dd,J＝8.8,3.2Hz,1H),3.90-3.87(m,1H),1.31(d,J＝6.8Hz,6H)。

The fifth step: 5-chloro-N²- (4-fluoro-2-methoxy-5-nitrophenyl) -N⁴Preparation of (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamines

The preparation of 2, 5-dichloro-N- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidin-4-amine (130mg, 0.37mmol) and 4-fluoro-2-methoxy-5-nitroaniline (70mg, 0.37mmol) were dissolved in 2-pentanol (10mL), p-toluenesulfonic acid (129mg, 0.75mmol) was added and heated to 120 ℃ for reaction overnight. It is cooled to room temperature, the solvent is evaporated off, the residue is taken up in dichloromethane (30mL), the organic phase is washed twice with water and dried. Evaporating to remove organic phase solvent to obtain crude product 5-chloro-N²- (4-fluoro-2-methoxy-5-nitrophenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (100mg) was used in the next step without purification.

LC-MS：t_R＝3.01min，497.0([M+H]⁺)。

And a sixth step: 5-chloro-N²- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N⁴Preparation of (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamines

Reacting 5-chloro-N²- (4-fluoro-2-methoxy-5-nitrophenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (100mg, 0.2mmol) was dissolved in 5ml of N, N-dimethylacetamide, and trimethylethylenediamine (204mg) was added to the solution to conduct microwave reaction for 1 hour. And cooling to room temperature. Evaporating to remove solvent, separating and purifying the residue by silica gel column chromatography to obtain 5-chloro-N²- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (70 mg). LC-MS: t is t_R＝2.30min，579.1([M+H]⁺)。

The seventh step: n is a radical of⁴- (5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine

Reacting 5-chloro-N²- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (70mg) was dissolved in 6mL of an ethanol-water mixed solvent (5:1), and 65mg of iron powder and 50mg of ammonium chloride were added thereto, followed by heating to reflux for 2 hours. Cooling to room temperature, filtering and collecting filtrate. The ethanol in the filtrate was distilled off, and 5ml of water and 5ml of methylene chloride-methanol (20:1) were added. The organic phase was separated and dried. Evaporating to remove organic solvent, separating residue by preparative thin layer chromatography to obtain N⁴- (5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (40 mg). LC-MS: t is t_R＝2.08min，549.3([M+H]⁺)。

Eighth step: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl) propenylamide

Will N⁴- (5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (40mg) was dissolved in 3mL of anhydrous tetrahydrofuran, purged with nitrogen, DIPEA (0.1mL) was added at 0 ℃, and a 1M acryloyl chloride tetrahydrofuran solution (0.3mL) was added dropwise. Stirring was carried out at 0 ℃ for 1 hour. Adding 5ml of water and 5ml of dichloromethane into the reaction solution, separating an aqueous phase from an organic phase, extracting the aqueous phase with 3ml of dichloromethane for three times respectively, combining the organic phases, drying, evaporating to remove the solvent, separating the residue by preparative thin layer chromatography to obtain a crude product, and purifying the crude product by reverse phase column chromatography (water: methanol: 25:75) to obtain N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl amide (6 mg).

LC-MS：t_R＝2.19min，603.3([M+H]⁺)；

¹HNMR(400MHz,CDCl₃)10.01(s,2H)，9.14(m,2H)，8.28(d,1H)，8.22(s,1H)，7.34(m,2H)，6.79(s,1H)，6.30(m,2H)，5.68(d,1H)，3.88(s,3H)，3.80(m,1H)，2.93(br,2H)，2.73(s,3H)，2.36(m,8H)，1.43(d,6H)。

Example 2: preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide the same as in the fourth to eighth steps of example 1.

LC-MS：t_R＝2.02min，569.3([M+H]⁺)；

¹HNMR(400MHz,CDCl₃)9.81(s,2H)，9.01(m,2H)，8.57(d,1H)，8.02(s,1H)，7.24-7.35(m,3H)，6.79(s,1H)，6.10(m,2H)，5.48(d,1H)，3.88(s,3H)，3.80(m,1H)，2.93(br,2H)，2.73(s,3H)，2.36(m,8H)，1.43(d,6H)。

Example 3: preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide the procedure was the same as for the fourth to eighth steps, m/z587.1 of example 1.

Example 4: preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide the procedure was the same as in the fourth to eighth step, m/z636.7 of example 1.

Example 5: preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethoxy) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethoxy) pyrimidin-2-yl) amino) -4-methoxyphenyl) propenylamide the procedure was the same as in the fourth to eighth step, m/z653.1 of example 1.

Example 6: preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide the fourth to eighth step, m/z597.3, of example 1 was performed.

Example 7: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-isopropoxyphenyl) propenylamide

Preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-isopropoxyphenyl) acryloylamide was carried out in the same manner as in the fourth to eighth step, m/z632.2, of example 1.

Example 8: preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-isopropoxyphenyl) acryloyl amide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-isopropoxyphenyl) propenylamide the procedure was the same as for the fourth to eighth steps, m/z615.2 of example 1.

Example 9: preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-isopropoxyphenyl) propenylamide

Preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-isopropoxyphenyl) acryloylamide was carried out in the same manner as in the fourth to eighth step, m/z622.3 of example 1.

Example 10: preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propenylamide the procedure was as for the fourth to eighth steps, m/z665.1 of example 1.

Example 11: preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -4-ethoxy-5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -4-ethoxy-5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide the procedure is as in the fourth to eighth step of example 1, m/z 601.3.

Example 12: preparation of N- (5- ((5- (tert-butoxy) -4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-ethoxyphenyl) propenylamide

Preparation of N- (5- ((5- (tert-butoxy) -4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-ethoxyphenyl) propenylamide the procedure is as in the fourth to eighth step, m/z655.3 of example 1.

Example 13: preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide

Preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide the fourth to eighth step, m/z605.2 of example 1 was performed.

Example 14: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acryloylamide

Preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acryloylamide was carried out in the same manner as in the fourth to eighth step, m/z639.6 of example 1.

Example 15: preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide

Preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide the procedure is as in the fourth to eighth steps of example 1, m/z 622.7.

Example 16: preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propenylamide

Preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propenylamide the procedure was as for the fourth to eighth steps of example 1, m/z 673.1.

Example 17: preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acryloylamide

Preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acryloylamide was carried out in the same manner as in the fourth to eighth step, m/z629.8 of example 1.

Example 18: preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5-isopropoxy-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide

Preparation of N- (4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5-isopropoxy-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) phenyl) propenylamide the procedure was as for the fourth to eighth steps of example 1, m/z 663.2.

Example 19: preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) propenoylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) propenylamide the fourth to eighth step, m/z622.7 of example 1 was followed.

Example 20: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) propenylamide

Preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) acryloylamide was carried out in the same manner as in the fourth to eighth step, m/z657.1 of example 1.

Example 21: preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (meth) amino) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) acryloylamide was carried out in the same manner as in the fourth to eighth step, m/z640.7 of example 1.

Example 22: preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) propenylamide the same procedure as in example 1 for the fourth to eighth step, m/z 690.7.

Example 23: preparation of N- (5- ((5- (difluoromethyl) -4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) propenylamide

Preparation of N- (5- ((5- (difluoromethyl) -4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) propenylamide the fourth to eighth steps of example 1, m/z672.7, were performed.

Example 24: preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethoxy) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) propenylamide

Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethoxy) pyrimidin-2-yl) amino) -4- (trifluoromethoxy) phenyl) propenylamide the same procedure as in example 1 for the fourth to eighth step, m/z 706.7.

Example 25: preparation of N- (4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide

The first step is as follows: n is a radical of²- (2-isopropoxy-4- (4-methylpiperazin-1-yl) -5-nitrophenyl) -N⁴Preparation of (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamines

Will N²- (4-fluoro-2-isopropoxy-5-nitrophenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (98mg, 0.2mmol) was dissolved in 5ml of N, N-dimethylacetamide, 1-methylpiperazine (20mg, 0.2mmol) was added, and the reaction was carried out by microwave for 1 hour. And cooling to room temperature. Evaporating to remove solvent, separating and purifying residue by silica gel column chromatography to obtain N²- (2-isopropoxy-4- (4-methylpiperazin-1-yl) -5-nitrophenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (72mg), m/z 570.7.

The second step is that: n is a radical of²- (5-amino-2-isopropoxy-4- (4-methylpiperazin-1-yl) phenyl) -N⁴Preparation of (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamines

Will N²- (2-isopropoxy-4- (4-methylpiperazin-1-yl) -5-nitrophenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (72mg, 0.13mmol) was dissolved in 6mL of an ethanol-water mixed solvent (5:1), 70mg of iron powder and 50mg of ammonium chloride were added, and the mixture was heated to reflux and reacted for 2 hours. Cooling to room temperature, filtering and collecting filtrate. The ethanol in the filtrate was distilled off, and 5ml of water and 5ml of methylene chloride-methanol (20:1) were added. The organic phase was separated and dried. Evaporating to remove organic solvent, separating residue by preparative thin layer chromatography to obtain N²- (5-amino-2-isopropoxy-4- (4-methylpiperazin-1-yl) phenyl) -N⁴- (2- (isopropyl) groupSulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (41mg), m/z 540.7.

The third step: preparation of N- (4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide

Will N²- (5-amino-2-isopropoxy-4- (4-methylpiperazin-1-yl) phenyl) -N⁴- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2, 4-diamine (41mg, 0.076mmol) was dissolved in 3mL of anhydrous tetrahydrofuran, and then DIPEA (0.1mL) was added thereto at 0 ℃ under nitrogen substitution protection, and a 1M acryloyl chloride tetrahydrofuran solution (0.3mL) was added dropwise. Stirring was carried out at 0 ℃ for 1 hour. Adding 5ml of water and 5ml of dichloromethane into the reaction solution, separating an aqueous phase from an organic phase, extracting the aqueous phase with 3ml of dichloromethane for three times respectively, combining the organic phases, drying, evaporating to remove the solvent, separating the residue by preparative thin-layer chromatography to obtain a crude product, and purifying the crude product by reverse phase column chromatography (water: methanol: 25:75) to obtain N- (4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide (8mg), m/z 594.7.

Example 26: preparation of N- (5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-isopropoxy-2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-isopropoxy-2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 612.7.

Example 27: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-isopropoxy-2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-isopropoxy-2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 628.7.

Example 28: preparation of N- (4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide

Preparation of N- (4-isopropoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 663.1.

Example 29: preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide was analogous to example 25, m/z 592.2.

Example 30: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) propenylamide is analogous to example 25, m/z 601.6.

Example 31: preparation of N- (5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 634.7.

Example 32: preparation of N- (4-ethoxy-5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide

N- (4-ethoxy-5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide was prepared in analogy to example 25, m/z 598.7.

Example 33: preparation of N- (4-ethoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) propenylamide

N- (4-ethoxy-5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was prepared in analogy to example 25, m/z 610.7.

Example 34: preparation of N- (4- (difluoromethoxy) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide

Preparation of N- (4- (difluoromethoxy) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloyl amide was analogous to example 25, m/z 602.7.

Example 35: preparation of N- (4- (difluoromethoxy) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide

Preparation of N- (4- (difluoromethoxy) -5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 620.7.

Example 36: preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (5- ((5-chloro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 637.6.

Example 37: preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 627.8.

Example 38: preparation of N- (4- (difluoromethoxy) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) propenylamide

Preparation of N- (4- (difluoromethoxy) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) propenylamide is analogous to example 25, m/z 632.8.

Example 39: preparation of N- (4- (difluoromethoxy) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide

Preparation of N- (4- (difluoromethoxy) -5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acryloylamide was analogous to example 25, m/z 670.8.

Example 40: preparation of N- (5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) -4- (trifluoromethoxy) phenyl) acryloylamide

Preparation of N- (5- ((4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) -4- (trifluoromethoxy) phenyl) acryloylamide was analogous to example 25, m/z 621.2.

Example 41: preparation of N- (5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) -4- (trifluoromethoxy) phenyl) acryloylamide

Preparation of N- (5- ((5-fluoro-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) -4- (trifluoromethoxy) phenyl) acryloylamide was analogous to example 25, m/z 638.6.

Example 42: preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) -4- (trifluoromethoxy) phenyl) propenylamide

Preparation of N- (5- ((5-cyano-4- ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) -4- (trifluoromethoxy) phenyl) acryloylamide was analogous to example 25, m/z 645.7.

Example 43: preparation of N- (5- ((4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide

The first step is as follows: preparation of N- (3-bromopyridin-2-yl) -2-chloropyrimidin-4-amine

3-bromopyridin-2-amine (680mg,4.0mmol) was dissolved in anhydrous DMF (5mL) and NaH (320mg,8.0mmol) was added portionwise while cooling on ice and after stirring for 20 minutes the resulting suspension was added to 2, 4-dichloropyrimidine (650mg,4.4mmol) in DMF (5mL) and the reaction stirred for 2 hours while cooling on ice and LCMS showed completion. Saturated NH for reaction solution₄After quenching with Cl (3mL), concentration to dryness, dichloromethane (20mL), water (20mL), organic phase drying, filtration and concentration, the residue was purified by flash column chromatography to give N- (3-bromopyridin-2-yl) -2-chloropyrimidin-4-amine (850mg, 75% yield).

The second step is that: preparation of N- (3-bromopyridin-2-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine

N- (3-Bromopyridin-2-yl) -2-chloropyrimidin-4-amine (850mg,3.0mmol), 4-fluoro-2-methoxy-5-nitroaniline (560mg,3.0mmol), p-toluenesulfonic acid monohydrate (680mg,3.6mmol) was dissolved in 1, 4-dioxane (15 mL). The reaction was heated to 120 ℃ and stirred for 16 h, LCMS indicated complete reaction, the reaction was concentrated, water (10mL), methanol (5mL) were added to the residue, the mixture was stirred for 10 min, filtered, and the filter cake was washed with methyl tert-butyl ether to give N- (3-bromopyridin-2-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine (800mg, 60% yield).

The third step: preparation of N- (3-bromopyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine

Dissolving N- (3-bromopyridin-2-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine (800mg,1.84mmol), triethylamine (1mL), N, N, N-trimethylethylenediamine (280mg,2.76mmol) in DMF (10mL), heating the reaction to 110 deg.C and stirring for 2 hours, LCMS shows the reaction, concentrating the reaction to dryness, layering the residue with dichloromethane (20mL), water (20mL), filtering the insoluble matter, drying the organic phase, filtering, concentrating, subjecting the residue to flash column chromatography to obtain N- (3-bromopyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine (300mg, 32% yield).

The fourth step: preparation of N- (3- (cyclopropylsulfonyl) pyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine

N- (3-bromopyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine (70mg,0.14mmol), sodium cyclopropylene sulfonate (86mg,0.7mmol), CuI (27mg,0.14mmol), sodium prolinate (20mg,0.14mmol) were dissolved in DMSO (5 mL). The reaction solution was replaced with nitrogen three times, heated to 120 ℃ and reacted for 2 hours. LCMS showed reaction completion and dichloromethane (10mL), water (10mL) were added to the reaction. The organic phase was washed three times with water, dried over magnesium sulfate, filtered, the filtrate was concentrated, and the residue was isolated and purified on a thick preparative plate to give N- (3- (cyclopropylsulfonyl) pyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine (30mg, 40% yield).

The fifth step: preparation of N- (4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) pyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N-methylbenzene-1, 2, 4-triamine

N- (3- (cyclopropylsulfonyl) pyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) pyrimidine-2, 4-diamine (30mg,55.3umol) was dissolved in methanol (5mL) and Pd/C (10mg) was added. The reaction was stirred at room temperature for 10 min under hydrogen atmosphere, LCMS showed completion of the reaction, the reaction was filtered and the filtrate was dried by spinning to give N4- (4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) pyrimidin-2-yl) -N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (20mg, 70% yield) which was used in the next reaction without purification.

And a sixth step: preparation of N- (5- ((4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide

N- (4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) pyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N-methylbenzene-1, 2, 4-triamine (20mg, 39.0. mu. mol), triethylamine (0.2mL) were dissolved in tetrahydrofuran (10mL), and the reaction was cooled to-10 to-5 ℃. Acryloyl chloride (78ul,1MinTHF) was added slowly under nitrogen. The reaction was stirred at-10 to-5 ℃ for 30 minutes, after the reaction was complete, methanol (3mL) was added and stirring was continued for 10 minutes, the reaction solution was concentrated to dryness, and the residue was separated by preparative plates and purified by reverse phase column chromatography to give N- (5- ((4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl) acryloylamide (3.5mg, 16% yield).

¹HNMR(400MHz,MeOD)8.78-8.67(m,1H),8.43-8.31(m,1H),8.19–8.13(m,1H),7.92-7.84(m,1H),7.83-7.76(m,1H),7.54-7.42(m,1H),7.02(s,1H),6.66-6.55(m,1H),6.52-6.44(m,1H),5.98-5.86(m,1H),3.98(s,3H),3.59-3.47(m,2H),3.33(dt,J＝3.3,1.6Hz,2H),2.89(s,6H),2.76(s,3H),1.31(s,4H),1.17-1.11(m,1H).m/z567.3。

Example 44: preparation of N- (5- ((4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide

The first step is as follows: preparation of N- (3-bromopyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine

3-Bromopyridin-2-amine (350mg,2.0mmol) was dissolved in anhydrous DMF (5mL) and NaH (160mg,4.0mmol) was added portionwise while ice was allowed to cool and after stirring for 20 minutes, the resulting suspension was added to 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (440mg,2.0mmol) in DMF (5mL) and the reaction stirred for 2 hours while ice was allowed to cool and LCMS showed completion. Saturated NH for reaction solution₄After quenching with Cl (3mL), concentration to dryness, dichloromethane (20mL), water (20mL), organic phase drying, filtration and concentration, the residue was purified by flash column chromatography to give N- (3-bromopyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine (500mg, 70% yield).

The second step is that: preparation of N- (3-bromopyridin-2-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

N- (3-Bromopyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine (500mg,1.41mmol), 4-fluoro-2-methoxy-5-nitroaniline (290mg,1.56mmol), p-toluenesulfonic acid monohydrate (325mg,1.7mmol) was dissolved in 1, 4-dioxane (30 mL). The reaction was heated to 120 ℃ and stirred for 16 h, LCMS indicated complete reaction, the reaction was concentrated, water (10mL), methanol (5mL) were added to the residue, the mixture was stirred for 10 min, filtered, and the filter cake was washed with methyl tert-butyl ether to give N- (3-bromopyridin-2-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (400mg) which was used in the next reaction without purification.

The third step: preparation of N- (3-bromopyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Dissolving N- (3-bromopyridin-2-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (400mg,0.79mmol), triethylamine (1mL), N, N, N-trimethylethylenediamine (120mg,1.19mmol) in DMF (10mL), heating the reaction to 110 ℃ and stirring for 2 hours, LCMS shows the reaction, concentrating the reaction to dryness, layering the residue with dichloromethane (20mL), water (20mL), filtering the insoluble material, drying the organic phase, filtering, concentrating, subjecting the residue to flash column chromatography to obtain N- (3-bromopyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (270mg, 58% yield).

The fourth step: preparation of N- (3- (cyclopropylsulfonyl) pyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

N- (3-bromopyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (270mg,0.46mmol), sodium cyclopropylene sulfonate (120mg,0.92mmol), CuI (176mg,0.92mmol), sodium prolinate (126mg,0.92mmol) were dissolved in DMSO (5 mL). The reaction solution was replaced with nitrogen three times, heated to 120 ℃ and reacted for 2 hours. LCMS showed reaction completion and dichloromethane (10mL), water (10mL) were added to the reaction. The organic phase was washed three times with water, dried over magnesium sulfate, filtered, the filtrate was concentrated, and the residue was isolated and purified on a thick preparative plate to give N- (3- (cyclopropylsulfonyl) pyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (50mg, 18% yield).

The fifth step: preparation of N- (4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine

N- (3- (cyclopropylsulfonyl) pyridin-2-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (50mg, 81.8umol) was dissolved in methanol (5mL), water (5mL), and iron powder (50mg), ammonium chloride (50mg) was added. The reaction was stirred at room temperature for 2 h, LCMS showed completion, the reaction was filtered, the filtrate was spun dry, and the residue was purified by flash silica gel column to give N- (4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (30mg, 63% yield).

And a sixth step: preparation of N- (5- ((4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide

N- (4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N-methylbenzene-1, 2, 4-triamine (30mg, 51.0. mu. mol), triethylamine (0.2mL) were dissolved in tetrahydrofuran (10mL), and the reaction was cooled to-10 to-5 ℃. Acryloyl chloride (78ul,1MinTHF) was added slowly under nitrogen. The reaction was stirred at-10 to-5 ℃ for 30 minutes, after the reaction was complete, methanol (3mL) was added and stirring was continued for 10 minutes, the reaction was concentrated to dryness, and the residue was separated by preparative plates and purified by reverse phase column chromatography to give N- (5- ((4- ((3- (cyclopropylsulfonyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide (3.0mg, 10% yield).

¹HNMR(400MHz,MeOD)8.70-8.62(m,1H),8.61-8.53(m,1H),8.50-8.42(m,1H),8.09-7.93(m,1H),7.53-7.39(m,1H),7.09-7.00(m,1H),6.65-6.41(m,3H),5.97-5.85(m,1H),3.97(s,3H),3.59-3.53(m,2H),3.32-3.27(m,2H),2.89(s,6H),2.78(s,3H),1.69-1.57(m,1H),1.17-1.06(m,3H),1.00-0.84(m,1H).m/z635.2。

Example 45: preparation of N- (5- ((4- ((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) -5-methylpyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide

The first step is as follows: preparation of 2- (cyclopropylsulfonyl) -3-nitropyridine

2-chloro-3-nitropyridine (1.0g, 6.31mmol), sodium cyclopropylene sulfonate (1.2g, 9.5mmol) were dissolved in DMSO (15mL), the reaction was heated to 120 deg.C and stirred for 8 h, LCMS showed completion of the reaction, the reaction was partitioned with dichloromethane (30mL), water (30mL), organic phase was filtered dry, concentrated, and the residue was purified by flash silica gel column to give 2- (cyclopropylsulfonyl) -3-nitropyridine (1.2g, 84% yield).

The second step is that: preparation of 2- (cyclopropylsulfonyl) pyridin-3-amine

2- (Cyclopropylsulfonyl) -3-nitropyridine (1.2g,5.26mmol), Pd/C (200mg) was dissolved in methanol (20mL), stirred at room temperature for 30 minutes under a hydrogen atmosphere, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash silica gel column to give 2- (cyclopropylsulfonyl) pyridin-3-amine (800mg, 76% yield).

The third step: preparation of 2-chloro-N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -5-methylpyrimidin-4-amine

2- (Cyclopropylsulfonyl) pyridin-3-amine (400mg, 2.0mmol) was dissolved in anhydrous DMF (10mL) and NaH (160mg,4.0mmol) was added portionwise while cooling on ice and after stirring for 20 minutes the resulting suspension was added to DMF (10mL) of 2, 4-dichloro-5-methylpyrimidine (400mg,2.4mmol) and the reaction stirred for 2 hours while cooling on ice and LCMS indicated completion. Saturated NH for reaction solution₄After quenching with Cl (3mL), concentration to dryness, dichloromethane (20mL), water (20mL), organic phase drying, filtration and concentration, the residue was purified by flash column chromatography to give 2-chloro-N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -5-methylpyrimidin-4-amine (500mg, 75% yield).

The fourth step: preparation of N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -5-methylpyrimidine-2, 4-diamine

2-chloro-N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -5-methylpyrimidin-4-amine (500mg, 1.54mmol), 4-fluoro-2-methoxy-5-nitroaniline (350mg, 1.85mmol), p-toluenesulfonic acid monohydrate (440mg,2.31mmol) was dissolved in 1, 4-dioxane (20 mL). The reaction was heated to 120 ℃ and stirred for 16 h, LCMS indicated complete reaction, the reaction was concentrated, water (10mL), methanol (5mL) were added to the residue, the mixture was stirred for 10 min, filtered, and the filter cake was washed with methyl tert-butyl ether to give crude N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -5-methylpyrimidine-2, 4-diamine (600mg, 80% yield).

The fifth step: preparation of N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5-methylpyrimidine-2, 4-diamine

Dissolving N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -5-methylpyrimidine-2, 4-diamine (600mg, 1.26mmol), triethylamine (1mL), N, N, N-trimethylethylenediamine (200mg, 1.9mmol) in DMF (10mL), heating the reaction to 110 ℃ and stirring for 2 hours, LCMS shows the reaction, concentrating the reaction to dryness, layering the residue with dichloromethane (20mL), water (20mL), filtering the insoluble material, drying the organic phase, filtering, concentrating, and subjecting the residue to flash column chromatography to obtain N4- (2- (cyclopropylsulfonyl) pyridin-3-yl) -N2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrobenzene Yl) -5-methylpyrimidine-2, 4-diamine (600mg, 85% yield).

And a sixth step: preparation of N- (4- ((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) -5-methylpyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine

N- (2- (cyclopropylsulfonyl) pyridin-3-yl) -N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -5-methylpyrimidine-2, 4-diamine (300mg,0.54mmol) was dissolved in methanol (20mL), water (10mL) and iron powder (300mg), ammonium chloride (500mg) was added. The reaction was stirred at room temperature for 2 h, LCMS showed completion, the reaction was filtered, the filtrate was spun dry, and the residue was purified by reverse phase column to give N- (4- ((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) -5-methylpyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N-methylbenzene-1, 2, 4-triamine (250mg, 88% yield).

The seventh step: preparation of N- (5- ((4- ((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) -5-methylpyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide

N- (4- ((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) -5-methylpyrimidin-2-yl) -N- (2- (dimethylamino) ethyl) -5-methoxy-N-methylbenzene-1, 2, 4-triamine (250mg,0.47mmol), triethylamine (0.5mL) was dissolved in tetrahydrofuran (20mL), and the reaction was cooled to-10 to-5 ℃. Acryloyl chloride (0.72mL,1MinTHF) was added slowly under nitrogen. The reaction was stirred at-10 to-5 ℃ for 30 minutes, after the reaction was complete, methanol (3mL) was added and stirring was continued for 10 minutes, the reaction was concentrated to dryness, and the residue was separated by preparative plates and purified by reverse phase column chromatography to give N- (5- ((4- ((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) -5-methylpyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide (150mg, 54% yield).

¹HNMR(400MHz,MeOD)8.68-8.59(m,1H),8.58-8.51(m,1H),7.95-7.80(m,1H),7.66-7.60(m,1H),7.57(s,1H),7.00(s,1H),6.66-6.46(m,2H),6.03-5.88(m,1H),3.95(s,3H),3.56-3.48(m,2H),3.32-3.27(m,2H),3.20-3.08(m,1H),2.90(s,6H),2.73(s,3H),2.26(d,J＝0.8Hz,3H),1.34-1.24(m,2H),1.21-1.11(m,2H).m/z581.3。

Biological test evaluation

EGFR 790M mutant enzymology experiment

In the experiment, the inhibition effect of the compound on the exon 20T790M mutant EGFR enzyme is tested by adopting a fluorescence resonance energy transfer (TR-FRET) method, and the half inhibition concentration IC of the compound on the enzyme activity is obtained₅₀。

1) Adding 1-5 ul EGFRT790M enzyme solution into a 384-well plate, wherein the final concentration of the enzyme is 0.1-1 nM.

2) Adding 1-5 ul of the compound solution which is diluted in a gradient manner.

3) Incubate for 10 minutes at room temperature.

4) Adding 1-5 ul of substrate mixed solution containing 5-50 nM of substrate polypeptide and 1-10 uM of ATP.

5) And incubating for 0.5-2 hours at room temperature.

6) 5ul of EDTA stop solution was added to stop the reaction for 5 minutes.

7) 5ul of the detection solution containing the labeled antibody was added and incubated at room temperature for 1 hour.

8) The microplate reader measures the 665nm fluorescence signal value of each plate.

9) The inhibition rate was calculated from the fluorescence signal value.

10) Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀。

EGFR Wild Type (WT) enzymology experiment

In the experiment, the inhibition effect of the compound on the wild type EGFR enzyme is tested by adopting a fluorescence resonance energy transfer (TR-FRET) method, and the half inhibition concentration IC of the compound on the activity of the enzyme is obtained₅₀。

1) Adding 1-5 ul of EGFR wild type enzyme solution into a 384-well plate, wherein the final enzyme concentration is 0.1-1 nM.

3) Incubate for 10 minutes at room temperature.

4) Adding 1-5 ul of substrate mixed solution containing 5-50 nM of substrate polypeptide and 0.1-5 uM of ATP final concentration.

5) And incubating for 0.5-2 hours at room temperature.

6) 5ul of EDTA stop solution was added to stop the reaction for 5 minutes.

9) The inhibition rate was calculated from the fluorescence signal value.

The biochemical activity of the compound of the present invention was determined by the above test, and the IC was determined₅₀The values are given in the following table.

Wherein the compound EGFRIC of example 6 to example 45₅₀The values are similar to those of example 1, and all show good EGFR mutant kinase inhibitory activity.

And (4) conclusion: the embodiment of the invention has strong inhibitory activity to EGFR mutant kinase, and simultaneously has weak inhibitory activity to wild type kinase, thereby showing good selectivity.

NCI-H1975 cell proliferation inhibition assay

The experiment adopts the method of CellTiter-Glo to test the inhibition effect of the compound on the proliferation of NCI-H1975 cells and obtainsHalf inhibitory concentration IC of compound for inhibiting cell proliferation activity₅₀。

1) Inoculating 90 mu L of H1975 cell suspension in a 96-well cell culture plate, wherein the density is 1-5 x 10³Cells/ml, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)₂)。

2) To the cells of the plate, solutions of the test compounds at different concentrations were added in a gradient and the plate was incubated in an incubator for 72 hours (37 ℃ C., 5% CO)₂)。

3) Adding 50-100 mu LCellTiter-Glo reagent into each hole, shaking for 10 minutes, and standing for 10 minutes at room temperature.

4) The microplate reader measures the chemiluminescence signal value of each plate.

5) The inhibition rate was calculated from the chemiluminescence signal value.

6) Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀。

A431 cell proliferation inhibition assay

The experiment adopts the CellTiter-Glo method to test the inhibition effect of the compound on the proliferation of A431 cells and obtains the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity₅₀。

1) Inoculating 90 mu L of A431 cell suspension in a 96-well cell culture plate, wherein the density is 1-5 x 10³Cells/ml, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)₂)。

5) The inhibition rate was calculated from the chemiluminescence signal value.

Wherein the compound EGFRIC of example 3 to example 45₅₀The values for H1975 and A431 inhibitory activities are similar to those of example 1, and both of them show good inhibitory activities.

And (4) conclusion: the embodiment of the invention has strong inhibitory activity on the proliferation of EGFR mutant cell H1975, has low inhibition on the proliferation of wild type A431 cell, and has good selectivity on wild type/mutant cell.

Claims

1. A compound N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog having formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x, Y are each independently selected from CH or N, and X, Y is different;

R₃Selected from the following structures:

R₄is selected from C_1-8Alkyl radical, C_3-8A cycloalkyl group;

2. The compound N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) allylamide analog of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is₃Selected from:X、Y、R₁、R₂、R₄、R₅、R₆、R₇、R₈as defined in claim 1.

3. The compound N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is R₁Is selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, optionally further substituted by one or more groups selected from fluoro, chloro, bromo, iodo, hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy, halogen substituted C_1-8Alkoxy radical, C_3-8Cycloalkyl or C_3-8Cycloalkoxy is substituted by a substituent; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined in claim 1.

4. The compound N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is R₁Is selected from C_1-4Alkyl radical, C_3-6Cycloalkyl optionally further substituted with one or more substituents selected from fluoro, chloro, bromo, iodo or hydroxy; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined in claim 1.

5. The compound N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is R₁Is selected from C_1-4Alkyl, optionally further substituted with one or more substituents selected from fluoro or hydroxy; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined in claim 1.

6. The compound N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is R₁Selected from methyl, ethyl, isopropyl, trifluoromethyl or difluoromethyl; x, Y, R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined in claim 1.

7. The compound N- (5- ((4- ((2- (alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R is R₂Selected from hydrogen, fluorine, chlorine, cyano, C_1-8Alkoxy, difluoromethyl, trifluoromethyl or trifluoromethoxy; r₄Selected from isopropyl or cyclopropyl; x, Y, R₂、R₃、R₅、R₆、R₇、R₈As defined in claim 1.

8. The compound N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds:

9. a process for the preparation of a compound of formula (I), N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloylamide analogue, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 comprising the steps of:

wherein, X₁、X₂Each independently selected from fluorine, chlorine, bromine or iodine; x, Y, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈As defined in claim 1.

10. A pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I) N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, and a pharmaceutically acceptable carrier.

11. Use of a compound of formula (I) N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analog, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, or a pharmaceutical composition of claim 10, for the manufacture of a therapeutic medicament for treating a disease mediated by the activity of an EGFR mutant or an exon 19 deletion activation mutant, preferably, the EFGR mutant is selected from the group consisting of an L858REGFR mutant and a T790MEGFR mutant.

12. Use according to claim 11, wherein the compound of formula (I) N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analogue according to any of claims 1-8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition of claim 10 in the manufacture of a medicament for the treatment of a disease mediated alone or in part by EGFR mutant activity.

13. Use according to claim 12, wherein the compound of formula (I) N- (5- ((4- ((2- (alkyl substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -phenyl) acryloyl amide analogue according to any of claims 1-8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition according to claim 10 in the manufacture of a medicament for the treatment of cancer.

14. The use according to claim 13, wherein the cancer is selected from 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 cancer, gastric cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, or mesothelioma; non-small cell lung cancer is preferred.