CN108503627A - 2,4- disubstituted benzenes -1,5- diamine derivatives as EGFR inhibitor and its application - Google Patents

Abstract

The invention discloses 2,4 disubstituted benzenes, 1,5 diamine derivative, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrugs shown in a kind of formula I, and each symbol therein is as defined in the claims.The 2 of the present invention, 4 disubstituted benzenes 1,5 diamine derivatives can inhibit activation or the resistant mutation of one or more EGFR, it can be used for the treatment of EGFR sensitive mutant cancers, the case for applying also for generating secondary resistance in current EGFR TKI treatments is a kind of medicine being preferably mutated caused disease by EGFR.

Description

2,4-disubstituted benzene-1,5-diamine derivatives as EGFR inhibitors and their applications

technical field

The invention relates to the field of medical technology, in particular to 2,4-disubstituted benzene-1,5-diamine derivatives used as EGFR inhibitors and their preparation for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases. Especially in the application of drugs for non-small cell lung cancer.

Background technique

Epidermal Growth Factor Receptor EGFR (Epidermal Growth Factor Receptor) is a transmembrane protein tyrosine kinase of the erbB receptor family. When it binds to a growth factor ligand (such as epidermal growth factor (EGF)), the receptor Homodimerization can occur with additional EGFR molecules, or heterodimerization with another family member such as erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4). Homodimerization and/or heterodimerization of the erbB receptor leads to phosphorylation of key tyrosine residues in the intracellular domain and to 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, among others.

Therefore, the erbB family is represented as a reasonable target for the development of anticancer drugs, such as many drugs targeting EGFR or erbB2, which are now widely used clinically, including gefitinib (IRESSA ^TM ), erlotinib ( TARCEVA ^TM ) and lapatinib (TYKERB ^TM ), etc. New England Journal of Medicine (2008, Issue 358, 1160-1174) and Biochemical and Biophysical Research Communications (2004, Issue 319, 1-11) provide insights into erbB receptor signaling and its involvement in tumorigenesis detailed discussion of.

Lung cancer is the cancer with the highest incidence in the world. In China, the incidence of lung cancer ranks first among all cancers, and it is also the cancer with the highest incidence and mortality in China. About 30% of lung cancer patients in China have EGFR mutations, among which L858R and exon 19 deletion mutations account for more than 90%. These patients are more sensitive to EGFR inhibitors. The existing first-generation EGFR inhibitors on the market, such as erlotinib and gefitinib, have a good effect on such patients, and can shrink the tumors of more than 60% of the patients, significantly prolonging the progression-free survival of the patients . However, the vast majority of patients will acquire drug resistance within 6-12 months. This drug resistance mode is further mutation of EGFR, which reduces their sensitivity to the first generation of EGFR inhibitors. The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. Threonine (T) is replaced by L-methionine (M), and the mutated EGF tyrosine kinase R no longer binds to gefitinib and erlotinib, so that the first generation of EGFR inhibitors will no longer works, leaving such patients currently in a state of no drug available. It is found that 50% of patients who are resistant to the first generation of EGFR inhibitors have EGFR T790M mutation. In the T790M mutant cell line H1975, first-generation EGFR inhibitors, such as gefitinib and erlotinib, were greater than 3 μM and had little activity.

The current development and marketing of the second-generation irreversible pan-EGFR inhibitor (Afatinib BIBW2992) has significantly better curative effect on patients with EGFR-mutated lung cancer than the first-generation EGFR inhibitor. Unlike first-generation EGFR inhibitors, they contain electrophilic groups that can undergo Michael addition reactions with the conserved cysteine group (Cyst797) in EGFR. This covalent bonding method makes the second-generation EGFR inhibitors have a stronger ability to occupy the ATP site than reversible inhibitors. EGFR T790M can still be inhibited in the model (Engelman, Zejnullahu et al., 2007, Cancer Res, 67, 11924-11932; Li, Ambrogio et al., 2008, Oncogene, 27, 4702-4711). However, the ability of existing irreversible inhibitors to inhibit the EGFR T790M mutation in cell line models is still lower than the ability to inhibit only the activating mutation of EGFR, and at clinically available concentrations, these compounds cannot inhibit EGFR in vitro T790M (Yuza, Glatt et al., 2007, Cancer Biol Ther, 6, 661-667; Godin-Heymann, Ulkus et al., 2008, Mol Cancer Ther, 7, 874-879). Since the affinity of EGFR T790M to ATP is similar to that of wild-type EGFR to ATP, this type of quinoline-based second-generation EGFR inhibitor will also inhibit wild-type EGFR while inhibiting EGFRT790M. The inhibitory activity to wild-type EGFR is significantly higher than that of the drug-resistant T790M mutation, and the toxic side effects such as skin rash in patients are so serious that the plasma concentration of the drug is not enough to inhibit the T790M mutation, which greatly limits the clinical effectiveness of this type of drug. For example CI-1033, HKI-272 and PF00299804 etc. The clinical treatment for non-small cell lung cancer resistant to gefitinib and erlotinib is very limited, and side effects such as diarrhea and rash will occur in a dose-dependent manner (Janne, Von Pawel et al., 2007, J Clin Oncol, 25 , 3936-3944; Advani, Coiffier et al., 2010, J Clin Oncol, 28, 2085-2093).

In order to specifically inhibit EGFR T790M, the third generation of selective inhibitors of EGFR mutations has been developed. Compared with the second-generation quinoline compounds, this type of irreversible inhibitors has higher selectivity to EGFR T790M, and may have higher clinical activity and better tolerance. For example, WZ4002 and CO-1686, as well as AZD9291 (Osimertinib), which has just been launched recently, have a selective inhibition of EGFR T790M that is 30-100 times higher than that of the second generation.

In order to improve the inhibitory activity against mutations such as drug-resistant EGFR T790M, and at the same time reduce the inhibitory activity against wild-type EGFR, it is important to develop third-generation selective inhibitors of EGFR mutants with higher activity, better selectivity, and lower toxicity. meaning.

At present, many documents have reported such protein kinase inhibitors and their anti-tumor applications.

For example, WO2013014448 discloses pyrimidine derivatives that can be used as EGFR inhibitors and their use in the treatment of cancer, wherein G is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3- Base, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo[1,5-a]pyridin-3-yl, R ² is methyl or methoxy , with the following structure:

The structural formula of the successfully marketed compound (AZD9291) in this patent is:

CN104140418 also discloses pyrimidine derivatives that can be used as EGFR inhibitors and their application for treating cancer, wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are methyl or deuterated methyl, and the activity of the compound Consistent with the activity of AZD9291, the structure is shown in the following formula:

In addition, CN105237515 also discloses pyrimidine derivatives that can be used as EGFR inhibitors and their use in treating cancer, wherein R ¹ is deuterium, R ² , R ³ , R ⁴ and R ⁵ are methyl groups; or R ¹ is hydrogen, At least two of R ² , R ³ , R ⁴ and R ⁵ are CD ₃ , and the rest are methyl groups. Most of the activities of the compounds in this patent are below 15nM, which is consistent with the activity of AZD9291. The structure is as follows:

Contents of the invention

The present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

in:

_R is selected from hydrogen, halogen, trifluoromethyl or cyano;

R ₂ is selected from C _1～6 deuterated haloalkoxy;

_R3 is selected from any of the following structures, or _R3 is selected from any of the following structures with all deuterated or partially deuterated:

R ₄ is selected from any of the following structures:

Wherein, X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are each independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl or C _1-6 alkylamino;

R ₅ is selected from a C _5-15 heterocycle or a C _5-15 deuterated heterocycle, and the heterocycle contains 1 to 4 heteroatoms selected from N, O, S or P.

Another technical solution adopted by the present invention is: a compound as shown in formula II, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

in:

_R is selected from hydrogen, halogen, trifluoromethyl or cyano;

_R is selected from deuterated monofluoromethoxy or deuterated difluoromethoxy;

_R3 is selected from any of the following structures:

Wherein, R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R 15 , R ₁₆ , R ₁₇ , R ₁₈ , _{R 19 ,} R ₂₀ , and R ₂₁ are each independently selected from from hydrogen, methyl or deuterated methyl;

R ₅ selected from

Wherein, _R is selected from hydrogen, methyl or deuterated methyl;

X ₁ , X ₂ , and X ₃ are each independently selected from hydrogen or halogen.

In one embodiment of the invention,

_R3 is R ₇ , R ₈ , and R ₉ are each independently selected from methyl or deuterated methyl.

The compound, or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, is preferably selected from the compounds represented by the following structural formula:

Above-mentioned pharmaceutically acceptable salt is inorganic acid salt or organic acid salt, and described inorganic acid salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, Phosphate, acid phosphate; said organic acid salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonic acid Salt, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate , Glutamate, Salicylate, Ascorbate, Camphorate, Camphorsulfonate.

The 2,4-disubstituted benzene-1,5-diamine derivative of the present invention is a compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the compound Can inhibit one or more activating or resistant mutations of EGFR, such as L858R activating mutants, Exon19 deletion EGFR activating mutants, T790M resistant mutants; the compound improves the inhibitory activity against mutations such as drug-resistant EGFR T790M, and At the same time, it reduces the inhibitory activity on wild-type EGFR, and can be used to develop third-generation EGFR mutant selective inhibitors with higher activity, better selectivity and lower toxicity.

The 2,4-disubstituted benzene-1,5-diamine derivatives of the present invention, in vitro experiments show that they can inhibit the proliferation of EGFR T790M/L858R double mutant enzymes at nanomolar concentrations, while inhibiting wild-type EGFR enzymes is relatively weak. Therefore, this type of compound can not only be used for the treatment of EGFR sensitive mutation cancer, but also suitable for the cases of secondary drug resistance in the current EGFR-TKI treatment; at the same time, its mutation selectivity greatly reduces the inhibition of wild-type EGFR. It is an ideal drug for the treatment of diseases caused by EGFR mutations.

Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below.

"Alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon radical consisting only of carbon and hydrogen atoms, containing 1 to 12 carbon atoms. "Alkyl" is preferably an alkyl group of 1 to 6 carbon atoms, ie a C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"Alkoxy" refers to a radical of formula -OR wherein R is an alkyl radical as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

"Halogen (halo)" means a fluoro, chloro, bromo, or iodo substituent.

"Haloalkyl" means an alkyl group as defined herein in which one or more hydrogens is replaced by the same or different halogen. Examples of haloalkyl include -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , perfluoroalkyl (eg, -CF ₃ ), and the like.

"Haloalkoxy" refers to a group of formula -OR wherein R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

"Deuterated haloalkoxy" refers to an alkoxy group as defined herein in which one or more hydrogens are replaced by the same or different halogen and deuterium (D). Examples of deuterated haloalkoxy groups include -CD ₂ F, -CDF ₂ , -CD ₂ CF ₃ , -CD ₂ CD ₂ CF ₃ , -CD ₂ CD ₂ CDF ₂ and the like.

"Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having 3-12, preferably 3-10, more preferably 3-6 ring atoms. Cycloalkyl groups can be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Cycloalkoxy" refers to a radical of formula -OR wherein R is cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

"Acyl" refers to a radical of formula -C(O)R where R is alkyl as defined herein. Exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl, and the like.

Ester refers to a group of formula -C(O)OR where R is alkyl as defined herein. Exemplary ester groups include -C(O)OMe, -C(O)OEt, and the like.

"Alkylthio" refers to a group of formula -SRa where Ra is H or alkyl as defined herein.

"Alkylamino" refers to a group of formula -NRaRb where Ra is H or alkyl as defined herein and Rb is alkyl as defined herein.

"Cycloalkylamino" refers to a group of formula -NRaRb where Ra is H, alkyl as defined herein, or cycloalkyl as defined herein and Rb is cycloalkyl as defined herein.

"Heteroaryl" means a monocyclic, bicyclic or tricyclic group of 5 to 12 ring atoms containing at least 1 ring heteroatom comprising 1, 2 or 3 selected from N, O or S, The remaining ring atoms are aromatic rings of C and it should be clear that the point of attachment of the heteroaryl should be on the aromatic ring. Heteroaryl preferably has specifically 5-8 ring atoms, more preferably has 5-6 ring atoms. Examples of heteroaryl groups include, but are not limited to: imidazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, Diazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolyl, benzofuryl, Benzofuryl, Benzothienyl, Benzothienyl, Benzimidazolyl, Benzo Azolyl, benzo Oxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazoline Base, quinazinyl, naphthyridinyl, pteridinyl, carbazolyl, aza base, diazepine base, acridinyl, etc.

Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as (but not limited to): ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ^32P , ^35S , ^18F , ^36Cl .

The solvate mentioned in the present invention refers to the complex formed by the compound of the present invention and a solvent. They are either reacted in the solvent or precipitated or crystallized from the solvent. For example, complexes formed with water are called hydrates; others include alcoholates, ketones, etc. The solvates in the present invention include the solvates of the compounds represented by formula I in the present invention, their salts, and stereoisomers.

The stereoisomer mentioned in the present invention means that the compound represented by formula I in the present invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound contains enantiomers. The present invention includes both these isomers and mixtures of isomers, such as racemic mixtures. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography. When compounds of formula I contain more than one chiral center, diastereoisomers may exist. Stereoisomers of the present invention include resolved optically pure specific isomers as well as mixtures of diastereoisomers. Diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.

The prodrug mentioned in the present invention refers to the parent compound which includes the known amino protecting group and carboxyl protecting group, and is hydrolyzed or released through enzyme reaction under physiological conditions. Concrete prodrug preparation method can refer to prior art (Saulnier, M.G.; Frennesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.ChemLett.1994,4,1985-1990; And Greenwald, R.B.; Choe, Y.H.; Conover, C.D.; Shum, K.; Wu, D.; Royzen, M.J. Med. Chem. 2000, 43, 475.).

On the other hand, the present invention also provides a preparation method for the above-mentioned compound of formula I, comprising dissolving intermediate A, intermediate B and p-toluenesulfonic acid in an organic solvent, reacting in a protective atmosphere at 50-100°C, and reacting After the end, add dichloromethane and saturated aqueous sodium carbonate solution, separate layers, take the organic phase to remove the solvent, separate and purify to obtain intermediate C, and then react intermediate C with the amine corresponding to substituent R3 to obtain intermediate D, intermediate D is reduced with palladium carbon plus hydrogen to generate intermediate E, and intermediate E is amidated to obtain the above-mentioned compound of formula I;

The structural formulas of the intermediates A, B, C, D and E are respectively as follows:

Wherein, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in formula I.

The reaction formula involved in this preparation method is as follows:

In another aspect, the present invention provides the above-mentioned compound of formula I, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug for use as an EGFR inhibitor.

In another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula I above and a pharmaceutically acceptable carrier.

The compound of formula I of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers can be formulated into a suitable dosage form for administration. These dosage forms include those suitable for oral, rectal, topical, buccal and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).

The pharmaceutical compositions of the present invention can be formulated, dosed and administered in a manner consistent with medical practice. The "effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

The EGFR inhibitor of the present invention can be used to prepare drugs for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, etc., especially suitable for EGFR mutations , including sensitive mutations (such as L858R mutation or exogenous factor 19 deletion) and drug-resistant mutations (such as EGFRT790M mutation), caused by the treatment of non-small cell lung cancer.

Therefore, in another aspect, the present invention provides the compound of formula I of the present invention, or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug in the preparation for regulating EGFR tyrosine kinase activity or treating EGFR Drug applications for related diseases.

In one embodiment, the regulation of EGFR tyrosine kinase activity or the treatment of EGFR-related diseases refers to the treatment of cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases.

In another embodiment, the present invention provides the use of the compound of formula I of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in the preparation of a medicament for treating non-small cell lung cancer. The EGFR inhibitor of the present invention is especially suitable for preparing medicines for treating cancer, such as non-small cell lung cancer.

The compound of formula I of the present invention, or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, can be used as the drug application of single treatment in anticancer treatment, or can also be combined with conventional A combination of surgery or radiation therapy or chemotherapy or immunotherapy. The above-mentioned therapy and the EGFR inhibitor of the present invention can be administered in parallel, simultaneously, sequentially, or separately.

The medicine for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases of the present invention, in addition to the EGFR inhibitor of the present invention, may also contain any one or more of the following medicines: gefitinib, errone Lotinib, Icotinib, Lapatinib, XL647, NVP-AEE-788, ARRY-334543, Vandetanib, PF00299804, Cetuximab, Panitumumab, Pertuzumab , zalutumumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tanspirulin, aspiramycin, IPI-504, NVP-AUY922.

Detailed ways

The technical solution of the present invention will be further described below in combination with specific embodiments.

Examples 1-12 respectively prepare a series of specific compounds.

Example 1: Compound N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-difluorodeuteromethoxy-5-((4-(1H-ind Indol-3-yl) pyrimidin-2-yl) phenyl) allylamine (DA-1) synthesis, the reaction formula is as follows:

1) Synthesis of Compound A1: Add 6.8mmol of Compound a1-1 into a 100ml three-neck flask, add 30ml of 1,2-dichloroethane; then protect the mixture with argon, and cool the mixture to 0°C with a cold bath. Add 2.3 ml of methylmagnesium bromide (3mol/L) dropwise within 5 minutes, react at low temperature for 15 minutes after the addition, then add a2 10mmol, go to the cooling bath and warm up to room temperature, stir overnight, and the reaction solution is quenched with aqueous sodium hydroxide solution , the solvent was evaporated to dryness under reduced pressure, the residue was added 100ml of ethyl acetate (EA), then 50ml of water was added to wash twice, the organic phase was evaporated to dryness, and the residue was separated by column chromatography (eluent was ethyl acetate Ester: Petroleum ether = 1:30 (volume ratio)) to obtain intermediate A1. ¹ H-NMR (400MHz,d ₆ -DMSO)δ7.2-7.29 (2H,m),7.40-7.53(1H,m),7.91(1H,d),8.44(1H,dd),8.52 (1H, d), 8.53(1H,d), 12.16(1H,s); m/z(ES+)(M+H) ⁺ =230.

2) Synthesis of compound DA-1-2: 50g of compound b1-1 was dissolved in 250ml of tetrahydrofuran, 12.6g of sodium hydroxide was dissolved in 250ml of water, the two solutions were mixed and stirred overnight, and the tetrahydrofuran was removed by rotary evaporation, and the aqueous phase was used Wash twice with dichloromethane, remove most of the water by rotary evaporation, evaporate the remaining part to dryness naturally, and dry thoroughly in a vacuum oven to obtain 55 g of an orange solid, which is compound b1-2. The analytical data of this compound are as follows: ¹ H-NMR (400 MHz, & DMSO): δ: 7.73 (t, 1H); 6.02 (dd, 1H); 5.77 (dt, 1H).

3) Synthesis of compound DA-1-3: 7g of compound b1-2 and 17.5g of potassium carbonate were added to the reaction flask, and then under the protection of argon, 700ml of DMF (dimethylformamide), 70g of Deuterium water and 17.5g ethyl bromodifluoroacetate were gradually heated to 50°C and stirred overnight. TLC showed that most of the raw materials disappeared. After cooling, the reaction solution was diluted with water and extracted three times with dichloromethane. The organic phases were combined and washed with water. After washing 5 times, the organic layer was dried and spin-dried, and the residue was separated by column chromatography to obtain 6.2 g of light yellow oil, which was compound b1-3. The analytical data of this compound are as follows: ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 8.01 (q, 1H); 7.07-7.15 (m, 2H).

4) Synthesis of compound DA-1-4: Dissolve 1 g of compound b1-3 in 25 ml of ethanol, add palladium carbon, and stir overnight at room temperature and pressure under a hydrogen atmosphere; TLC detects that the raw materials disappear, filter out palladium carbon, and wash with ethanol. The solvent was spin-dried to obtain 0.78 g of compound b1-4 as a yellow oil. The analytical data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ):: δ: 6.70-6.84 (m, 3H); 3.71 (br, 2H); m/z (ES+) (M+H) ⁺ = 179.

5) Synthesis of compound DA-1-5: Add 0.78g of compound b1-4 in batches to 5ml of concentrated sulfuric acid cooled in an ice-water bath at a temperature lower than 10°C to dissolve it completely, then add 0.45g of potassium nitrate and stir at room temperature Overnight, the reaction is over, the reaction solution is poured into ice water, then alkalized with ammonia water, the organic layer is extracted with ethyl acetate, the organic layer is combined, washed once with saturated brine, dried and spin-dried the organic layer, and the residue is subjected to column chromatography After separation, 0.8 g of yellow solid was obtained, namely compound b1-5. The analytical data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ): δ: 7.46 (d, 1H); 6.99 (d, 1H); 4.03 (br, 1H); m/z (ES+) (M+ H) ⁺ =224.

6) Synthesis of compound DA-1-6: p-toluenesulfonic acid (2.2g, 12.0mmol) was added to 2-pentane of A1 (1.4g, 6.0mmol) and DA-1-5 (1.3g, 6.0mmol) Alcohol (50mL) solution. Then the reaction solution was heated to 130°C and reacted for 12 hours. The reaction solution was spin-dried, added 2M sodium carbonate aqueous solution, stirred for 30 minutes, then extracted with dichloromethane, combined organic phases, then dried, spin-dried, and passed through a silica gel column to obtain 1.02 g of the product, m/z (ES+) (M+H) ⁺ =417.

7) Synthesis of compound DA-1-7: Compound DA-1-6 (300mg, 0.7mmol) was added to trifluoroethanol (8mL), then N1, N1, N2-trimethylethylenediamine (70mg , 0.7mmol) and diisopropylethylamine (180mg, 1.4mmol). The reaction was then reacted in the microwave at 140°C for 70 minutes. Cool the reaction solution to room temperature, then spin the reaction solution to dryness, and directly pass through the column to obtain 261 mg of the product, ¹ H-NMR (400MHz,d ₆ -DMSO)δ2.16(6H,s), 2.45-2.49(2H,m ),2.84(3H,s),3.21-3.36(2H,m),6.95(1H,s), 7.11(1H,t),7.21(1H,d),7.20-7.26(1H,m),7.52( 1H,d), 8.12(1H,s),8.33(1H,d),8.36(1H,s),8.49(1H,d),8.58(1H,s); m/z(ES+)(M+H ) ⁺ =499.3.

8) Synthesis of Compound DA-1-8: Compound DA-1-7 (150 mg) was added to methanol (10 mL), at room temperature, under the protection of argon, 15 mg of palladium carbon was added, and then reacted overnight under hydrogen, The reaction solution was directly filtered and spin-dried to obtain a crude product, which was directly used in the next step.

9) Synthesis of compound DA-1: Add the crude product from the previous step into dichloromethane (5mL), then add diisopropylethylamine (77mg, 0.6mmol), then cool down to 0°C, and slowly add acryloyl chloride ( 27mg, 0.3mmol) of dichloromethane solution (2mL), after the addition, react at 0°C for 30 minutes, then warm up to room temperature and react for 2 hours, directly spin the reaction solution to dryness, add 2M aqueous sodium hydroxide solution, and use Dichloromethane was extracted, and the organic phases were combined, and spin-dried to obtain 26 mg of DA-1, which was separated by preparative chromatography. ¹ H-NMR (400MHz,d ₆ -DMSO) δ2.26(6H,s),2.22(2H,br),2.69(3H,br),2.89(2H,m),5.67 (1H,m),6.28 (1H,m),6.44(1H,dd),7.06(1H,s),7.25(1H,t),7.28(2H,m),7.54(1H,d),7.92(1H,s),8.14( 1H, d), 8.30 (1H, d), 8.60 (1H, s), 9.16 (1H, s), 10.22 (1H, s), m/z (ES+) (M+H) ⁺ = 523.2.

Embodiment 2: Compound N-(4-(difluorodeuteromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1 -Synthesis of methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (DA-2), the synthetic route is as follows:

Compound DA-1-5 was synthesized according to the synthesis method of steps 2) to 5) in Example 1. The synthesis of other compounds is as follows:

1) Synthesis of compound A2: 3.4 mmol of compound a2 and 3.4 mmol of ammonium chloride were added to ethylene glycol dimethyl ether, then stirred at room temperature for 10 minutes, then 3.4 mmol of compound a1-2 was added, and the reaction The solution was heated to 80 degrees to react for 2 hours, the reaction solution was cooled to room temperature, then 50 ml of water was added within 10 minutes, then stirred for 30 minutes, filtered, the filter cake was washed with 50 ml of water, and the crude product was purified by column purification to obtain intermediate Body A2. ¹ H-NMR (400MHz,d ₆ -DMSO)δ3.90(3H,s),7.35(2H,m),7.64(1H,dd),7.88(1H,d),8.45-8.52(1H,m) , 8.56 (1H, s), 8.62 (1H, d); m/z (ES+) (M+H) ⁺ = 244.4.

2) Synthesis of compound DA-2-6: For the synthesis method, refer to step 6 in Example 1. The A1 raw material is changed to A2, and the equivalent ratio and reaction conditions are unchanged to obtain the compound DA-2-6.

3) Synthesis of compound DA-2-7: the synthesis method refers to step 7 in Example 1, raw materials DA-2-6 (200mg), N1,N1,N2-trimethylethylenediamine (70mg, 0.7mmol) and Diisopropylethylamine (180mg, 1.4mmol), the reaction product 201mg DA-2-7. ¹ H-NMR (400MHz,d ₆ -DMSO)δ2.16(6H,s),2.45-2.49(2H,m), 2.84(3H,s),3.21-3.36(2H,m),3.80(3H, s),6.94(1H,s),7.10(1H,t),7.25(1H,d),7.27(1H,m),7.54(1H,d),8.12(1H,s), 8.36(1H,d ), 8.38(1H,s), 8.49(1H,d), 8.58(1H,s); m/z(ES+)(M+H) ⁺ =513.2.

4) The synthesis method of compounds DA-2-8 and DA-2 refers to the description in steps 8 and 9 in Example 1. 200 mg of compound DA-2-7 was reduced according to the method in Example 1, and then acrylamidated to obtain 65 mg of compound DA-2. ¹ H-NMR(400MHz,d ₆ -DMSO) δ2.26(6H,s),2.22(2H,br),2.69(3H,br),2.89(2H,m), 3.84(3H,s),5.67 (1H,m),6.28(1H,m),6.44(1H,dd),7.06 (1H,s),7.25(1H,t),7.30(2H,m),7.54(1H,d),7.92( 1H,s), 8.14(1H,d), 8.30(1H,d), 8.60(1H,s), 9.16(1H,s), 10.22 (1H,s), m/z(ES+)(M+H ) ⁺ =523.2.

With DA-2-6 as intermediate C, with reference to the experimental method of steps 7), 8) and 9) in Example 1, a series of compounds shown in formula I were synthesized. The reaction equation is as follows, and the specific synthetic formula The series of compounds 3-9 shown in I are shown in Table 1:

Among them, R ₃ H was purchased from Bailingwei Reagent Company.

Table 1

Example 10: Compound N-(4-(monofluorodeuteromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1 -Synthesis of methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (DA-3), the reaction formula is as follows:

1) Synthesis of compound DA-3-B: Add 25 grams of deuterated DMSO and 61.5 grams of potassium carbonate into 300 milliliters of anhydrous dichloromethane with a 2-liter three-neck flask, then add a buffer ball of anti-shock material, and put it in a violent Under stirring, 42.5 grams of N-chlorosuccinimide was added at one time, and after stirring for about 10 minutes, the reaction was violent, a large amount of heat was released, and then the temperature gradually decreased. After falling to room temperature, TLC detected that most of the raw materials disappeared, and then argon Protected by an atmosphere, stirring was continued overnight. The succinimide produced by the reaction can be precipitated by potassium carbonate stirring but very slowly. Filter out the solid in the reaction flask, then add potassium carbonate and stir overnight, then add potassium carbonate until it is almost invisible on HNMR Succinimide (this impurity affects next step reaction). Then the reaction solution was spin-dried to obtain 30 g of light yellow oil.

2) Synthesis of compound DA-3-3: 12 grams of compound DA-1-2, 16 grams of DA-3-B, 5.5 grams of potassium iodide, and 10 milliliters of deuterated DMSO were added to the flask, and stirred under argon protection at 90 degrees Celsius for two For two days and two nights, after cooling, pour it into water and extract the aqueous layer twice with dichloromethane. The combined organic layer was washed five times with saturated brine, then dried and spin-dried through the column to obtain an oil-solid mixture, and then a small amount of methyl tert-butyl ether was added. Stir to grind the solid into powder, filter the filter cake and wash it with methyl tert-butyl ether, then dry the filter cake to obtain 4 grams of yellow solid, ¹ H-NMR (400MHz, CDCl ₃ ): δ: 8.00-7.97 (m, 1H); 2.21-7.18 (m, 1H); 6.91-6.86 (m, 1H). m/z(ES+)(M+H) ⁺ = 239.1.

3) Synthesis of compound DA-3-4: Add 4 grams of compound DA-3-3 and 0.64 grams of cuprous iodide into dry dichloromethane, add 5.4 grams of DAST dropwise at room temperature, and raise the temperature to 35 degrees Celsius and stir overnight after the addition , TLC shows that the raw material basically disappears, the main point is an intermediate state, then add 5.4 grams of DAST and continue to stir for two days and two nights GCMS shows that the reaction is not complete, then continue to add DAST, if most of the reaction is converted into products, stop the reaction, and the reaction solution Diluted with dichloromethane and poured into ice water for layering. The aqueous layer was washed once with dichloromethane. The combined organic layers were spin-dried and passed through the column to obtain 1.2 g of yellow oil. The NMR analysis data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ): δ: 7.99-7.95(m, 1H), 7.08-7.05(m, 1H), 6.96-6.91(m, 1H); m/ z(ES+)(M+H) ⁺ = 192.0.

4) Synthesis of compound DA-3-5: Dissolve 1.2 g of compound DA-3-4 in 60 ml of ethanol, add 0.2 g of palladium carbon, stir overnight under hydrogen atmosphere, TLC shows that the raw material disappears, filter out palladium carbon dichloride After washing with methane, the mother liquor was spin-dried to obtain 770 mg of oil. m/z(ES+)(M+H) ⁺ = 162.0.

5) Synthesis of compound DA-3-6: Dissolve 770 mg of compound DA-3-5 in 20 ml of chloroform, then add 20 ml of trifluoroacetic anhydride and 380 mg of ammonium nitrate, and stir overnight at room temperature under argon protection. TLC shows that the raw material disappears, spin off the reaction solution, then add dichloromethane and saturated aqueous sodium carbonate solution, separate layers, dry the organic layer, spin dry and pass through the column to obtain a pure amino group protected intermediate by trifluoroacetyl, and then this intermediate Dissolve in 20 ml of methanol, then add 20 ml of concentrated hydrochloric acid, heat up to 70 degrees Celsius, stir for 2 hours, TLC detects that almost all of it is converted into the product DA-3-6, then spin the reaction solution and add dichloromethane and saturated carbonic acid Sodium aqueous solution was separated into layers, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined, washed once with saturated brine, dried and spin-dried to obtain 135 mg of the target compound. The NMR analysis data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ): δ: 9.16(d, 1H), 8.32(br, 1H), 7.12(d, 1H); m/z(ES+)(M +H) ⁺ =207.

6) Synthesis of compound DA-3-7: Add compound DA-3-6, A2 and p-toluenesulfonic acid monohydrate to 2-pentanol and raise the temperature to 110 degrees Celsius, stir overnight under the protection of argon, filter after cooling, The filter cake was dried to obtain 450 mg of a yellow solid, which was the crude product of the target compound and was directly used in the next step without purification.

7) Synthesis of compound DA-3-8: 450 mg of crude compound DA-3-7, 226 mg of N,N,N'-trimethylethylenediamine and 284 mg of diisopropylethylamine were added to 10 ml In N,N-dimethylacetamide, the temperature was raised to 90°C, and stirred for 6 hours under the protection of argon. After the reaction was completed, water was added, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed five times with saturated brine, dried and spin-dried, and passed through a column to obtain 230 mg of a yellow solid. The NMR analysis data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ): δ: 9.40(s,1H), 8.29(d,1H),8.10-8.02(m,2H),7.50(s,1H) ,7.32-7.18(m,3H), 7.10(d,1H),6.95(s,1H),3.81(s,3H),3.36(t,2H),2.96(t,2H),2.77(s,3H ), 2.58(s,3H); m/z(ES+)(M+H) ⁺ =496.2.

8) Synthesis of compound DA-3-9: Dissolve 230 mg of compound DA-3-8 in 30 ml of ethyl acetate, then add 150 mg of palladium carbon, stir at room temperature for three hours under hydrogen atmosphere, TLC raw material disappears, Palladium carbon was filtered off, washed with methanol, and the obtained mother liquor was spin-dried to obtain 200 mg of yellow oil. used directly in the next step.

9) Synthesis of compound DA-3: 240 mg of compound DA-3-9 and 62 mg of diisopropylethylamine were dissolved in 15 ml of dry dichloromethane, and the temperature was lowered to about 0 degrees Celsius under the protection of argon with an ice bath . Then 39 mg of acryloyl chloride was diluted to 1 ml, slowly added dropwise to the reaction solution, gradually raised to room temperature and stirred overnight, then the reaction solution was spin-dried, and the crude product was directly separated by TLC to obtain 15 mg of the product. The NMR analysis data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ): δ: 10.06(br,1H),9.79(s,1H),8.93(s,1H),8.31(d,1H),7.99 (d,1H),7.51(s,1H),7.33-7.14(m,3H),6.98(s,1H),6.41-6.37(m,2H),5.67-5.64(m,1H),3.90(s , 3H), 2.85 (t, 2H), 2.61 (s, 3H), 2.32-2.25 (m, 8H); m/z (ES+) (M+H) ⁺ = 520.3.

Example 11: Compound N-(4-(difluorodeuteromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1 -Synthesis of -methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-2-fluoroacrylamide (DA-4), the synthetic route is as follows:

1) The synthesis of compound DA-2-8 refers to the method in Example 2.

2) Synthesis of compound DA-4: Compound DA-2-8 (245mg) was added to dichloromethane (10mL), then diisopropylethylamine (70mg) was added, the reaction solution was cooled to 0 degrees, and then 2-Fluoroacryloyl chloride (76 mg) was added dropwise. After the addition, the temperature was slowly raised to room temperature and reacted for 2 hours. Then, silica gel was directly added and spin-dried to obtain 90 mg of the product DA-4. The NMR analysis data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ): δ: 10.64(br,1H), 9.79(s,1H),8.83(s,1H),8.41(d,1H),8.08 (d,1H),7.46 (s,1H),7.41-7.21(m,3H),7.09(s,1H),5.78(dd,1H),5.23(dd,1H),3.96(s,3H), 2.95 (m, 2H), 2.67 (s, 3H), 2.24-2.20 (m, 8H); m/z (ES+) (M+H) ⁺ = 555.2.

Example 12: Compound N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-difluorodeuteromethoxy-5-((4-(pyrazolo[ 1,5-a] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (DA-6) synthesis, the reaction formula is as follows:

Compound DA-1-5 was synthesized according to the synthesis method of steps 2) to 5) in Example 1. The synthesis of other compounds is as follows:

1) Synthesis of compound A3-1: 2.7mmol of 2,4-dichloropyrimidine, 3.0mmol of 1-butoxyethylene, 3.0mmol of triethylamine and 0.8mmol of palladium acetate were added to 30 ml of polyethylene glycol. Under the protection of argon, react at 50°C for 6 hours. The reaction solution was cooled, then 100 ml of water was added, extracted three times with 30 ml of ethyl acetate, the organic phases were combined and concentrated through a column to obtain intermediate A3-1.

2) Synthesis of compound A3: 1.2mmol of intermediate A3-1, 1.2mmol of 1-amino-pyridin-1-ium and 3.0mmol of potassium carbonate were added to 20 ml of N,N-dimethylformamide, and then heated to React at 110 degrees for 5 hours. The reaction solution was cooled, and 30 ml of water was added, then extracted with ethyl acetate, and the organic phase was spin-dried to pass through the column intermediate A3. ¹ H-NMR (400MHz, d ₆ -DMSO) δ7.30(1H,m),7.76-7.70(1H,m),8.57-8.50(2H,m), 8.80(1H,s),8.95(1H, m), 9.08(1H,s); m/z(ES+)(M+H) ⁺ = 231.0.

3) Synthesis of compound DA-6-1: Add compound DA-1-5, A3 and p-toluenesulfonic acid monohydrate to 2-pentanol and raise the temperature to 110 degrees Celsius, stir overnight under the protection of argon, filter after cooling, The filter cake was dried to obtain 653 mg of a yellow solid, which was the crude product of the target compound and was directly used in the next step without purification.

4) Synthesis of compound DA-6-2: 653 mg of crude compound DA-6-1, 430 mg of N,N,N'-trimethylethylenediamine and 400 mg of diisopropylethylamine were added to 10 ml In N,N-dimethylacetamide, the temperature was raised to 90°C, and stirred for 6 hours under the protection of argon. After the reaction was completed, water was added, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed five times with saturated brine, dried and spin-dried, and passed through a column to obtain 230 mg of a yellow solid. The NMR analysis data of this compound are as follows: ¹ H-NMR (400MHz, d ₆ -DMSO): δ: 9.00(s, 1H), 8.87(d, 1H), 8.68(s, 1H), 8.41(s, 2H) ,8.16(s,1H),7.42(m,1H),7.13(m,1H),6.65(s,1H),3.37(t,2H),2.86(t,2H), 2.72(s,3H), 2.48(s,3H); m/z(ES+)(M+H) ⁺ = 500.2.

5) Synthesis of compound DA-6-3: 230 mg of compound DA-6-2 was dissolved in 30 ml of ethyl acetate, then 150 mg of palladium carbon was added, under hydrogen atmosphere, stirred at room temperature for three hours, the TLC raw material disappeared, Palladium carbon was filtered off, washed with methanol, and the obtained mother liquor was spin-dried to obtain 200 mg of yellow oil. used directly in the next step.

6) Synthesis of compound DA-6: 200 mg of compound DA-6-3 and 61 mg of diisopropylethylamine were dissolved in 12 ml of dry dichloromethane, and the temperature was lowered to about 0 degrees Celsius under the protection of argon with an ice bath . Then 40 mg of acryloyl chloride was diluted to 1 ml, slowly added dropwise to the reaction solution, gradually raised to room temperature and stirred overnight, then the reaction solution was spin-dried, and the crude product was directly separated by TLC to obtain 85 mg of the product. The NMR analysis data of this compound are as follows: ¹ H-NMR (400MHz, CDCl ₃ ): δ: 9.05(s,1H),8.93(s,1H),8.54-49(m, 2H),8.41(s,1H) ,8.21(s,1H),7.45(s,1H),7.40-7.29(m,2H), 6.98(t,1H),6.75(s,1H),6.36-6.30(m,2H),5.75-5.68 (m,1H), 3.90(s,3H), 2.85(t,2H), 2.61(s,3H), 2.32-2.25(m,8H); m/z(ES+)(M+H) ⁺ ＝524.2 .

Example 13

The compound of this embodiment is the mesylate salt of the compound shown in Example 2, and its structural formula is shown in formula DA-8:

The preparation method of the compound (mesylate) of this example is as follows: add 0.30 g of compound DA-2 into a 50 ml single-mouth bottle, add 10 ml of acetone and 1 ml of water, and slowly add 60 mg of After the addition of methanesulfonic acid, react at 50°C for 3h, evaporate the reaction solution to dryness, add 6ml of acetonitrile and heat up to 70°C, stir for 30min, cool slowly to precipitate the solid, filter the solid, wash with acetonitrile, and dry 112 mg of a white solid was obtained, namely compound DA-8. Its purity was 98.5% as detected by HPLC. The analytical data of the obtained compound DA-8 are: ¹ H-NMR (400M, d ₆ -DMSO): 10.26(br, 2H), 8.93(s, 1H), 8.50(s, 1H), 8.34(s, 1H) ,8.30-8.23(m,3H),7.51(d,1H), 7.24-7.19(m,3H),7.07(s,1H),6.48-6.25(m,2H),5.81-5.78(m, 1H) , 3.88(s,3H), 3.54(s,3H), 2.88(s,2H), 2.71(s,3H), 2.36(s, 2H), 2.23(s,6H).

Effect experiment example

Using the above compounds provided in the examples, the inhibitory effect on the kinase activity of wild-type EGFR and mutant EGFR was detected.

The inhibitory effect of the test substance on the activity of double mutant EGFR kinase (EGFR T790M/L858R kinase) and wild-type EGFR kinase (EGFR WT) was determined. Both wild-type EGFR and mutant EGFR (T790M/L858R) kinases used in the assay were purchased from Carna Bioscience.

The experimental process is as follows:

1. Preparation of test compounds

1. The compounds to be tested were prepared into 10mM (mmol/L) DMSO solutions respectively, and the reference compound AZD9291 was prepared into 1mM (mmol/L) DMSO solutions;

2. Through 3-fold dilution, serially dilute the test compound solution to 12 concentrations (or other required test concentrations) on the 384-well plate of TECAN EVO200;

3. Use Echo550 to transfer 20nL test solution to a 384-well plate (Coring 3570). Use DMSO as a blank control;

2. Perform an enzyme test

1. Prepare a 1.3X enzyme solution containing enzyme, substrate, and cofactor, as shown in Table 2 below;

2. At room temperature, add 15 μL of 1.3X enzyme solution to each well and incubate for 30 minutes;

3. Add 5 μL of 4X ATP solution to start the test reaction, the final solution volume in each well should be 20 μL, and the ingredients contained are shown in Table 2 below;

4. Incubate the plate at room temperature for 90 minutes, then add 40 μL of stop buffer (containing 0.5M EDTA) to stop the test reaction;

5. Use the EZ assay to analyze the experimental data for each well.

Enzyme solution parameter list in table 2 enzyme test

3. Data Analysis

1. Using the read conversion rate (CR), calculate the inhibition ratio according to the following formula:

2. According to the following formula, use XLFit (equation 201) to calculate IC ₅₀ and K _i value,

The detection results of some compounds are shown in Table 3 below.

Table 3 wild-type EGFR and mutant EGFR kinase activity inhibition detection results

The structure of the reference compound (AZD9291, trade name: Meritinib) is as follows:

It can be seen from the data in the above table that the compounds provided by the examples of the present invention have very good inhibitory activity on the double mutant EGFR kinase (T790M/L858R), and the activity is much better than that of the control compound, preferably up to 3.5 times. Unexpected results have been achieved.

The compounds provided in the embodiments of the present invention can be mixed with pharmaceutically acceptable carriers to prepare a pharmaceutical composition.

The compounds provided in the examples of the present invention can be used to prepare EGFR inhibitors.

The compounds provided in the embodiments of the present invention can be used to prepare drugs for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases.

The EGFR-associated disease is selected from cancer, diabetes, immune system disease, neurodegenerative disease and cardiovascular disease.

The compounds provided in the examples of the present invention can be used to prepare medicines for treating non-small cell lung cancer.

The above descriptions are only examples of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent transformations made using the content of the description of the present invention, or directly or indirectly used in other related technical fields, are included in the scope of the present invention. within the scope of patent protection.

Claims (10)

1. I compound represented of formula or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug：

Wherein：

R₁Selected from hydrogen, halogen, trifluoromethyl or cyano；

R₂Selected from C_1~6Deuterated halogenated alkoxy；

R₃Selected from any one following structure or R₃Selected from any one all deuterated or deuterated part following structure：

R₄Selected from any one following structure：

Wherein, X₁、X₂、X₃、X₄、X₅It is independently selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Cycloalkanes Base, C_3-6Halogenated cycloalkyl or C_1-6Alkylamino；

R₅Selected from C_5-15Heterocycle or C_5-15Deuterated heterocycle, the heterocycle contain 1 to 4 be selected from N, O, S or P hetero atom.

2. compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding Medicine, as shown in formula II：

Wherein：

R₁Selected from hydrogen, halogen, trifluoromethyl or cyano；

R₂Selected from deuterated single fluorine methoxyl group or deuterated difluoro-methoxy；

R₃Selected from any one following structure：

Wherein, R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈、R₁₉、R₂₀、R₂₁It is independently selected from hydrogen, methyl Or deuterated methyl；

R₅It is selected from

Wherein, R₆Selected from hydrogen, methyl or deuterated methyl；

X₁、X₂、X₃It is independently selected from hydrogen or halogen.

3. compound according to claim 2 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding Medicine, wherein R₃It isR₇、R₈、R₉It is independently selected from methyl or deuterated methyl.

4. compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding Medicine, the compound indicated selected from following structural formula：

5. according to claim 1-4 any one of them compounds, wherein the pharmaceutically acceptable salt is inorganic acid salt Or acylate, the inorganic acid salt are selected from hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphorus Hydrochlorate, acid phosphate；The acylate is selected from formates, acetate, trifluoroacetate, propionate, acetonate, hydroxyl second Hydrochlorate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, first Sulfonate, esilate, benzene sulfonate, salicylate, picrate, glutamate, salicylate, ascorbate, camphor Hydrochlorate, camsilate.

6. a kind of pharmaceutical composition, including the compound described in any one of claim 1-5 and pharmaceutically acceptable load Body.

7. application of the compound in preparing EGFR inhibitor described in any one of claim 1-5.

8. the compound described in any one of claim 1-5 is being prepared for regulating and controlling EGFR tyrosine kinase activities or treatment Application in the drug of EGFR relevant diseases.

9. application according to claim 8, wherein the disease is selected from cancer, diabetes, disease of immune system, nerve Degenerative disease and angiocardiopathy.

10. compound the answering in preparing the drug for treating non-small cell lung cancer described in any one of claim 1-5 With.