WO2017143842A1 - Substituted diaminopyrimidine compound and composition comprising same and use thereof - Google Patents

Abstract

The present invention provides a substituted diaminopyrimidine compound, a composition comprising the same and use thereof. The substituted diaminopyrimidine compound is a diaminopyrimidine compound represented by formula (I), or a crystal form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, a hydrate or a solvate thereof. The substituted diaminopyrimidine compound and the composition comprising the same disclosed in the present invention have excellent inhibition on EGFR kinases with improved pharmacokinetic parameters, and can increase the drug concentration of the compound in animal so as to improve drug efficacy and safety.

Description

Substituted diaminopyrimidine compound and composition containing the same and use thereof Technical field

The present invention belongs to the field of medical technology, and in particular to substituted diaminopyrimidine compounds and compositions comprising the same and uses thereof.

Background technique

Epidermal growth factor receptors (EGFR, ErbB-1, HER1) are members of the ErbB receptor family, and the ErbB receptor family is the four closely related receptor tyrosine kinases EGFR (ErbB-1), HER2/c-neu (ErbB-2), a subfamily of Her3 (ErbB-3) and Her4 (ErbB-4). EGFR is a cell surface receptor for members of the epidermal growth factor family (EGF family) of the extracellular protein ligand. Mutations that affect EGFR expression or activity may result in cancer. It has been reported that EGFR is unregulated in most solid tumors such as lung cancer, breast cancer and brain tumors. It is estimated that 30% of epithelial cancers are associated with mutations, amplification or dysregulation of EGFR or family members.

Treatments for inhibition of EGFR have been developed based on drugs or small molecule inhibitor drugs such as gefitinib and erlotinib. In the case of non-small cell lung cancer, gefitinib and erlotinib are beneficial for 10% to 40% of patients. However, acquired resistance to gefitinib or erlotinib after a period of treatment has become a major clinical problem. Studies have confirmed that one of the main causes of drug resistance is due to the new mutation in T790M, which is the "guard" of EGFR. Then, the researchers developed an inhibitor of T790M, such as BIBW2992, and showed an advantage in clinical trials. However, these T790Ms targeting EGFR inhibitors also have relative inhibitory activity against wild-type EGFR, which limits clinical applications. Therefore, it is necessary to further develop more effective types of EGFR inhibitors that only target mutant proteins rather than wild-type proteins.

In addition, gefitinib, erlotinib and other EGFR inhibitors (EGFR-TKI) have achieved remarkable results in the treatment of advanced NSCLC with EGFR mutation, but subsequently found that EGFR-TKI is primary resistant in the treatment of NSCLC. Or secondary resistance, we are facing new challenges in the treatment of advanced NSCLC, and then carry out new exploration and find countermeasures.

Summary of the invention

In view of the above technical problems, the present invention discloses a substituted diaminopyrimidine compound and a composition comprising the same and use thereof, which have better EGFR kinase inhibitory activity and/or have better pharmacodynamics/pharmacokinetics Kinetic properties that can be used to treat, prevent, and alleviate diseases mediated by EGFR kinases.

In this regard, the technical solution of the present invention is:

a substituted diaminopyrimidine compound, such as a diaminopyrimidine compound represented by formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvent compound,

Wherein R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ^9c , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^17a and R ^17b are each independently hydrogen, deuterium, halogen or trifluoromethyl;

Additional conditions are: R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ^9a , R ^{At least one of 9b} , R ^9c , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^17a and R ^17b is deuterated or deuterated.

As a further improvement of the present invention, R ¹¹ is a trifluoromethyl group.

As a further improvement of the invention, the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:

As a further improvement of the present invention, it is prepared by using Reaction Scheme 1 or Reaction Scheme 2,

The first route is as follows: a 2,4-dihalopyrimidine compound and m-N-Boc aniline are reacted under basic conditions to produce a 2-halopyrimidine compound, and the 2-halopyrimidine compound is protected by Boc to obtain an amino compound. And the amino compound is reacted with deuterated or undeuterated acrylic acid, or deuterated or undeuterated acryloyl halide to obtain an amide compound VI; the phenolic compound is reacted with an alkyl halide under basic conditions to obtain an alkoxy compound, The alkoxy compound is substituted under basic conditions, 4-F is substituted with a fatty amine to obtain a nitro compound, the nitro compound is reduced to an aniline, and the aniline is reacted with the 2-halopyrimidine compound to obtain a formula (1). a substituted diaminopyrimidine compound;

The second reaction scheme is as follows: an alkoxy compound is reacted with an N-Boc-protected piperazine compound under basic conditions to obtain XI, a nitro group is reduced to an amine group to form a compound XII, and a 2-halopyrimidine compound VI The reaction results in a docking compound XIII which is decarboxylated under acidic conditions to give the piperazine compound XIV and is reacted with an acid anhydride to give a substituted diaminopyrimidine compound of the formula (1).

As a further improvement of the present invention, the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content. More than 95%, more preferably more than 99%.

In another preferred embodiment, the strontium isotope content of strontium at each metamorphic position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. More preferably greater than 95%, more preferably greater than 99%.

Specifically, in the present invention, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , The yttrium isotope content of each of the R ^9a , R ^9b , R ^9c , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^17a and R ^17b is at least 5%, preferably More than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably More than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably more than 99%.

In another embodiment, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ of the compound of formula (I), R ⁷ , R ⁸ , R ^9a , R ^9b , R ^9c , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^17a and R ^17b , at least one of which contains ruthenium, Preferably, the two Rs contain ruthenium, more preferably three R 氘, more preferably four R 氘, more preferably five R 氘, more preferably six R 氘, more preferably seven R氘, preferably eight R 氘, more preferably nine R 氘, more preferably ten R 氘, more preferably eleven R 氘, more preferably twelve R 氘, More preferably, thirteen R 氘, more preferably fourteen R 氘, more preferably fifteen R 氘, more preferably sixteen R 氘, more preferably seventeen R 氘, More preferably, eighteen R-containing strontiums, more preferably nineteen R-containing hydrazines, more preferably twenty-six s containing hydrazines, more preferably twenty-one R-containing hydrazines, more preferably twenty-two argon-containing, more preferably twenty-two R-containing氘, more preferably twenty-three R 氘, more preferably twenty-four R 氘, more preferably twenty-five R 氘, more preferably twenty-six R 氘.

As a further improvement of the present invention, the solvent used in the first scheme or the second reaction scheme is dichloromethane, dichloroethane, ethyl acetate, methyl acetate, isopropyl acetate, n-hexane, n-heptane, petroleum. Ether, n-butanol, ethanol, isobutanol, tert-butanol, isopropanol, n-propanol, n-pentanol, isoamyl alcohol, acetone, acetonitrile, n-hexane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1 At least one of 4-dioxane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide One type;

The base used in the first scheme or the second reaction scheme is potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, At least one of 4-N,N-lutidine or pyridine;

The acid used in the first scheme or the second reaction scheme is trifluoroacetic acid, acetic acid, concentrated hydrochloric acid, dilute hydrochloric acid, concentrated sulfuric acid, dilute sulfuric acid, concentrated nitric acid, dilute nitric acid, hydrochloric acid dioxane solution, hydrochloric acid ethanol solution, p-toluene At least one of a sulfonic acid or a benzenesulfonic acid.

Wherein, the above reaction temperature is from -30 ° C to 200 ° C, more preferably from -10 ° C to 100 ° C.

Wherein, the above reaction time is from 0 to 48 h, more preferably from 0 to 24 h, still more preferably from 0 to 6 h.

As a further improvement of the present invention, a pharmaceutically acceptable carrier is hydrated with a compound described in the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant The solvates or solvates are mixed to form a pharmaceutical composition.

The present invention also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a substituted diaminopyrimidine compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, A pharmaceutical composition of a stereoisomer, prodrug or isotopic variation.

The invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. Examples of isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, respectively. , ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention . Certain isotopically-labeled compounds of the present invention, such as the radioisotopes of ³ H and ¹⁴ C, are also among them, useful in tissue distribution experiments of drugs and substrates.氚, ie ³ H and carbon-14, ie ¹⁴ C, are easier to prepare and detect and are preferred in isotopes. Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.

As a further improvement of the present invention, it further comprises other therapeutic agents, which are drugs for cancer, cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases. .

The pharmaceutical compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 1000 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or tablet.

The present invention also discloses the use of a substituted diaminopyrimidine compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, for the preparation of a therapeutic, prophylactic and mitigating mediated by a protein kinase A pharmaceutical composition of the disease.

Since the compound of the present invention has excellent inhibitory activity against protein kinase (Kinase), particularly against EGFR kinase, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, Hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the invention as the main active ingredient, are useful for the treatment, prevention, and alleviation of diseases mediated by protein kinases, particularly against EGFR kinases. According to the prior art, the compounds of the invention are useful in the treatment of diseases such as cancer, cell proliferative diseases, inflammation, infections, immune diseases, organ transplants, viral diseases, cardiovascular diseases or metabolic diseases.

The beneficial effects of the invention are:

The substituted diaminopyrimidine compound disclosed in the present invention and the composition comprising the same have excellent inhibition to EGFR kinase, and have better pharmacokinetic parameter characteristics, and can increase the drug concentration of the compound in the animal, Improving drug efficacy and safety; the substituted diaminopyrimidine compounds disclosed herein and compositions comprising the same are useful for the treatment, prevention, and alleviation of diseases mediated by protein kinases, particularly EGFR kinases.

detailed description

Further details of the preferred embodiments of the present invention are provided below.

It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Parts and percentages are parts by weight and percentage by weight unless otherwise stated.

Example 1

According to the following Scheme Preparation of N- (3- (2- (4-acetyl-piperazin-1-yl) 2-d ₃ - methoxyphenoxy) -5-trifluoromethyl-pyrimidin-4- ylamino) benzene Acrylamide, that is, compound 11 in the following synthetic route;

Take the following steps:

Step 1: Preparation of 3-(2-chloro-5-trifluoromethyl)pyrimidine-4-aminophenyl tert-butyl ester (Compound 3);

Add n-butanol (9 mL) to a 50 mL three-necked flask equipped with magnetic stirring, N ₂ ball, thermometer, and cool in an ice water bath to keep the internal temperature not exceeding 5 ° C. Add 3-N-Boc-aniline (0.96 g, 4.6 mmol). ), 2,4-dichloro-5-trifluoromethylpyrimidine (1.0 g, 4.6 mmol) was slowly added dropwise, and then N,N-diisopropylethylamine (0.67 g, 5.5 mmol) was slowly added dropwise. After the mixture was added, the mixture was stirred in an ice water bath for 1 hour, stirred at room temperature for 4 hours, and a large amount of white solid was filtered, washed with n-butanol (2 mL), dried, and dried under vacuum at 50 ° C to give the white solid 1.4 g, yield 78.3% .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 9.53 (s, 1H), 9.46 (s, 1H), 8.57 (s, 1H), 7.58 (s, 1H), 7.28-7.26 (m, 2H) , 7.04-7.01 (m, 1H), 1.48 (s, 9H); LC-MS (APCI): m / z = 389.1 (m + 1) +.

Step 2: Preparation of 3-(2-chloro-5-trifluoromethyl)pyrimidine-4-aminophenyl acrylamide (Compound 5);

Dichloromethane (15 mL) was added to a 100 mL three-necked flask, and 3-(2-chloro-5-trifluoromethyl)pyrimidine-4-aminophenyl tert-butyl ester (1.0 g, 2.57 mmol) was added with stirring. After cooling, trifluoroacetic acid (3 mL) was added dropwise, and the ice bath was removed, and the mixture was stirred at room temperature for 1 hour under N ₂ atmosphere. Dichloromethane (50 mL) was added again, and triethylamine (5.6 mL, 40.4 mmol) was added dropwise to the trifluoroacetic acid. The mixture was cooled to -10 ° C, and acryloyl chloride (0.27 g) was slowly added dropwise under N2 atmosphere. , 3mmol), stir for 5 minutes. Add H ₂ O (100mL) to quench the reaction, the organic layer was separated, washed successively with water (100mL x 2), 0.5M HCl (aq., 15mL), washed with saturated aqueous sodium bicarbonate (15 mL), dried over anhydrous sodium sulfate The mixture was filtered, and the filtrate was evaporated. EtOAcjjjjjjjjj

^{1 HNMR (300MHz, DMSO-d} 6) δ (ppm) 10.25 (s, 1H), 9.59 (s, 1H), 8.59 (s, 1H), 7.80-1.79 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.50-6.41 (m, 1H), 6.30-6.23 (m, 1H), 5.77 ( Dd, J = 9.3 Hz, 2.1 Hz, 1H); LC-MS (APCI): m/z = 343.1 (M + 1) ⁺ .

Step 3: Preparation of 4-fluoro-2-d ₃ -methoxynitrobenzene (Compound 7);

Acetone (30 mL) was added to a 100 mL vial, and 5-fluoro-2-nitrophenol (2.0 g, 12.7 mmol), anhydrous potassium carbonate (3.5 g, 25.4 mmol), and deuterated iodomethane (2.4) were sequentially added with stirring. g, 16.5 mmol), warmed to 60 ° C and stirred for 2 h. The mixture was cooled to room temperature, and the residue was evaporated. EtOAcjjjjjjjjjjjjj .

¹ H NMR (CDCl ₃ , 300 MHz) δ (ppm) 8.00-7.95 (m, 1H), 6.83-6.71 (m, 2H); LC-MS (APCI): m/z=175.2 (M+1) ⁺ .

Step 4: Preparation of 1-[4-(3-d ₃ -methoxy-4-nitrophenyl)]acetylpiperazine (Compound 9);

N,N-dimethylformamide (4 mL) was added to a 25 mL single-necked flask, and 4-fluoro-2-d3-methoxynitrobenzene (0.4 g, 2.3 mmol) and anhydrous potassium carbonate were added sequentially with stirring. 0.64g, 4.6mmol), 1- acetyl-piperazine (0.38g, 3.0mmol), the reaction mixture was warmed to 80 ℃, the reaction overnight under N ₂ phenol. After cooling to room temperature, water (20 mL) was added, and ethyl acetate (30 mL) was evaporated. The yield was 77.0%.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 8.01 (d, J = 9.6 Hz, 1H), 6.43 (dd, J = 9.6 Hz, 2.7 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H) , 3.83-3.80 (m, 2H), 3.70-3.67 (m, 2H), 3.49-3.41 (m, 4H), 2.17 (s, 3H); LC-MS (APCI): m/z = 283.2 (M+ 1) ⁺ .

Step 5: Preparation of 1-[4-(3-d ₃ -methoxy-4-aminophenyl)]acetylpiperazine (Compound 10);

Add ethanol (6 mL) and water (2 mL) to a 25 mL vial and add 1-[4-(3-d3-methoxy-4-nitrophenyl)]acetylpiperazine (0.2 g, 0.71) in turn. Methyl), reduced iron powder (0.24 g, 4.26 mmol), ammonium chloride (19 mg, 0.35 mmol), the reaction mixture was heated to 85 ° C under N ₂ atmosphere, and stirred for 1 hour with stirring. The mixture was cooled to room temperature, the solid was filtered, and the filtrate was evaporated. EtOAcjjjjjjjjjjjjjj The rate is 84.1% and is directly invested in the next step.

Step 6: Preparation of N- (3- (2- (4- acetyl-piperazin-1-yl) 2-d ₃ - methoxyphenoxy) -5-trifluoromethyl-pyrimidin -4-yl) phenyl Acrylamide (Compound 11)

Add 1-[4-(3-d3-methoxy-4-nitrophenyl)]acetylpiperazine (0.15 g, 0.59 mmol), 1,4-dioxane (4 mL) to a 25 mL single-neck flask 3-(2-chloro-5-trifluoromethyl)pyrimidine-4-aminophenylacrylamide (0.2 g, 0.59 mmol) was added with stirring, three drops of trifluoroacetic acid were added dropwise, and stirred at 60 ° C under N ₂ atmosphere. Reaction for 3 hours. After cooling to room temperature, five drops of triethylamine and trifluoroacetic acid were added dropwise, and the mixture was evaporated to dryness.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 10.22 (s, 1H), 8.65 (br s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.76 (br s, 1H) , 7.54 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.17 - 7.14 (m, 1H), 6.60 (d, J=2.7 Hz, 1H), 6.51-6.42 (m, 1H), 6.29-6.21 (m, 2H), 5.78-5.74 (m, 1H), 3.57-3.55 (m, 4H), 3.08-3.00 (m, 4H), 2.05 (s, 3H ); LC-MS (APCI): m / z = 559.2 (m + 1) +.

Example 2

Prepared by the following synthetic route using N- (3- (2- (4- d 3 - acetyl-piperazin-1-yl) 2-methoxyphenyl) -5-trifluoromethyl-pyrimidin-4 amine) Phenyl acrylamide (compound 15),

Take the following steps:

step 1

The synthesis of the compounds 12, 13, and 14 was carried out by referring to the compounds 9, 10, and 11 of Example 1, wherein the spectrum of the compound 14 was: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 10.16 (s, 1H), 8.65(br s,1H), 8.29(s,1H),8.08(s,1H),7.76(br s,1H),7.55-7.48(m,2H),7.27(t,J=8.1Hz,1H) , 7.17-7.14 (m, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.49-6.40 (m, 1H), 6.28-6.21 (m, 2H), 5.78-5.74 (m, 1H), 3.77 (s, 3H), 3.44 (t, J = 4.8 Hz, 4H), 3.00 (t, J = 4.8 Hz, 4H), 1.43 (s, 9H); LC-MS (APCI): m/z = 614.2 ( M+1) ⁺ .

Step 2: Preparation of N-(3-(2-(4-d ₃ -acetylpiperazin-1-yl) 2-methoxyanilino)-5-trifluoromethylpyrimidin-4-amino)benzene Acrylamide (compound 15)

Add a tert-butyl-4-(4-(4-(3-acrylamidophenylamino)-5-trifluoromethylpyrimidin-2-amine)-3-methoxyphenyl) to a 25 mL single-necked flask Piperazine-1-carbonate (100 mg) and dichloromethane (10 mL) were stirred and dissolved, and trifluoroacetic acid (1 mL) was slowly added dropwise, and the reaction was stirred for 1 hour under a nitrogen atmosphere, and the Boc removal reaction was monitored completely, and the ice water bath was cooled. Triethylamine (2 mL) was slowly added dropwise to trifluoroacetic acid, and deuterated acetic anhydride (0.1 mL) was slowly added dropwise, and the reaction was stirred for 10 minutes in an ice water bath. After completion of the reaction, water (10 mL) was added to quench the reaction, and the mixture was separated. The organic layer was washed with EtOAc EtOAc EtOAc.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 10.22 (s, 1H), 8.65 (br s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.76 (br s, 1H) , 7.54 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.17 - 7.14 (m, 1H), 6.60 (d, J=2.7 Hz, 1H), 6.51-6.42 (m, 1H), 6.29-6.21 (m, 2H), 5.78-5.74 (m, 1H), 3.77 (s, 3H), 3.57-3.55 (m, 4H) , 3.08-3.00 (m, 4H); LC-MS (APCI): m / z = 559.2 (m + 1) +.

Example 3

Preparation of N-(3-(2-(4-acetyl-d ₈ -piperazin-1-yl) 2-methoxyanilino)-5-trifluoromethylpyrimidin-4-ylamino by the following synthetic route Phenyl acrylamide (compound 19)

The procedure described in Example 1 was carried out except that N-acetyl-d ₈ -piperazine was used instead of N-acetylpiperazine to obtain the target compound 19, ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ( Ppm) 10.52 (s, 1H), 9.79 (br s, 1H), 9.33 (br s, 1H), 8.51 (br s, 1H), 7.85 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H) ), 7.45-7.42 (m, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.13-7.10 (m, 1H), 6.77 (s, 1H), 6.58-6.49 (m, 1H), 6.47- 6.22 (m, 2H), 5.78-5.74 (m, 1H), 3.80 (s, 3H), 2.06 (s, 3H); LC-MS (APCI): m / z = 564.2 (m + 1) +.

Example 4

Preparation of N-(3-(2-(4-acetylpiperazin-1-yl)2-methoxy-3,5,6-d3-anilino)-5-trifluoromethylpyrimidine using the following synthetic route 4-amino)phenylacrylamide (compound 24),

Take the following steps:

step 1

Step 4 as described in Case 1, the method step 5, except that, in this example using 4-fluoro-2-methoxy-nitrobenzene instead of 4-fluoro -2-d ₃ - methoxy nitrobenzene, whereby to give 1- [4- (3-methoxy-4-aminophenyl)] acetyl piperazine (compound 22), LC-MS (APCI ): m / z = 253.3 (m + 1) +.

Step 2

Add a solution of deuterated hydrochloric acid (122 mmL, 1.47 mmol) to a solution of 1-[4-(3-methoxy-4-aminophenyl)]acetylpiperazine (400 mg, 1.61 mmol) in EtOAc (5 mL) The reaction was carried out in a microwave at 140 ° C for 50 minutes. After the reaction solution was cooled to room temperature, a 2 M sodium hydroxide solution was added to adjust the pH to 10. Acetone and acetic anhydride were added in this order, and the mixture was stirred for 10 minutes at room temperature. The acetone was removed and extracted with ethyl acetate. The organic phase was collected and washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and dried to give the desired product 1-[4- (3-methoxy-4-amino -2,5,6-d ₃ - phenyl)] acetyl piperazine 100mg, yield 54.1%. ^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm): 4.26 (br s, 2H), 3.73 (s, 3H), 3.58-3.51 (m, 4H), 2.94-2.84 (m, 4H), 2.03 (s, 3H); LC-MS (APCI): m/z = 507.3 (M + 1) ⁺ .

Step 3

Case according to one embodiment of the method step 6, except that, this example uses 1- [4- (3-methoxy-4-amino -2,5,6-d ₃ - phenyl)] acetyl piperazine Instead of 1-[4-(3-d ₃ -methoxy-4-nitrophenyl)]acetylpiperazine, it is worthy of the target compound 24, ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 10.14 ( s, 1H), 8.65 (br s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.76 (br s, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.25 (t , J=8.1 Hz, 1H), 7.14 (br s, 1H), 6.48-6.39 (m, 1H), 6.28-6.21 (m, 1H), 5.74 (dd, J = 9.9 Hz, 2.1 Hz, 1H), 3.76(s,3H),3.56-3.50(m,4H),3.05-2.95(m,4H),2.03(s,3H);LC-MS(APCI):m/z=559.4(M+1) ⁺ .

Example 5

step 1

2,4,6-d ₃ -1,3-phenylenediamine (111 mg, 11 mmol), MeOD (5 ml), dichloromethane (40 ml) were sequentially added to a 250 mL two-necked flask, and triethylamine was added thereto. (1.8g, 18mmol) and 2,2-dimethylolbutanoic acid (0.22g, 1.8mmol), the reaction solution was cooled with ice water under nitrogen atmosphere, di-tert-butyl dicarbonate solution in ice It was added dropwise under a bath and stirred at room temperature for 4 hours. The reaction was quenched with EtOAc (EtOAc m.). 1H NMR (300MHz, DMSO-d 6) δ (ppm) 8.98 (s, 1H), 6.82 (m, 1H), 4.95 (s, 2H), 1.44 (s, 9H); LC-MS (APCI): m /z=112(M+1) ⁺ .

Step 2

According to the method described in the first embodiment, the difference is that this example uses 2,4,6-d ₃ -3-N-Boc-aniline instead of 3-N-Boc-aniline to obtain the target product (Compound 30) 80 mg. The yield was 37%. ^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm) 10.16 (s, 1H), 8.65 (br, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.49 (d, J = 2.7 Hz, 1H), 7.25 (s, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.39-6.44 (m, 1H), 6.25 (dd, J = 16.8 Hz, 2.1 Hz, 2H), 5.73 5.77 (m, 1H), 3.76 (s, 3H), 3.56 (s, 4H), 3.05 (d, J = 18.9 Hz, 4H), 2.04 (s, 3H); LC-MS (APCI): m/z =559.2 (M+1) ⁺ .

Example 6

step 1

Dissolving N-(3-d ₃ -methoxy-nitrophenyl)-2,2,3,3,5,5,6,6-d ₈ -piperazine, triethylamine in dichloromethane Into the acetic anhydride, acetic anhydride was added, and the mixture was stirred at room temperature for 10 minutes, and the mixture was evaporated to dryness. ^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm) 7.89 (d, J = 9.3Hz, 1H), 6.56 (dd, J = 9.3Hz, 2.7Hz, 1H), 6.50 (d, J = 2.7Hz , 1H), 2.03 (s, 3H); LC-MS (APCI): m/z = 291.5 (M + 1) ⁺ .

Step 2

According to the method described in the first embodiment, the difference is that N-(3-d ₃ -methoxy-nitrophenyl)-2,2,3,3, 5,5,6,6-d is used in this example. ₈ -acetylpiperazine was used in place of N-acetylpiperazine to obtain 150 mg of the target product (Compound 34) in a yield of 41.9%. ^{1 HNMR (300MHz, DMSO-d} 6) δ (ppm) 10.15 (s, 1H), 8.63 (br, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.74 (br s, 1H), 7.53-7.46 (m, 2H), 7.25 (t, J = 8.1 Hz, 1H), 7.14 (br, 1H), 6.58 (d, J = 2.1 Hz, 1H), 6.48-6.39 (m, 1H), 6.27 - 6.18 (m, 2H), 5.75 (dd, J = 9.9 Hz, 1.5 Hz, 1H); LC-MS (APCI): m/z = 570.5 (M+1) ⁺ .

Example 7

step 1

Adding deuterated hydrochloric acid solution to an aqueous solution of N-(3-d ₃ -methoxy-nitrophenyl)-2,2,3,3,5,5,6,6-d ₈ -piperazine After microwave reaction at 140 ° C for 50 minutes, after cooling to room temperature, it was neutralized to pH 10 by adding 2M sodium hydroxide solution, extracted with ethyl acetate, and the organic phase was collected to obtain 380 mg of the desired product (Compound 35). 94.3%. ^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm) 7.87 (s, 1H); LC-MS (APCI): m / z = 251.3 (M + 1) +.

Step 2

The method according to one embodiment of the case, except that, in this case using N- _(3-d 3 - methoxy - nitro -2,6-d ₂ - phenyl) -2,2,3,3,5 ,5,6,6-d ₈ -acetylpiperazine instead of N-(3-d ₃ -methoxy-nitrophenyl)-2,2,3,3,5,5,6,6-d ₈ -Acetylpiperazine, 155 mg of the target product (Compound 38) was never obtained, and the yield was 51.2%. ^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm) 10.15 (s, 1H), 8.65 (br s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.74 (br, 1H) , 7.53-7.47 (m, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.14 (br s, 1H), 6.48-6.39 (m, 1H), 6.28-6.21 (m, 1H), 5.74 ( Dd, J = 9.9 Hz, 1.8 Hz, 1H), 2.03 (s, 3H); LC-MS (APCI): m/z = 570.5 (M + 1) ⁺ .

Example 8

According to the method described in Example 7, the difference is that N-(3-d ₃ -methoxy-nitro-2,6-d2-phenyl)-d ₃ -acetyl-2,2 is used in this example. 3,3,5,5,6,6-d ₈ -piperazine instead of N-(3-d ₃ -methoxy-nitro-2,6-d ₂ -phenyl)-2,2,3, 3,5,5,6,6-d ₈ -acetylpiperazine, 190 mg of the target product (Compound 40) was never obtained, and the yield was 54.8%. ^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm) 10.14 (s, 1H), 8.64 (br s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.74 (br s, 1H ), 7.53-7.48 (m, 2H), 7.25 (t, J = 8.1 Hz, 1H), 7.14 (br s, 1H), 6.47-6.39 (m, 1H), 6.28-6.21 (m, 1H), 5.74 (dd, J = 9.9 Hz, 2.1 Hz, 1H); LC-MS (APCI): m/z = 570.5 (M + 1) ⁺ .

Example 9

The procedure described in Example 3 was carried out except that in the present example, Compound 29 was used instead of Compound 5 to give the title compound 41, 83 mg, yield 37%. ^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm) 10.15 (s, 1H), 8.64 (br, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.48 (d, J = 3.0 Hz, 1H), 7.25 (s, 1H), 6.58 (d, J = 1.2 Hz, 1H), 6.38-6.44 (m, 1H), 6.25 (dd, J = 17.1 Hz, 2.1 Hz, 2H), 5.73 5.77 (m, 1H), 3.76 (s, 3H), 2.03 (s, 3H); LC-MS (APCI): m / z = 567.1 (m + 1) +.

Biological activity test of compounds

The biological evaluation of the compounds was carried out by evaluating the compounds of the invention in a number of tests to determine their biological activity. For example, the ability of a compound of the invention to inhibit a variety of protein kinases of interest can be tested. Some of the compounds tested showed potent inhibitory activity against EGFR kinase. Furthermore, anti-proliferative activity in some of these compounds was screened in human A431 skin cancer cells and human NCI-H1975 and HCC827 lung cancer cell lines, and the activity was demonstrated to be in the range of 1-50 nM. The cytotoxic or growth inhibitory effects of the compounds on the tumor cells of interest were evaluated.

(1) Kinase inhibition

Compound Formulation: Test compounds were dissolved in DMSO to make a 20 mM stock solution. The solution was diluted in DMSO to a final concentration of 100 times the dilution. Dilute to 10 times the final concentration of the dilution solution with the buffer.

EGFR and EGFR [T790M/L858R] kinase assay: After buffer preparation, the enzyme was mixed with different concentrations of pre-diluted compounds for 10 minutes, each double well. The corresponding substrate and ATP were added and reacted at room temperature for 20 minutes (in which a negative positive control was set). After the reaction is completed, the detection reagent is added, and after incubation at room temperature for 30 minutes, the machine is detected and data is collected. Data analysis and mapping according to Graphpad 5.0 software.

EGFR [d746-750] Kinase Assay: After the buffer was prepared, the mixed solution of the enzyme and the antibody was mixed with the different concentrations of the compound prepared by pre-dilution for 10 minutes, and the concentration was doubled. Kinase tracer 199 was added and incubated for 60 minutes at room temperature (where a negative positive control was set). After the reaction is completed, the machine is tested, the data is collected, and the analysis and mapping are performed according to the following formula.

IC50=[(ABS test-ABS start)/(ABS control-ABS start)]x100

The kinase inhibitory effects of the substituted diaminopyrimidines synthesized in Examples 1 to 3 are summarized in Table 1 below:

Table 1 Table of Kinase Inhibition Analysis of Substituted Diaminopyrimidine Compounds of Examples 1 to 3

Example number	WT EGFR IC 50 (nM)	EGFR (L858R/T790M) IC 50 (nM)
Example 1	>60	<10
Example 2	>60	<10
Example 3	>60	<10
Example 4	>60	<10
Example 5	>60	<10
Example 6	>60	<10
Example 7	>60	<10
Example 8	>60	<10
Example 9	>60	<10

As shown in Table 1, the substituted diaminopyrimidines of Examples 1 to 9 exhibited relatively low inhibitory activity (IC ₅₀ greater than 60) and EGFR L858R/T790M mutants (associated with EGFR WT). It is resistant to commercially available EGFR inhibitors) and exhibits excellent inhibitory activity (IC ₅₀ less than 10), indicating that the compounds of the present invention have a strong selective inhibitory ability against EGFR.

(2) Cytotoxicity experiment

Cell lines: skin cancer cells A431; lung cancer cells HCC827; all cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, 100 μg/ml streptomycin.

Compound preparation: The test compound was dissolved in DMSO to prepare a 20 mM stock solution and stored at -20 °C. The solution was diluted to a final concentration of 200 times with a DMSO gradient. When the drug is added, it is diluted with a cell culture medium to a 4-fold final concentration of the working solution.

MTS cell viability assay: Trypsin digested logarithmic growth phase cells, inoculate 150 μl in 96-well plates at an optimized density, and add 4 μl of compound 50 μl/well diluted in the medium 24 hours later (see Table 2. for concentration settings). A well of the same volume of 0.5% DMSO was added as a control. After the cells were cultured for 72 hours, MTS was assayed for cell viability. The specific method is as follows: adherent cells, the medium is discarded, and a mixture containing 20 μl of MTS and 100 μl of the medium is added to each well. OD490 was detected after being placed in an incubator for 1-4 hours, with the OD650 value as a reference. The GraphPad Prism software produces a dose-effect curve and calculates the IC ₅₀ . The results are shown in Table 2.

Table 2 Cytotoxicity experimental data of the substituted diaminopyrimidines of Examples 1-9

Example number	Skin cancer cell IC 50 (nM)	Lung cancer cell IC 50 (nM)
Example 1	>1000	<60
Example 2	>1000	<60
Example 3	>1000	<60
Example 4	>1000	<60
Example 5	>1000	<60
Example 6	>1000	<60
Example 7	>1000	<60
Example 8	>1000	<60
Example 9	>1000	<60

As can be seen from Table 2, it was revealed that the compound of the present invention has an inhibitory effect on the proliferation of cancer cells in vitro; wherein the inhibition of proliferation of lung cancer cells in vitro is stronger than that of skin cancer cells in vitro.

(3) Pharmacokinetic evaluation in rats

Eight male Sprague-Dawley rats, 7-8 weeks old, weighing 210 g, were divided into 2 groups, 4 in each group, and a single oral dose of 5 mg/kg (a) control group: N-(3-(2) -(4-acetylpiperazin-1-yl)2-methoxyanilino)-5-trifluoromethylpyrimidin-4-amino)phenyl acrylamide; (b) Test group: Examples 1-9 Compare the differences in pharmacokinetics.

Rats were fed a standard diet and given water. Fasting began 16 hours before the test. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.

Rats were briefly anesthetized after inhalation of ether, and 300 μL of blood samples were collected from the eyelids in test tubes. There was 30 μL of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.

Immediately after the blood sample is collected, gently invert the tube at least 5 times to ensure adequate mixing and place on ice. Blood samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 μL of plasma into a clean plastic centrifuge tube to indicate the name and time point of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

The experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.

(4) Metabolic stability evaluation

Microsomal experiments: human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).

Preparation of stock solution: A certain amount of the powder of the compound example was accurately weighed and dissolved to 5 mM with DMSO, respectively.

Preparation of phosphate buffer (100 mM, pH 7.4): Mix 150 mL of pre-formed 0.5 M potassium dihydrogen phosphate and 700 mL of 0.5 M potassium dihydrogen phosphate solution, and adjust the mixture with 0.5 M potassium dihydrogen phosphate solution. The pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.

A solution of NADPH regeneration system (containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-PD, 3.3 mM magnesium chloride) was prepared and placed on wet ice before use.

Formulation stop solution: acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 μL of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 μL of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.

Incubation of the sample: The stock solution of the corresponding compound was diluted to 0.25 mM with an aqueous solution containing 70% acetonitrile as a working solution, and was used. 398 μL of human liver microsomes or rat liver microsome dilutions were added to 96-well incubation plates (N=2), and 2 μL of 0.25 mM working solution was added and mixed.

Determination of metabolic stability: 300 μL of pre-cooled stop solution was added to each well of a 96-well deep well plate and placed on ice as a stop plate. The 96-well incubation plate and the NADPH regeneration system were placed in a 37 ° C water bath, shaken at 100 rpm, and pre-incubated for 5 min. 80 μL of the incubation solution was taken from each well of the incubation plate, added to the stopper plate, and mixed, and 20 μL of the NADPH regeneration system solution was added as a sample of 0 min. Then, 80 μL of the NADPH regeneration system solution was added to each well of the incubation plate to start the reaction and start timing. The corresponding compound had a reaction concentration of 1 μM and a protein concentration of 0.5 mg/mL. 100 μL of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min. The plate was centrifuged at 5000 x g for 10 min at 4 °C. 100 μL of the supernatant was taken into a 96-well plate to which 100 μL of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.

Data analysis: The peak area of the corresponding compound and the internal standard was detected by LC-MS/MS system, and the ratio of the peak area of the compound to the internal standard was calculated. The slope is measured by the natural logarithm of the percentage of the remaining amount of the compound versus time, and t _1/2 and CL _{int are} calculated according to the following formula, where V/M is equal to 1/protein concentration.

The compounds of Examples 1-9 were analyzed according to the above procedure, and the results are shown in Table 3.

Table 3 Experimental Results of Metabolic Stability of Substituted Diaminopyrimidine Compounds of Examples 1 to 9

As shown in Table 3, the deuterated diaminopyrimidines of Examples 1 to 9 can improve metabolic stability by comparison with the undeuterated compound CO-1686.

The above is a further detailed description of the present invention in connection with the specific preferred embodiments, and the specific embodiments of the present invention are not limited to the description. It will be apparent to those skilled in the art that the present invention may be made without departing from the spirit and scope of the invention.

Claims (11)

1. A substituted diaminopyrimidine compound characterized by a diaminopyrimidine compound represented by formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvent compound,

   

   Wherein R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ^9c , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^17a and R ^17b are each independently hydrogen, deuterium, halogen or trifluoromethyl;

   Additional conditions are: R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ^9a , R ^{At least one of 9b} , R ^9c , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^17a and R ^17b is deuterated or deuterated.
2. The substituted diaminopyrimidine compound according to claim 1, wherein R ¹¹ is a trifluoromethyl group.
3. The substituted diaminopyrimidine compound according to claim 2, wherein the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

   

   

   
4. The substituted diaminopyrimidine compound according to claim 1, which is prepared by using the first route or the second reaction route.

   The first route is as follows: a 2,4-dihalopyrimidine compound and m-N-Boc aniline are reacted under basic conditions to produce a 2-halopyrimidine compound, and the 2-halopyrimidine compound is protected by Boc to obtain an amino compound. And the amino compound is reacted with deuterated or undeuterated acrylic acid, or deuterated or undeuterated acryloyl halide to obtain an amide compound VI; the phenolic compound is reacted with an alkyl halide under basic conditions to obtain an alkoxy compound, The alkoxy compound is substituted under basic conditions, 4-F is substituted with a fatty amine to obtain a nitro compound, the nitro compound is reduced to an aniline, and the aniline is reacted with the 2-halopyrimidine compound to obtain a formula (1). a substituted diaminopyrimidine compound;

   The second reaction scheme is as follows: an alkoxy compound is reacted with an N-Boc-protected piperazine compound under basic conditions to obtain XI, a nitro group is reduced to an amine group to form a compound XII, and a 2-halopyrimidine compound VI The reaction results in a docking compound XIII which is decarboxylated under acidic conditions to give the piperazine compound XIV and is reacted with an acid anhydride to give a substituted diaminopyrimidine compound of the formula (1).
5. The substituted diaminopyrimidine compound according to claim 4, wherein the solvent used in the first scheme or the second reaction scheme is dichloromethane, dichloroethane, ethyl acetate, methyl acetate, acetic acid. Isopropyl Ester, n-hexane, n-heptane, petroleum ether, n-butanol, ethanol, isobutanol, tert-butanol, isopropanol, n-propanol, n-pentanol, isoamyl alcohol, acetone, acetonitrile, n-hexane, toluene , tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethyl At least one of an amide or dimethyl sulfoxide;

   The base used in the first scheme or the second reaction scheme is potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, At least one of 4-N,N-lutidine or pyridine;

   The acid used in the first scheme or the second reaction scheme is trifluoroacetic acid, acetic acid, concentrated hydrochloric acid, dilute hydrochloric acid, concentrated sulfuric acid, dilute sulfuric acid, concentrated nitric acid, dilute nitric acid, hydrochloric acid dioxane solution, hydrochloric acid ethanol solution, p-toluene At least one of a sulfonic acid or a benzenesulfonic acid.
6. A process for the preparation of a substituted diaminopyrimidine compound according to any one of claims 1 to 5, wherein a pharmaceutically acceptable carrier and a compound described in the first aspect of the invention, or a crystal thereof The pharmaceutically acceptable salts, prodrugs, stereoisomers, isotopic variant hydrates or solvates are combined to form a pharmaceutical composition.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a substituted diaminopyrimidine compound according to any one of claims 1 to 5, or a crystalline form thereof, a pharmaceutically acceptable salt, A pharmaceutical composition of a hydrate or solvate, stereoisomer, prodrug or isotopic variation.
8. The pharmaceutical composition according to claim 7, which further comprises other therapeutic agents, which are cancer, cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, viral diseases, and heart. A drug for vascular disease or metabolic disease.
9. Use of a substituted diaminopyrimidine compound according to any one of claims 1 to 5, or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvent compound, for use in the preparation of a treatment, A pharmaceutical composition for preventing and alleviating a disease caused by mutation of epidermal growth factor.
10. A method of treating and/or preventing a protein kinase-associated disease in a subject, the method comprising administering to the subject a compound of formula (I) according to any one of claims 1 to 5 or A polymorphic form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotopic variation, a hydrate or a solvent compound, or a pharmaceutical composition as set forth in claim 8.
11. A compound of formula (I) according to any one of claims 1 to 5, or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotope variant, hydrate or solvent compound thereof, or a compound thereof The pharmaceutical composition of claim 8 for use in the treatment and/or prevention of a protein kinase-associated disease.