CN115806548A

CN115806548A - Pharmaceutical composition containing EGFR inhibitor and preparation method and application thereof

Info

Publication number: CN115806548A
Application number: CN202211125170.3A
Authority: CN
Inventors: 沈孝坤; 黄金文; 明从梅; 宋赠; 栗增
Original assignee: Fukang Shanghai Health Technology Co ltd
Current assignee: Fukang Shanghai Health Technology Co ltd
Priority date: 2021-09-15
Filing date: 2022-09-15
Publication date: 2023-03-17

Abstract

The invention discloses a pharmaceutical composition containing an EGFR inhibitor, a preparation method and application thereof. The pharmaceutical composition comprises particles, wherein the particles comprise the following components in percentage by mass: 30-45% of anhydrous neratinib maleate, 7-28% of copovidone, 25-48% of filler, 1.0-8.0% of disintegrant, 0.5-4.0% of glidant and 0.5-4.0% of lubricant. The pharmaceutical composition has good stability and in vivo bioactivity with the effects of a reference preparation and the like, and has good application prospect.

Description

Pharmaceutical composition containing EGFR inhibitor and preparation method and application thereof

Technical Field

The invention relates to a pharmaceutical composition containing an EGFR inhibitor, a preparation method and application thereof.

Background

(E) -N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino-3-cyano-7-ethoxyquinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate, also known as neratinib maleate, having the specific structure below, is a specific protein kinase inhibitor.

Studies have shown that there is high or abnormal expression of EGFR (epidermal growth factor receptor) in many solid tumors. EGFR is involved in the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. Overexpression of EGFR plays an important role in the evolution of malignant tumors, and EGFR overexpression exists in tissues such as glial cells, kidney cancer, lung cancer, prostate cancer, pancreatic cancer and breast cancer. Increased EGFR and HER2 concentrations can be found in more than 30% of breast cancer patients, with HER2 being one of the most important genes in the EGFR family.

The effective component of the neratinib maleate is neratinib, is an irreversible HER2/EGFR inhibitor, and can effectively inhibit the activity of HER1 and HER2 tyrosine kinases. Thereby inhibiting the growth of tumor cells. Neratinib maleate was originally produced by the Hewlett-packard companyDepartment of research, after being co-purchased by pfeiy pharmaceutical company, authorized PUMA biotech company in the united states to be responsible for development, marketing, production and sale. Approved by the United states Food and Drug Administration (FDA) to be marketed in 2017, 7 months and 17 days, and has the trade name of

The neratinib maleate tablet is prepared by taking neratinib maleate in an anhydrous crystal form as a raw material, mixing the neratinib maleate with auxiliary materials, and performing a fluidized bed granulation process, tabletting and coating, wherein the crystal form of the neratinib maleate serving as an active ingredient is finally converted into an aqueous crystal form.

Neratinib has a good effect of inhibiting the growth of tumor cells, but neratinib is easy to degrade and has poor stability, and particularly after a pharmaceutical composition is prepared, due to the existence of various auxiliary materials and water, the problems in the following two aspects are mainly solved:

1. the degradation of neratinib maleate is accelerated, the specific structural formula of the degradation impurity is shown in the specification, the degradation impurity is accelerated to grow under the conditions of high temperature and high humidity, and the requirement that high temperature and water are avoided as far as possible in the preparation process is met. In clinical applications, because neratinib has a great side effect, generally, the content of degrading impurities in neratinib preparations needs to be controlled to be less than 1.5%, and therefore, providing stable neratinib preparations is a challenge for those skilled in the art.

2. Neratinib maleate is easy to be changed into a monohydrate crystal form from an anhydrous crystal form when meeting water, the change of the crystal form can influence the control of the quality of the medicament, the dissolution and the release of the medicament, and further influence the treatment effect and the side effect of the medicament, which requires that the use of water is avoided as much as possible in the preparation process. Based on the above two, the need to provide stable neratinib formulations is a challenge for those skilled in the art.

Patent CN102724970 discloses a preparation method of neratinib maleate tablet, but the method is only aimed at improving the adhesion of neratinib in the granulation process. In the process, a fluidized bed wet granulation process is adopted, so that the environment of high temperature and water exists, the chemical characteristics that neratinib is unstable and is easy to convert into crystal and degrade are not provided, and the final preparation has good stability and dissolution property cannot be ensured. Meanwhile, the neratinib maleate is converted from an anhydrous crystal form into a crystal form in the granulation process, and the complete conversion of the crystal form cannot be controlled, so that the challenge is brought to the quality control of the drug delivery product.

Patent CN106913529 discloses a preparation method of neratinib maleate tablets, which adopts a fluidized bed granulation process, controls the maximum water content of granules in the granulation preparation process to be less than 10%, and removes water through high temperature (70-90 ℃) in the granulation process, and controls the water content of the final granules to be less than 2%. After the coating is finished, the moisture can be reduced to below 2% by drying with a rotary vacuum dryer alone. This procedure is not generally used in large scale production. In combination with the preparation process of the patent, it can be seen that the Lenellatinib maleate inevitably undergoes crystal form transformation. This tends to cause inconsistent degrees of drug crystallization from batch to batch. Moreover, in the patent, the dissolution speed of the neratinib capsule is high, more than 80% of neratinib can be dissolved within 15min, and the dissolution speed is obviously higher than that of the neratinib maleate primary grinding medicine on the market; compared with the original research, the tablet of the patent has larger risk of in vivo bioequivalence.

In summary, for the clinical application of the drug, it is necessary to develop a stable and high temperature-free tablet preparation process to obtain a drug with good stability and low impurity content.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defect that the type of the pharmaceutical composition containing the EGFR inhibitor is limited in the prior art, and therefore, the pharmaceutical composition containing the EGFR inhibitor, the preparation method and the application thereof are provided. The pharmaceutical composition containing the EGFR inhibitor has good stability, the dissolution curve of the pharmaceutical composition is consistent with that of a reference preparation, and the pharmaceutical composition has in vivo biological activity with the effects of the reference preparation and the like.

The invention solves the technical problems through the following technical scheme.

The invention provides a compound shown as the following formula I,

wherein R is ¹ 、R ² And R ³ Each independently is H or substituted by one or more R ^1-1 Substituted C _1-6 An alkyl group;

each R ^1-1 Each independently is a 4-6 membered heterocycloalkyl group of 1, 2 or 3 heteroatoms, independently selected from N, O and S, and substituted with one or more R ^1-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms, or-SO ₂ -C _1-6 An alkyl group;

each R ^1-a Each independently is halogen or-N (C) _1-6 Alkyl radical) ₂ 。

In some embodiments, R ¹ And R ² Is H, R ³ Is represented by one or more R ^1-1 Substituted C _1-6 An alkyl group.

In some embodiments, R ² And R ³ Is H, R ¹ Is represented by one or more R ^1-1 Substituted C _1-6 An alkyl group.

In some embodiments, each R is ^1-1 Each independently by one or more R ^1-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms, or-SO ₂ -C _1-6 An alkyl group.

In some embodiments, the R is ¹ 、R ² 、R ³ 、R ^1-1 And R ^1-a Said is "substituted by one or more R ^1-1 Substituted C _1-6 Alkyl ", said" -SO ₂ -C _1-6 Alkyl "and said" -N (C) _1-6 Alkyl radical) ₂ "C in _1-6 Alkyl is independently methyl or ethylN-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In some embodiments, the substituted aryl is substituted with one or more R ^1-a The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms" is

In some embodiments, the R is ^1-1 Wherein said "heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms" and said "substituted with one or more R ^1-a The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom in the 4-6 membered heterocycloalkyl group "having 1, 2 or 3 hetero atoms is selected from 1, 2 or 3 of N, O and S, the 4-6 membered heterocycloalkyl group" having 1, 2 or 3 hetero atoms is independently N, the 4-6 membered heterocycloalkyl group having 1 hetero atom is preferred

In some embodiments, the R is ^1-a In (1), the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, R ¹ And R ² Is H, R ³ Is composed of

In some embodiments, R ² And R ³ Is H, R ¹ Is composed of

In some embodiments, the compound of formula I is any one of the following:

the invention also provides a pharmaceutical composition 1, which comprises a compound shown as a formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutical excipient.

The invention also provides application of the compound shown as the formula I or pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating diseases related to EGFR.

The EGFR-related disease is preferably breast cancer, ovarian cancer, epithelioid tumor, colon cancer, prostate cancer, renal cancer, bladder cancer, laryngeal cancer, esophageal cancer, gastric cancer or lung cancer.

The invention also provides a pharmaceutical composition 2, which comprises the following components in percentage by mass: 30-45% of a compound shown as a formula II or pharmaceutically acceptable salt thereof, 7-28% of copovidone, 25-48% of a filling agent, 1.0-8.0% of a disintegrating agent, 0.5-4.0% of a glidant and 0.5-4.0% of a lubricant;

the sum of the mass fractions of all the components in the particles is 100%; the mass fraction is the mass percentage of the mass of each component in the particulate matter in the total mass of each component;

R ⁴ 、R ⁵ and R ⁶ Each independently is H or substituted by one or more R ^4-1 Substituted C _1-6 An alkyl group;

each R ^4-1 Are each independently-N (C) _1-6 Alkyl radical) ₂ And 1, 2 or 3 heteroatoms selected from N, O and S, the number of the heteroatoms is 1, 2 or 3 ", 4-6 membered heterocycloalkyl substituted with one or more R ^4-a The substituted' hetero atom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 hetero atoms or-SO ₂ -C _1-6 An alkyl group;

each R ^4-a Each independently is halogen or-N (C) _1-6 Alkyl radical) ₂ 。

In some embodiments, R ⁴ And R ⁶ Is H, R ⁵ Is represented by one or more R ^4-1 Substituted C _1-6 An alkyl group.

In some embodiments, R ⁵ And R ⁶ Is H, R ⁴ Is represented by one or more R ^4-1 Substituted C _1-6 An alkyl group.

In some embodiments, each R is ^4-1 Are each independently-N (C) _1-6 Alkyl radical) ₂ By one or more R ^4-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms, or-SO ₂ -C _1-6 An alkyl group.

In some embodiments, the R is ⁴ 、R ⁵ 、R ⁶ 、R ^4-1 And R ^4-a Said is "substituted by one or more R ^4-1 Substituted C _1-6 Alkyl', said "-SO ₂ -C _1-6 Alkyl "and said" -N (C) _1-6 Alkyl radical) ₂ "C in _1-6 Alkyl is independently of each other methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In some embodiments, the R is ^4-1 Wherein said "heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms" and said "substituted with one or more R ^4-a The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom in the 4-6 membered heterocycloalkyl group "having 1, 2 or 3 hetero atoms is selected from 1, 2 or 3 of N, O and S, the 4-6 membered heterocycloalkyl group" having 1, 2 or 3 hetero atoms is independently N, the 4-6 membered heterocycloalkyl group having 1 hetero atom is preferred

In some embodiments, the R is ^4-a In (1), the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

In some embodiments, R ⁴ And R ⁶ Is H, R ⁵ Is composed of

In some embodiments, R ⁵ And R ⁶ Is H, R ⁴ Is composed of

In some embodiments, the compound of formula II is any one of the following:

in some embodiments, the pharmaceutically acceptable salt thereof is a maleate salt of the compound of formula II.

In some embodiments, the pharmaceutically acceptable salt thereof is present in an anhydrous crystalline form or an amorphous form, preferably in an anhydrous crystalline form.

In some embodiments, the mass fraction of the compound represented by formula II or the pharmaceutically acceptable salt thereof may be 35-42%, for example, 36%.

In some embodiments, the copovidone may have a mass fraction of 8-22%, for example 21%.

In some embodiments, the filler may be a filler conventional in the pharmaceutical field, preferably a sugar alcohol and/or a water-swellable additive, further preferably mannitol and microcrystalline cellulose.

The sugar alcohol is preferably one or more of mannitol, erythritol and xylitol, such as mannitol.

The water-swellable filler is preferably one or more of pregelatinized starch, gelatinized starch, microcrystalline cellulose (crystalline cellulose), corn starch, hydroxypropylmethyl cellulose (HPMC-K100 LV), calcium sulfate, sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose), calcium carboxymethyl cellulose, croscarmellose sodium (croscarmellose sodium), soybean lecithin, low-substituted hydroxypropyl cellulose, tragacanth powder, and bentonite, such as microcrystalline cellulose.

In some embodiments, the filler may have a mass fraction of 34-45%, for example 37%.

In some embodiments, the disintegrant may be a disintegrant conventional in the pharmaceutical arts, preferably one or more of adipic acid, alginic acid, gelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydrated silicon dioxide, calcium citrate, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose (microcrystalline cellulose), synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, low substituted hydroxypropyl cellulose, corn starch, tragacanth powder, potato starch, hydroxyethyl methyl cellulose, hydroxypropyl starch, pregelatinized starch, monosodium fumarate, povidone, anhydrous citric acid, methyl cellulose, and calcium dihydrogen phosphate, more preferably crospovidone, such as crospovidone XL-10.

In some embodiments, the mass fraction of the disintegrant may be 1.7 to 4.9%, e.g., 2.0%.

In some embodiments, the glidant may be a glidant conventional in the pharmaceutical art, preferably one or more of hydrated silicon dioxide (colloidal silicon dioxide), colloidal silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch, and magnesium aluminum metasilicate, preferably colloidal silicon dioxide or colloidal silicon dioxide.

In some embodiments, the glidant may be used in an amount conventional in the pharmaceutical art. The mass fraction of the glidant may be 1.0 to 4.0%, for example 2.0%.

In some embodiments, the lubricant may be a lubricant conventional in the pharmaceutical field, preferably one or more of cocoa fat, carnauba wax, hydrated silicon dioxide (colloidal silica), aluminum hydroxide xerogel, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium fumarate stearate, stearyl alcohol, and polyethylene glycol 40 stearate, preferably sodium fumarate stearate or magnesium stearate.

In some embodiments, the lubricant may have a mass fraction of 1.0 to 4.0%, for example 2%.

In some embodiments, the pharmaceutical composition 2 further comprises a coating agent.

In some embodiments, the coating agent may be a coating agent conventional in such drugs in the art, preferably one or more of hypromellose, methylcellulose, ethylcellulose, methylcellulose or hydroxypropylcellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer dispersion, sucrose, mannitol and OPADRY (trade name, OPADRY), preferably OPADRY.

In some embodiments, the pharmaceutical composition 2 comprises a particulate material comprising the following components in mass fractions: 30-45% of anhydrous neratinib maleate, 7-28% of copovidone, 25-48% of filler, 1.0-8.0% of disintegrant, 0.5-4.0% of glidant and 0.5-4.0% of lubricant;

the sum of the mass fractions of all the components in the particles is 100%; the mass fraction is the mass percentage of the mass of each component in the particulate matter in the total mass of each component.

In the pharmaceutical composition 2, the anhydrous neratinib maleate can be in a crystal form of anhydrous neratinib maleate, and an X-ray powder diffraction pattern represented by a diffraction angle of 2 theta has characteristic peaks at 6.0 +/-0.2 °, 7.3 +/-0.2 °, 10.1 +/-0.2 °, 12.1 +/-0.2 °, 15.6 +/-0.2 °, 17.3 +/-0.2 ° and 19.9 +/-0.2 °. The X-ray powder diffraction pattern of the crystalline form of neratinib maleate may be substantially as shown in figure 1, 2 or 3.

In the pharmaceutical composition 2, the anhydrous neratinib maleate may be 35 to 42% by mass, for example, 36% by mass.

In the pharmaceutical composition 2, the mass fraction of the copovidone can be 8-22%, for example 21%.

In the pharmaceutical composition 2, the filler may be a conventional filler in the pharmaceutical field, preferably a sugar alcohol and/or a water-swellable additive, and more preferably mannitol and microcrystalline cellulose.

In the pharmaceutical composition 2, the mass fraction of the filler may be 34 to 45%, for example, 37%.

In the pharmaceutical composition 2, the disintegrant may be a disintegrant which is conventional in the pharmaceutical field, and is preferably one or more of adipic acid, alginic acid, gelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydrated silicon dioxide, calcium citrate, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose (microcrystalline cellulose), synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, corn starch, tragacanth gum powder, potato starch, hydroxyethyl methyl cellulose, hydroxypropyl starch, pregelatinized starch, monosodium fumarate, povidone, anhydrous citric acid, methyl cellulose, and calcium dihydrogen phosphate, and more preferably crospovidone, such as crospovidone XL-10.

In the pharmaceutical composition 2, the mass fraction of the disintegrant may be 1.7 to 4.9%, for example, 2.0%.

In the pharmaceutical composition 2, the glidant may be a conventional glidant in the pharmaceutical field, and is preferably one or more of hydrated silicon dioxide (colloidal silicon dioxide), colloidal silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch and magnesium aluminum metasilicate, and is preferably colloidal silicon dioxide or colloidal silicon dioxide.

In the pharmaceutical composition 2, the amount of the glidant may be an amount conventionally used in the pharmaceutical field. The mass fraction of the glidant may be 1.0 to 4.0%, for example 2.0%.

In the pharmaceutical composition 2, the lubricant may be a conventional lubricant in the pharmaceutical field, and is preferably one or more of cocoa fat, carnauba wax, hydrated silicon dioxide (colloidal silicon dioxide), aluminum hydroxide xerogel, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium fumarate stearate, stearyl alcohol, and polyethylene glycol 40 stearate, and is preferably sodium fumarate or magnesium stearate.

In the pharmaceutical composition 2, the mass fraction of the lubricant may be 1.0 to 4.0%, for example, 2%.

In the pharmaceutical composition 2, the components of the particulate matter preferably comprise an inner component of the particulate matter and an outer component of the particulate matter;

the inner component of the particulate matter: 30-45% anhydrous neratinib maleate (e.g., 35%, 36%, or 42%), 7-28% copovidone (e.g., 8%, 21%, or 22%), 25-48% filler (e.g., 34%, 37%, or 45%), 1.0-8.0% disintegrant (e.g., 2.4%), 1.0-4.0% glidant (e.g., 1%, 2%, or 4%), and 0.5-4.0% lubricant (e.g., 1%);

the external component of the particulate matter: 0-2.5% of disintegrant and/or 0-1% of lubricant, and the disintegrant and the lubricant are not 0 at the same time.

In one embodiment, the particulate material consists of the following components in mass fraction: the above anhydrous neratinib maleate (including the type and mass fraction of neratinib maleate), the above copovidone, the above filler (including the type and mass fraction of filler), the above disintegrant (including the type and mass fraction of disintegrant), the above glidant (including the type and mass fraction of glidant), the above lubricant (including the type and mass fraction of lubricant), and the above coating agent (including the type and mass fraction of coating agent).

Preferably, the particulate material consists of components of group (1), group (2) or group (3) as follows:

group (1): the inner component of the particulate matter: 34.9% anhydrous neratinib maleate, 26.2% mannitol, 8.3% microcrystalline cellulose, 21.7% copovidone, 2.5% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 2.5% crospovidone XL-10 and 1.0% magnesium stearate;

group (2): the inner component of the particulate matter: 42.3% anhydrous neratinib maleate, 31.7% mannitol, 13.1% microcrystalline cellulose, 8.0% copovidone, 2.0% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 1.0% magnesium stearate;

group (3): the inner component of the particulate matter: 36.1% anhydrous neratinib maleate, 27.1% dry dew alcohol, 8.6% microcrystalline cellulose, 22.4% copovidone, 1.7% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 1.0% magnesium stearate.

The pharmaceutical composition 2 may further comprise a coating agent.

The coating agent may be a coating agent conventional in such drugs in the art, preferably one or more of hypromellose, methylcellulose, ethylcellulose, methylcellulose or hydroxypropylcellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer dispersion, sucrose, mannitol and OPADRY (trade name, OPADRY), preferably OPADRY.

The coating agent may be used in amounts conventional in the art for such drugs. The mass ratio of the coating agent to the drug particles can be 0.01.

In the pharmaceutical composition 2, the pharmaceutical granule components consist of the following components in percentage by mass: the above anhydrous neratinib maleate (including the type and mass fraction of neratinib maleate), the above copovidone, the above filler (including the type and mass fraction of filler), the above disintegrant (including the type and mass fraction of disintegrant), the above glidant (including the type and mass fraction of glidant), the above lubricant (including the type and mass fraction of lubricant), and the above coating agent (including the type and mass fraction of coating agent).

The pharmaceutical composition 2 consists of the following components in group (a), group (b) or group (c):

group (a): the mass ratio of the particle material to the Opadry is 0.03:1;

the inner component of the particulate matter: 34.9% anhydrous neratinib maleate, 26.2% mannitol, 8.3% microcrystalline cellulose, 21.7% copovidone, 2.5% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

group (b): the mass ratio of the particle material to the Opadry is 0.034:1;

the inner component of the particulate matter: 42.3% anhydrous neratinib maleate, 31.7% mannitol, 13.1% microcrystalline cellulose, 8.0% copovidone, 2.0% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 1.0% magnesium stearate;

group (c): the mass ratio of the particle material to the Opadry is 0.036:1;

the inner component of the particulate matter: 36.1% anhydrous neratinib maleate, 27.1% mannitol, 8.6% microcrystalline cellulose, 22.4% copovidone, 1.7% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 1.0% magnesium stearate.

The invention also provides a preparation method of the pharmaceutical composition 2, which comprises the following steps: granulating the following raw materials in parts by mass to obtain particles;

the raw materials comprise 30-45% of anhydrous neratinib maleate, 7-28% of copovidone, 25-48% of filler, 1.0-8.0% of disintegrant, 0.5-4.0% of glidant and 0.5-4.0% of lubricant; the sum of the mass fractions of all the components in the particles is 100%; the mass fraction is the mass percentage of the mass of each component in the particulate matter in the total mass of each component.

In the present invention, the neratinib maleate is preferably anhydrous neratinib maleate, and the anhydrous neratinib maleate is the same as the anhydrous neratinib maleate (including the species and content).

In the present invention, the copovidone, the filler (including type and content), the disintegrant (including type and content), the glidant (including type and content) and the lubricant (including type and content) are the same as described above.

In the present invention, the granulation method may be a method conventional in the art, and is preferably dry granulation. The conditions and operations of the dry granulation are conventional in the field of formulation, and the following conditions and operations are particularly preferred in the present invention:

in the dry granulation, a dry granulator is adopted, and the dry granulator preferably has the following parameters:

the pressure of the dry granulator is preferably between 65 and 100bar, for example 80bar.

The feeding speed of the dry granulating machine is preferably 40-50rpm.

The roll speed of the dry granulator is preferably 5 to 15rpm, for example 6rpm.

The granulation speed of the dry granulator is preferably 50 to 500rpm, for example 100rpm.

The mesh size of the dry granulator is preferably 0.6-1.2mm, for example 0.8mm.

The preparation method of the pharmaceutical composition can further comprise a coating step.

In the coating step, the water content of the pharmaceutical composition is less than or equal to 3 percent.

The coating agent is the same as the coating agent in type and amount.

In the coating step, a coating machine is adopted for coating, and the coating machine preferably has the following parameters:

the air inlet temperature of the coating machine is preferably 55-60 ℃.

The atomizing pressure of the coating machine is preferably 0.10-0.30MPa.

The speed of the peristaltic pump of the coating machine is preferably 2.0-12.0rpm.

The air outlet temperature of the coating machine is preferably 35-42 ℃.

In one embodiment of the present invention, the preparation method of the pharmaceutical composition 2 preferably comprises the following steps:

step 1: granulating the inner raw material of the particles by a dry method to obtain particles 1;

internal raw material of the particles: 30-45% of anhydrous neratinib maleate, 7-28% of copovidone, 25-48% of filler, 1-8% of disintegrant, 1-4% of glidant and 0.5-4% of lubricant;

step 2: compressing the particulate matter 1 with an external charge of particulate matter (e.g., mixing particulate matter 1 with an external charge of particulate matter 1 and compressing the mixture into a tablet with a tablet press (10.5 mm x 5.5mm shaped die)) to provide particulate matter:

the particle external raw material: 0-2.5% of disintegrant and/or 0-1% of lubricant, and the disintegrant and the lubricant are not 0 at the same time.

The invention also provides a pharmaceutical composition 2 prepared by the preparation method of the pharmaceutical composition 2.

The invention also provides a pharmaceutical solid preparation, which comprises the pharmaceutical composition 2 and pharmaceutically acceptable auxiliary materials.

The solid formulation may be a tablet, granule, powder (including fine granules), or capsule, such as a tablet.

When the solid preparation is a tablet, when the pharmaceutical composition 2 of the present invention is a tablet, a tablet can be obtained by compressing the granules obtained as described above.

Wherein the pressing pressure can be 10-20kN. The shape of the tablet is not particularly limited, and may be, for example, a lenticular shape, a disc shape, a circular shape, an oval shape (e.g., a caplet), a teardrop shape, or a polygonal shape (e.g., a triangle or a diamond shape).

The tablets prepared may be coated by spraying a suspension/solution of the coating agent through a pan coater. After coating is complete, the moisture content of the final tablet can be controlled to within 3% by a drying process. The drying temperature may be selected from 40-80 deg.C, for example 40-50 deg.C.

Controlling the humidity of the pressing environment during the pressing process ensures that the moisture content of the final tablet is less than 3% (below 3%), and ensures that the moisture content of the final composition is less than 3% by applying a vacuum drying process to the final composition.

The invention also provides an application of the substance A in preparing an EGFR inhibitor, wherein the substance A is the pharmaceutical composition 2 or the pharmaceutical solid preparation.

In some embodiments, the substance a can also be a compound of formula I, or a pharmaceutically acceptable salt thereof, as described above.

The invention also provides application of the substance A in preparation of a medicament for preventing or treating diseases related to EGFR, wherein the substance A is the medicinal composition 2 or the medicinal solid preparation.

The invention also provides a pharmaceutical composition 3 comprising a substance X and a substance Y;

the substance X is neratinib maleate, the substance Y is a compound CVL218 or a pharmaceutically acceptable salt thereof, and the structure of the compound CVL218 is as follows:

the present invention also provides a pharmaceutical composition 4 comprising a substance M and a substance N;

the substance M is neratinib maleate, the substance N is a compound CVL237 or a pharmaceutically acceptable salt thereof, and the structure of the compound CVL237 is as follows:

the invention also provides application of the pharmaceutical composition 3 in preparation of a medicine for preventing or treating bile duct cancer.

The invention also provides application of the pharmaceutical composition 4 in preparation of a medicine for preventing or treating cholangiocarcinoma.

As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from the compounds of this invention and relatively non-toxic, pharmaceutically acceptable acids.

In the present invention, the term "particulate matter" means particulate matter having a particle size of 30 to 200 mesh.

In the present invention, the term "pharmaceutical excipients" may be those which are widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

Neratinib, or a pharmaceutically acceptable salt or solvate thereof and the like described herein may be obtained as described in US6002008, US6288082, US6297258, US6384051, and US7399865, or commercially available.

The neratinib maleate reference preparation is a neratinib maleate primary drug (coated tablet) produced by Puma Biotechnology company.

The positive progress effects of the invention are as follows: the pharmaceutical composition has good stability and achieves the same in-vitro dissolution effect as the original research reference preparation; the product obtained by the preparation method of the invention has the advantages of uniform and stable particle size distribution, small tablet weight difference and easy control of tablet hardness.

Drawings

Figure 1 is the XRPD pattern (anhydrous crystalline form) of example 1.

Figure 2 is the XRPD pattern (anhydrous crystalline form) of example 2.

Figure 3 is the XRPD pattern (anhydrous crystalline form) of example 3.

Figure 4 is an XRPD pattern (with crystals) of the reference formulation.

Fig. 5 is a dissolution profile for example 1, example 2 and the reference formulation.

Figure 6 is the XRPD pattern (anhydrous crystalline form) of example 4.

Figure 7 is the XRPD pattern (anhydrous crystalline form) of enlarged batch 1 from example 5.

Figure 8 is the XRPD pattern (anhydrous crystalline form) of enlarged batch 2 of example 5.

Figure 9 is the XRPD pattern (anhydrous crystalline form) of enlarged batch 3 from example 5.

Figure 10 is the XRPD pattern (anhydrous crystalline form) of the enlarged batch 1 after accelerated 6 months of the experiment in example 5.

Figure 11 is the XRPD pattern (anhydrous crystalline form) of the enlarged batch 2 after 6 months of accelerated testing in example 5.

Figure 12 is the XRPD pattern (anhydrous crystalline form) of the enlarged batch 3 after 6 months of accelerated testing in example 5.

Figure 13 is the XRPD pattern (anhydrous crystalline form) of the enlarged batch 1 of example 5 after an extended 12 month experiment.

Figure 14 is the XRPD pattern (anhydrous crystalline form) of the enlarged batch 2 of example 5 after an extended 12 month experiment.

Figure 15 is the XRPD pattern (anhydrous crystalline form) of enlarged batch 3 of example 5 after an extended 12 month experiment.

Fig. 16 is a dissolution profile of the enlarged batch and reference formulation of example 5.

FIG. 17 is a dissolution profile of the test and reference formulations after 6 months accelerated from the scaled-up batch of example 5.

FIG. 18 is a dissolution profile of the enlarged batch of example 5 after a long 12 month experiment.

FIG. 19 is a graph showing the change in body weight of a mouse in a biological example.

FIG. 20 is a graph showing the change in tumor volume in the biological examples.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Preparation example 1

(E) Synthesis of (E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -4- (3- (dimethylamino) azetidin-1-yl) but-2-enamide (Compound A0901)

Step 1: (E) -4-bromo-N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) but-2-enamide

(E) -4-bromobut-2-enoic acid (1.1g, 6.70mmol) was dissolved in dichloromethane (10 mL), cooled in an ice bath, oxalyl chloride (850mg, 6.70mmol) was added, stirring was carried out at a temperature of 10 ℃ for 4 hours, and then 6-amino-4- { [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] was added]Amino } -7-ethoxyquinoline-3-carbonitrile (2.5g, 5.60mmol) and dipotassium carbonate (2.32g, 16.8mmol) in acetonitrile (50 mL), and the reaction was stirred at 10 ℃ for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL. Times.2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired compound, intermediate 2 (2.30 g), as a yellow solid. LC-MS (ESI, m/z) 592.1[ 2 ], [ M + H ]] ⁺ . ¹ HNMR(400MHz,DMSO-d ₆ )δ9.94-9.70(m,2H),9.00-8.89(m,1H),8.61-8.53(m,2H),7.90-7.86(m,1H),7.59(d,J＝7.6Hz,1H),7.44-7.34(m,3H),7.29-7.22(m,2H),6.96-6.70(m,1H),5.34(s,2H),4.35-4.27(m,2H),3.36(br s,2H),1.47(t,J＝6.8Hz,3H).

Step 2: (E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -4- (3- (dimethylamino) azetidin-1-yl) but-2-enamide

To (2E) -4-bromo-N- (4- { [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]To a solution of amino } -3-cyano-7-ethoxyquinolin-6-yl) but-2-enamide (100mg, 0.1699 mmol) in DMF (3 mL) was added N, N-dimethylazetidin-3-amine hydrochloride (58.4mg, 0.337mmol) and ethyldiisopropylamine (65.4mg, 0.169mol), the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL. Times.2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered. Concentrating, and purifying by column chromatography to obtain yellow solid 100 mg. LC-MS (ESI, m/z) 612.1[ 2 ], [ M + H ]] ⁺ . ¹ HNMR(400MHz,DMSO-d ₆ )δ9.64(s,1H),9.57(s,1H),8.95(s,1H),8.60(d,J＝4.4Hz,1H),8.48(s,1H),7.90-7.86(m,1H),7.59(d,J＝7.2Hz,1H),7.40(s,2H),7.38-7.36(m,1H),7.26(d,J＝8.8Hz,1H),7.21-7.19(m,1H),6.71-6.66(m,1H),6.61-6.57(m,1H),5.29(m,2H),4.32(q,J＝6.8Hz,2H),3.69-3.61(m,2H),3.52-3.42(m,2H),3.27-3.09(m,3H),2.26(br s,6H),1.47(t,J＝6.8Hz,3H).

Preparation example 2

(E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -4- (3,3-difluoroazetidin-1-yl) but-2-enamide (Compound A0902)

To (2E) -4-bromo-N- (4- { [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]To a solution of amino } -3-cyano-7-ethoxyquinolin-6-yl) but-2-enamide (100 mg, 83% purity, 0.169 mmol) in DMF (3 mL) was added dipotassium carbonate (70.0 mg, 0.506 mmol) and 3-fluoroazetidine hydrochloride (25.5 mg,0.337 mmol) and the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL. Times.2). The combined organic phase was washed with brine (10 mL)The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography to give 110mg of a yellow solid. LC-MS (ESI, m/z) 587.2[ 2 ], [ M + H ]] ⁺ .

Preparation example 3

(E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -4- (3,3-difluoroazetidin-1-yl) but-2-enamide (Compound A0903)

To (2E) -4-bromo-N- (4- { [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]To a solution of amino } -3-cyano-7-ethoxyquinolin-6-yl) but-2-enamide (100 mg, 83% purity, 0.169 mmol) in DMF (3 mL) was added dipotassium carbonate (70.0 mg, 0.506 mmol) and 3,3-difluoroazetidine hydrochloride (43.7 mg,0.337 mmol) and the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL. Times.2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography to give 120mg of a yellow solid. LC-MS (ESI, m/z) 605.0[ 2 ], [ M + H ]] ⁺ . ¹ HNMR(400MHz,DMSO-d ₆ )δ9.61(s,1H),9.52(s,1H),8.95(s,1H),8.60(d,J＝4.0Hz,1H),8.47(s,1H),7.90-7.85(m,1H),7.58(d,J＝7.6Hz,1H),7.39-7.36(m,3H),7.25(d,J＝8.8Hz,1H),7.20-7.18(m,1H),6.76-6.70(m,1H),6.60-6.56(m,1H),5.28(s,2H),4.32(q,J＝6.8Hz,2H),3.70-3.63(m,4H),3.41(d,J＝4.0Hz,2H),1.47(t,J＝7.2Hz,3H). ¹⁹ F NMR(376MHz,DMSO-d ₆ )-97.41(s,2F)

Preparation example 4

(E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -4- (methanesulfonyl) -but-2-enamide (Compound A0904)

To (2E) -4-bromo-N- (4- { [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl at 25 deg.C]Amino } -3-carbonitrilesTo a solution of yl-7-ethoxyquinolin-6-yl) but-2-enamide (180mg, 0.304mmol) in dioxane (4 mL) and water (2 mL) was added sodium methyleneate (46.5 mg, 0.455 mmol), the mixture was then stirred at 100 deg.C to cool the reaction mixture to 25 deg.C, poured into water (10 mL), and extracted with EtOAc (10 mL. Times.2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 220mg as a yellow solid. LC-MS (ESI, m/z) 592.0[ m + H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ9.73(s,1H),9.63(s,1H),8.93(s,1H),8.60(d,J＝5.2Hz,1H),8.48(s,1H),7.90-7.85(m,1H),7.58(d,J＝8.0Hz,1H),7.40(d,J＝2.0Hz,2H),7.39-7.36(m,1H),7.27-7.25(m,1H),7.22-7.19(m,1H),6.76-6.74(m,2H),5.29(s,2H),4.32(q,J＝7.2Hz,2H),4.20(d,J＝5.2Hz,2H),3.02(s,3H),1.47(t,J＝7.2Hz,3H).

Preparation example 5

Preparation of N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -2- ((3- (dimethylamino) azetidin-1-yl) methyl) acrylamide (Compound A0905)

Step 1:2- ((3- (dimethylamino) azetidin-1-yl) meth) acrylic acid

N, N-Dimethylazetidin-3-amine (0.33g, 2.00mmol) and 2- (bromomethyl) propene (0.35g, 2.00mmol) were dissolved in N, N-dimethylacetamide (20 mL) followed by the addition of DIEA (1mL, 6.00mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated and directly purified in reverse phase (0-20% acetonitrile) to yield the desired product (0.20 g of white solid, 55.4% yield). LC-MS (ESI, m/z) 185.2[ 2 ], [ M + H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.06(s,1H),6.30(s,1H),5.97(s,1H),3.99-3.84(m,7H),2.54(s,6H).

Step 2: preparation of N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -2- ((3- (dimethylamino) azetidin-1-yl) methyl) acrylamide

6-amino-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinoline-3-carbonitrile (0.11g, 0, 25mmol) and 2- ((3- (dimethylamino) azetidin-1-yl) methyl) acrylic acid (0.10g, 0.5mmol) were dissolved in 1.5mL of DMSO, followed by DIEA (0.13ml, 0.75mmol). HOPO (0.03g, 0.28mmol) and EDCI (0.05g, 0.28mmol) were dissolved in 1.5ml DCM. The reaction was heated to 50 ℃ and stirred for 4 hours. The reaction mixture was concentrated, quenched with water (5 ml), extracted with ethyl acetate (5 ml _ 3), washed with brine (10ml _ 3), and dried over anhydrous sodium sulfate. The organic phase was subjected to rotary dry preparative high performance liquid chromatography (0.1% FA) to give the title compound (white solid, 121.00mg, yield 79.08%). LC-MS (ESI, m/z) 612.2[ 2 ], [ M + H ]] ⁺ ； ¹ H NMR(400MHz,MeOD-d ₄ )δ8.67(d,J＝4.8Hz,1H),8.62(s,1H),8.12-8.08(m,1H)7.84(d,J＝8.0Hz,1H),7.59-7.56(m,2H),7.40-7.25(m,4H),5.55(d,J＝8.0Hz,2H),5.42(s,2H),4.73(s,1H),4.62(S,1H),4.43-4.09(m,9H),2.83(s,6H)1.61(t,J＝7.2Hz,3H).

Preparation example 6

Preparation of N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -2- ((4- (dimethylamino) piperidin-1-yl) methyl) acrylamide (Compound A0906)

Step 1: preparation of 2- ((4- (dimethylamino) piperidin-1-yl) meth) acrylic acid

N, N-dimethylpiperidin-4-amine (0.40g, 2.00mmol) and 2- (bromomethyl) propene (0.33g, 2.00mmol) were dissolved in N, N-dimethylacetamide (20 mL), followed by the addition of DIEA (1ml, 6.0mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated and directly purified in reverse phase (0-20% acetonitrile) to give the desired product (white oil, 0.30g, 56.6% yield). LC-MS (ESI, m/z) 213.4[ 2 ], [ M + H ]] ⁺ ； ¹ H NMR(400MHz,MeOD-d ₁ )δ8.38(s,1H),6.27(s,1H),5.76(s,1H),3.69(s,2H),3.58-3.52(m,1H),3.45-3.30(m,4H),2.83-2.81(m,6H),2.30-2.20(m,4H).

And 2, step: preparation of N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -2- ((4- (dimethylamino) piperidin-1-yl) methyl) acrylamide

6-amino-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinoline-3-carbonitrile (0.09g, 0.20mmol) and 2- ((4- (dimethylamino) piperidin-1-yl) methyl) acrylic acid (0.06g, 0.30mmol) were dissolved in 1.0mL of DMSO, followed by the addition of DIEA (0.1mL, 0.6mmol). 2-hydroxypyridine-N-oxide (0.02g, 0.22mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.04g, 0.22mmol) were dissolved in 1.0ml of DCM. The reaction was heated to 50 ℃ and stirred for 4 hours. The reaction mixture was concentrated, quenched with water (5 ml), extracted with ethyl acetate (5 ml _ 3), washed with brine (10ml _ 3), and dried over anhydrous sodium sulfate. The organic phase was subjected to preparative high performance liquid chromatography (0.1% by weight of FA) to give the objective compound (white solid, 35.00mg, yield 79.08%). LC-MS (ESI, m/z) 640.2[ 2 ], [ M + H ]] ⁺ ；1H NMR(400MHz,MeOD-d ₄ )δ8.54(d,J＝4.8Hz,1H),8.51(s,1H),7.99-7.94(m,1H),7.72(d,J＝8.0Hz,1H),7.49(d,J＝2.4Hz,1H),7.46-7.43(m,1H),7.32-7.29(m,1H),7.20-7.14(m,4H),5.30(s,2H),5.27(s,1H),5.19(s,1H),4.64(s,1H),4.32-4.27(m,2H),4.20(s,1H),4.11(s,2H),3.41-3.34(m,1H),3.20(s,1H),2.77(s,6H),2.80(s,1H),2.02(s,2H),1.51-1.48(m,5H).

Effect example A inhibitor in vitro pharmacodynamic experiment

The experiment adopts CellTiter-Glo (CTG) kit, which is a cell viability detection method by a homogenization method, and cell viability of cultured cells is determined by quantifying ATP. The kit is a mainstream cell viability detection kit at present because of high sensitivity and simple operation process. The purpose of this experiment was to evaluate the effect of 6 test compounds on cell proliferation of 1 EGFR cell line using the CTG method, with afatinib as the control compound.

1) Experimental procedures

a) All cell lines were assayed at 37 ℃ and 5% CO ₂ Culturing under the condition of complete culture medium.

b) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability above 90%.

c) Cell density was adjusted using complete medium and then seeded in 96-well cell culture plates, with 90 μ L of each well for 3000 cells.

d) The cells in a 96 well plate were incubated at 37 ℃ and 5% CO ₂ Culturing under the condition.

e) 10-fold drug solution was prepared, tested to a maximum concentration of 1 μ M,9 concentrations, 4-fold dilutions, and then 10 μ L each of serially diluted compounds was transferred to corresponding assay wells of a 96-well cell plate, with three replicate wells per drug concentration.

f) The cells in the dosed 96-well plate were placed at 37 ℃ and 5% CO ₂ The culture was continued for 72 hours under the conditions, after which the CTG analysis was carried out.

g) The CTG reagents were thawed and the cell plates were equilibrated to room temperature for 30 minutes.

h) An equal volume of CTG solution was added to each well.

i) Cells were lysed by shaking on an orbital shaker for 5 minutes.

j) The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal.

k) And reading the cold light value and collecting data.

2) And (3) data analysis:

data were analyzed using GraphPad Prism 7.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom ₅₀ The value is obtained.

Cell survival rate (%) = (Lum) _{Drug to be tested} -Lum _{Culture fluid control} )/(Lum _{Solvent control} -Lum _{Culture fluid control} )×100％.

3) Anti-cell proliferation Effect of test Compounds

The method for measuring the moisture of the granular material or the composition is a common method for measuring the moisture by an infrared rapid moisture measuring instrument (measuring temperature is 105 ℃), which is well known by the technical personnel in the field and is widely applied to the moisture content measurement in granules, tablets, powder and the like. Neratinib maleate below is neratinib conjugated with 1 maleate.

Example 1

Neratinib maleate tablet size 40mg (as C) ₃₀ H ₂₉ ClN ₆ O ₃ Meter), the prescription is shown in table 1:

table 1 neratinib maleate tablets example 1 formulation

Following the above recipe, granulation was performed using a dry granulator according to the parameter settings in table 2.

TABLE 2 Dry granulation parameters

And continuously mixing the prepared granules with the extragranular components of the crospovidone XL-10 and the magnesium stearate, and pressing the mixture into tablets by a tablet press (10.5 mm x 5.5mm special-shaped stamping die), wherein the hardness is controlled to be 70-140N. Subsequently, these tablets were film-coated with 15w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol by using a high-performance coating machine so that the amount of coating in the tablets was 4.15mg. The X-ray powder diffraction pattern of the tablet is shown in figure 1.

During the coating process, the coating process was controlled according to the parameters of table 3. So that the maximum water content of the tablet in the coating process is controlled below 3 percent.

TABLE 3 coating Process parameter settings

Example 2

Neratinib maleate tablet prescription: specification 40mg (as C) ₃₀ H ₂₉ ClN ₆ O ₃ Meter) as shown in table 4.

Table 4 neratinib maleate tablet example 2 formula

Following the above recipe, granulation was performed using a dry granulator according to the parameter settings in table 5.

TABLE 5 Dry granulation parameters

The granules obtained were further mixed with magnesium stearate, an extragranular component, and the mixture was compressed into tablets by a tablet press (10.5 mm by 5.5mm special die) with hardness controlled to 70 to 140N. Subsequently, these tablets were film-coated with 15w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol by using a high-performance coating machine so that the amount of coating in the tablets was 4.15mg. The X-ray powder diffraction pattern of the tablet is shown in figure 2.

Example 3

Neratinib maleate tablet size 40mg (as C) ₃₀ H ₂₉ ClN ₆ O ₃ Meter) as shown in table 6.

TABLE 6 Nelatinib maleate tablets

Following the above recipe, granulation was performed using a dry granulator according to the parameter settings in table 7.

TABLE 7 Dry granulation parameters

The granules obtained were further mixed with magnesium stearate, an extragranular component, and the mixture was compressed into tablets by a tablet press (10.5 mm by 5.5mm special die) with hardness controlled to 70 to 140N. Subsequently, these tablets were film-coated with 15w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol by using a high-performance coating machine so that the amount of coating in the tablets was 4.15mg. The X-ray powder diffraction pattern of the tablet is shown in figure 3.

Example 4

Neratinib maleate tablet size 40mg (as C) ₃₀ H ₂₉ ClN ₆ O ₃ Meter), as shown in table 8 below.

Table 8 neratinib maleate tablets formula four:

following the above recipe, granulation was performed using a dry granulator according to the parameter settings in table 9 below.

Table 9 dry granulator parameters:

the granules obtained were further mixed with magnesium stearate, an extragranular component, and the mixture was compressed into tablets by a tablet press (10.5 mm by 5.5mm special die) with hardness controlled to 70 to 140N. Subsequently, these tablets were film-coated with 15w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol by using a high-performance coating machine so that the amount of coating in the tablets was 4.15mg. The X-ray powder diffraction pattern of the tablet is shown in FIG. 6.

Example 5:

the prescription process described in example 4 is put into a production workshop for scale-up production, the batch is scaled up from hundreds of pieces in laboratory scale to 10 thousands of pieces, and 3 batches are continuously produced, wherein the batch numbers are respectively scaled-up batch 1, scaled-up batch 2 and scaled-up batch 3. The recipe is given in table 10 below.

Table 10 neratinib maleate tablet formula five:

following the above recipe, granulation was performed using a dry granulator according to the parameter settings in table 11 below.

Table 11 dry granulator parameters:

the granules obtained were further mixed with magnesium stearate, an extragranular component, and the mixture was compressed into tablets by a tablet press (10.5 mm by 5.5mm shaped die) with a hardness controlled between 70 and 140N. Subsequently, these tablets were film-coated with 15w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol by using a high-performance coating machine so that the amount of coating in the tablets was 4.15mg. The X-ray powder diffraction pattern of the tablet is shown in figures 7-9.

During the coating process, the coating process was controlled according to the parameters of table 3. So that the maximum water content of the tablet in the coating process is controlled to be below 3 percent.

Effect embodiment:

pilot scale-up was performed on each of the neratinib maleate sheets of examples 1, 2 and 3. Pilot scale up was performed as in examples 1, 2, 3. These three batches of neratinib maleate tablets were compared to the reference formulation. For reference formulation, the primary drug of Puma Biotechnology neratinib maleate (coated tablet) was chosen.

Effect example 1: test of related substances

The substances of examples 1, 2 and 3 and the reference preparation in the first batch were tested and the results are shown in Table 12. The two batches of neratinib maleate tablets obtained in example 3 had less degradation impurity (impurity 1), total impurity than in the reference formulation.

TABLE 12 results of detection of related substances

Effect example 2: moisture and crystal form detection results

The moisture and crystal form of the first batch of the reference formulations of examples 1, 2 and 3 were tested and the test results are shown in table 13.

TABLE 13 moisture and Crystal form test results

Effect example 3: stability survey

Stability was released for the first batch of reference formulations, examples 1, 2 and 3, and the increase in degradation impurities was examined. The results are shown in Table 14.

TABLE 14 Neradinib maleate stability Studies with increasing degradation impurities

Acceleration of RH75% at 40 deg.C	Example 1	Example 2	Reference formulation
				0 month	0.12％	0.09％	0.98％
1 month	0.60％	0.57％	1.31％
				2 month	0.91％	0.81％	1.50％
3 month	1.11％	0.99％	1.61％
				6 month	1.34％	1.25％	1.77％

As seen from the above table, after accelerated 6 months, the degraded impurity content of examples 1, 2, 3 was less than that of the reference formulation and met the quality standard of 1.5% or less, whereas the reference formulation was out of compliance. It can be seen that the tablets of the invention have good stability.

Effect example 4: examination of dissolution curves

The dissolution curve was developed based on the determination of dissolution and release (second method of 0931 in the four-part general rules of the chinese pharmacopoeia 2020 edition).

The conditions for the dissolution profile were pH1.2, 500mL and 50rpm by the paddle method and pH3.0, 75rpm and 900mL by the paddle method. Sampling at each time point of 5-60 min, taking out appropriate amount of eluate, filtering, discarding at least 2ml of primary filtrate, and taking out the subsequent filtrate. Taking appropriate amount of neratinib maleate reference substance, precisely weighing, adding dissolution medium, ultrasonic dissolving, and diluting to obtain neratinib (based on C) contained in 1ml ₃₀ H ₂₉ ClN ₆ O ₃ Meter) 44 μ g of solution as a control solution. Performing high performance liquid chromatography (0512 of the four ministry of China pharmacopoeia 2020 edition) with octadecylsilane bonded silica gel as filler (Waters Xbridge C18,4.6mm × 150mm,5 μm or equivalent performance column is recommended); with 0.1% trifluoroacetic acid solution-methanol (67; the detection wavelength is 266nm; the column temperature was 40 ℃, the flow rate was 1.5ml/min, the run time was 10 minutes, and the injection volume was 10. Mu.l. Precisely measuring the test solution and the reference solution, injecting into a liquid chromatograph, and recording the chromatogram. Calculating the dissolution amount of each tablet at each time point by the external standard method according to the area of the neratinib peak, and comparing the f2 value of the first batch of the reference preparation by adopting a similarity factor comparison method.

In the formula, n is a time point, rt is the average percent of drug release of a reference preparation, and Tt is the average percent of drug release of a tested preparation. A f2 value of 50 or greater is considered to be similar in dissolution of the test formulation and the reference formulation. Specific dissolution data are shown in tables 15-16.

TABLE 15 dissolution data for each example in pH1.2 (50 rpm-500 mL) media

Time point/min	Reference formulation first batch	Example 1	Example 2	Example 3
					5	12	19	15	14
10	27	41	28	32
					15	45	59	39	47
20	64	72	52	60
					30	90	87	69	78
45	100	93	81	94
					60	100	95	90	99
Similarity factor f ₂ Value of	N/A	50	54	60

TABLE 16 dissolution data for each example at pH3.0 (75 rpm-900 mL) in media

Time point/min	Reference formulation first batch	Example 1	Example 2	Example 3
					5	6	7	9	4
10	22	20	24	15
					15	35	31	37	28
20	46	41	49	39
					30	60	56	66	58
45	68	73	78	77
					60	77	83	90	88
90	88	96	98	98
					120	90	N/A	N/A	N/A
Similarity factor f ₂ Value of	N/A	65	58	58

The products of the examples of the invention all showed similar dissolution behaviour (similarity factor f) as the reference formulation in dissolution curve tests with differentiated forces ₂ A value of 50 or more), has equivalent in vivo biological activity.

Effect example 5:

the total granulation of the neratinib maleate tablets of examples 1, 2 and 3 during the preparation process was examined and shown in tables 17, 18 and 19. The dissolution profiles of the first batch of examples 1, 2 and the reference formulation are shown in figure 5.

A +2.2S test method: taking 10 test samples, wherein the absolute value of the difference between the marked quantity and the measured mean value is represented by 100 as A, the standard deviation is S, and A +2.2S is less than or equal to 15.0, which indicates that the content uniformity of the product meets the requirement.

TABLE 17 examination of the mixing uniformity of the total mixed particles

TABLE 18 Sulfobenzhi weight difference and hardness test results

	Example 1	Example 2	Example 3
				Difference in tablet weight	<5％	<5％	<5％

Table 19 inspection results of various indexes of coated tablets

The results show that the total mixed particles obtained by the dry granulation process have uniform content and good mobile phase, and do not influence the compressibility and the mobile phase of the materials in the tabletting process.

Effect example 6:

the tablets prepared in example 4 were examined and the results are shown in Table 20.

Table 20 example 4 test results

As is clear from the above results, the respective indices of the tablets prepared in example 4 are equivalent to those of examples 1 to 3.

Effect example 7:

examine 3 lots produced at an enlarged scale in example 5. The production process was monitored and the results for particle size are shown in Table 21, the results for blend uniformity are shown in Table 22, and the results for sheet weight variation and hardness are shown in Table 23.

TABLE 21 particle size results

TABLE 22 blend uniformity results

TABLE 23 sheet weight variation and hardness results

The results show that 3 batches of the enlarged batches produced according to the invention have uniform particle size distribution and no obvious difference among 3 batches in the production process, the mixing uniformity of the particles meets the requirement, and the material is uniform and can be used for subsequent tabletting. In the tabletting process, the weight difference and the hardness of the tablets meet the requirements, which indicates that the compressibility of the material is good.

Effect example 8

The contents, related substances and moisture of the 3 batches of the product produced in the scale-up manner in example 5 were measured, and the results are shown in Table 24.

TABLE 24 content, related substances, moisture test results

The results show that the 3 batches of products produced according to the invention meet the requirements on related substances, moisture, content and the like, and have no obvious difference among the 3 batches, thus the products produced in an enlarged mode according to the invention have uniform and qualified quality.

Effect example 9

The stability of 3 batches of the formulation produced in the scale-up of example 5 was examined under accelerated (temperature 40 ℃. + -. 2 ℃, relative humidity 75% RH. + -.5% RH), long-term (temperature 25 ℃. + -. 2 ℃, relative humidity 60% RH. + -.5% RH), accelerated test sampling time points of 1, 2, 3 and 6 months, and long-term sampling time points of 3, 6, 9 and 12 months, respectively. The investigation indexes are related substances, contents, moisture, crystal forms and dissolution curves. For reference formulation, the primary drug of Puma Biotechnology neratinib maleate (coated tablet) was chosen.

The X-ray powder diffraction pattern of 3 amplified batches accelerated for 6 months is shown in figures 10-12, the X-ray powder diffraction pattern of 12 months for a long time is shown in figures 13-15, and the crystal form is not changed.

The dissolution curve results of three amplified batches directly prepared without accelerated experiments and long-term experiments are shown in figure 16, and compared with the second batch of the reference preparation, the dissolution curve results of the three batches are similar to the reference, which shows that the product produced according to the description has similarity to the reference quality.

The dissolution curve of 3 batches of amplified batches accelerated for 6 months is shown in figure 17, the dissolution curve of 12 months for a long time is shown in figure 18, and the dissolution curves are synchronously compared with the dissolution curve of a second batch of a reference preparation, so that the dissolution characteristics of 3 batches of products are unchanged and are similar to the reference preparation.

The stability results of the substances, contents, moisture in the accelerated stability test and the long-term stability test of 3 scaled-up batches are shown in tables 25-30, and are simultaneously compared with the stability results of a second batch of the reference formulation (tables 31-32).

Table 25 amplification of batch 1 accelerated stability results

Table 26 scale-up batch 2 accelerated stability results

Table 27 scale-up batch 3 accelerated stability results

Table 28 scale-up batch 1 long term stability results

Table 29 scale-up batch 2 long term stability results

Table 30 scale-up batch 3 long term stability results

Table 31 accelerated stability results for the reference formulation

Table 32 long term stability results for reference formulations

The results show that 3 batches of the preparation produced in large scale according to the invention have good stability, small batch-to-batch difference and uniform quality. Compared to the reference formulation, the impurities are smaller than the reference formulation.

Comparative examples 1 to 5 and effects comparative examples 1 to 5:

the kind or content of the binder in table 33 below was substituted for copovidone or its content in example 1, and the others were the same as in example 1. The obtained product was tested for dissolution by the method of effect example 4, and the test results are shown in tables 34 and 35. The reference formulation was a third batch of Puma Biotechnology neratinib maleate prodrug (coated tablet).

TABLE 33 Binder screening type and amount information

TABLE 34 results of dissolution profile in medium at pH1.2 (50 rpm-500 mL)

Time point/min	Reference formulation third batch	1	2	3	4	5
							5	14	12	9	13	56	13
10	28	22	22	24	76	27
							15	43	30	35	35	81	42
20	60	38	48	45	84	51
							30	85	52	69	59	87	65
45	98	68	88	72	90	75
							60	98	78	94	80	93	81
f2 value	/	36	49	43	23	50

TABLE 35 pH3.0 (70 rpm-900 mL) media dissolution Profile results

Time point/min	Reference formulation third batch	1	2	3	4	5
							5	6	13	15	14	87	55
10	22	32	58	31	93	93
							15	35	49	72	51	94	99
20	46	67	82	69	94	100
							30	60	95	89	90	95	99
45	68	92	94	94	95	98
							60	77	99	96	93	95	98
90	88	99	97	/	/	100
							120	90	99	97	/	/	/
f2 value	/	32	24	32	10	12

From the screening results, the dissolution curves of the samples prepared by using 3.0% and 6.5% of copovidone S630, 15% of hydroxypropyl cellulose HPC-L, 8% of povidone K25 and 8% of hydroxypropyl cellulose are not similar to those of the reference preparation, and the risk of bioequivalence in the original research body is high.

Biological examples

(A009 is neratinib maleate; CVL218 is a compound of patent CN 103242273B)

CVL237 is a compound

1. In vitro anti-proliferation experiment of PDX model LD1-0060-200791 of bile duct cancer.

Tumor tissues were harvested from tumor-bearing mice by subcutaneous surgery and immersed in HBSS buffer. Removing non-tumor tissue and necrotic tissue from the biosafety cabinet, cutting the tissue into pieces of 1-3 cubic millimeters, digesting the tumor with collagenase at 37 ℃The blocks were for 1-2 hours. The single cell suspension was collected through a screen. The supernatant was removed by centrifugation at 1200rpm for 3 minutes. The cells were resuspended and counted using serum-free medium, adjusted to a cell concentration of 1.11X 10 ⁵ and/mL. The 1000 Xhigh concentration drug stock solutions were diluted to 20 Xintermediate concentrations using BIO-MPM-1 medium, respectively. Each 96-well plate was loaded with 7.5. Mu.L of 20X drug at various concentrations or 2% DMSO in BIO-MPM-1 (specific concentration settings are shown in the following table) to give a final DMSO concentration of 0.2% per well. Adding 135 mu L of cell suspension into each hole to detect the ATP content of the cells before culture, continuously culturing for 6 days in a cell culture box at 37 ℃, adding 50 mu L of CTG reagent into each hole, uniformly mixing, reacting, and taking 80 mu L of the CTG reagent to detect the ATP content in a multifunctional enzyme-linked immunosorbent assay. Recording the signal of each hole by a plate reader for drawing an inhibition curve and calculating related parameters such as IC ₅₀ . The anti-tumor proliferation inhibition rate corresponding to each drug concentration is calculated by using Excel software, and the formula is as follows:

inhibition (%) = ((VControl-VBlank) - (V drug treatment group-VBlank))/(VControl-VBlank) × 100%

The inhibition plots were plotted using Xlfit (IDBS) and the corresponding parameters (maximum inhibition, minimum inhibition, absolute IC) were calculated ₅₀ Opposite IC ₅₀ Sum slope)

Proliferation rate (fold of proliferation) = (V) _day6 Control-V _day6 Blank)/(V _day0 Control-V _day0 Blank)

The concentration settings are as follows in table 36:

watch 36

Compound (I)	Range of concentration
		CVL218	0.23～30μM
CVL237	0.23～15μM
		A009	0.23～15μM
CVL218+A009	0.05～15μM
		CVL237+A009	0.05～15μM

The in vitro antiproliferative assay data are shown in table 37:

watch 37

In vitro anti-proliferation assay of EGFR-G719X/E709X mutation in Ba/F3 engineered cells.

The experiment adopts CellTiter-Glo (CTG) kit, which is a cell viability detection method by a homogenization method, and cell viability of cultured cells is determined by quantifying ATP. The kit is a mainstream cell viability detection kit at present due to high sensitivity and simple operation process. The purpose of this experiment was to evaluate the effect of 1 test compound on cell proliferation of 5 EGFR cell lines using CTG method, with afatinib as control compound.

The test steps are as follows:

a) All cell lines were cultured in complete medium at 37 ℃ and 5% CO2.

d) The cells in the 96-well plate were cultured at 37 ℃ in 5% CO2.

e) 10-fold drug solution was prepared, the highest concentration tested was 10 μ M,9 concentrations, 3.16-fold dilution, and then 10 μ L each of the serially diluted compounds was transferred to corresponding experimental wells of a 96-well cell plate, with three replicate wells per drug concentration.

f) The cells in the dosed 96-well plate were placed under 37 ℃ C.and 5% CO2 conditions for further culture for 72 hours, after which CTG analysis was performed.

h) An equal volume of CTG solution was added to each well.

i) Cells were lysed by shaking on an orbital shaker for 5 minutes.

k) And reading the cold light value and collecting data.

And (3) data analysis:

Cell survival rate (%) = (Lum test drug-Lum culture solution control)/(Lum solvent control-Lum culture solution control) × 100%.

The anti-cell proliferation activity of the test compounds is given in the following table:

(the cell lines in Table 38 below are all rare types of mutations for non-small cell lung cancer)

Watch 38

In vivo anti-tumor experiments in EGFR-G719S allogenic models of Ba/F3 engineered cells.

Recovering Ba/F3-EGFR-G719S cell, in vitro culturing to obtain 8X 10 ⁷ A cell. The mice were injected with 1mL solution after eliminating the hairs of the inoculated part and disinfecting the inoculated part with iodophor cotton ballsThe mice were inoculated subcutaneously on the right shoulder with 0.1mL of cell suspension, 2X 10 ⁶ Cells/spot. When the mean tumor volume reached about 100mm ³ Randomly divided into 5 groups by tumor volume and body weight, 8 per group: vehicle control group, 20, 40, 80mg/kg A009 group, 40mg/kg Afatinib group. The experimental animal body weight and tumor volume were measured once a week after inoculation and before grouping. After the vaccination group, animal body weights and tumor volumes were measured 3 times per week. The length and length of the tumor were measured with a vernier caliper using the formula TV =1/2 × a × b ² Tumor volume was calculated. Where a is the major diameter of the tumor and b is the minor diameter of the tumor. The anti-tumor activity indexes include:

relative tumor proliferation rate% Δ T/C = (mean (T) -mean (T0))/(mean (C) -mean (C0)). 100%;

tumor inhibition ratio TGI% = ((mean (C) -mean (C0)) - (mean (T) -mean (T0)))/(mean (C) -mean (C0))) 100%

Wherein T-dose group tumor volume, T0-dose group initial tumor volume, C-control group tumor volume, C0-control group initial tumor volume.

Body weight and tumor volume data are expressed as Mean + standard error (Mean + SEM). All data were statistically analyzed using Graphpad prism 6. For pairwise comparison, a T-Test analysis method is adopted; for more than three comparisons between groups, two-Way analysis of variance (Two-Way ANOVA), and Bonferroni's test were used. P < 0.05 was considered to be significantly different.

The body weight change curves and tumor volume changes of the mice in each group are shown in FIGS. 19 and 20. A009 can inhibit Ba/F3-EGFR-G719S cell proliferation in a dose-dependent manner, and can cause tumor regression at high and high dose, which indicates that the potential of treating G719X rare mutant non-small cell lung cancer (NSCLC) is provided; the anti-tumor effect under the same dosage is similar to that of Afatinib, but the overall safety is better than that of Afatinib.

In fig. 19 and 20, QD indicates once daily dosing; Q2D indicates dosing once every two days.

Claims

1. A compound shown as a formula I is provided,

each R ^1-a Each independently is halogen or-N (C) _1-6 Alkyl radical) ₂ 。

2. A compound of formula I according to claim 1, which satisfies one or more of the following conditions:

(1) Each R ^1-1 Each independently by one or more R ^1-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms, or-SO ₂ -C _1-6 An alkyl group;

(2) Said R is ¹ 、R ² 、R ³ 、R ^1-1 And R ^1-a Said is "substituted by one or more R ^1-1 Substituted C _1-6 Alkyl ", said" -SO ₂ -C _1-6 Alkyl "and said" -N (C) _1-6 Alkyl radical) ₂ "C in _1-6 Alkyl is independently from each other methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; preferably methyl;

(3) The R is ^1-1 Wherein said "heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms" and said "substituted with one or more R ^1-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of the heteroatom is 1, 2 or 3, the heteroatom number is 4-6-membered heteroThe "hetero atoms" in the cycloalkyl group "are selected from 1, 2 or 3 of N, O and S, and the 4-6 membered heterocycloalkyl group having 1, 2 or 3 hetero atoms is independently a 4-6 membered heterocycloalkyl group having 1 hetero atom as N; preference is given to

(4) The R is ^1-a Wherein said halogen is fluorine, chlorine, bromine or iodine; fluorine is preferred.

3. A compound of formula I according to claim 1, which satisfies any one of the following conditions:

(1)R ² and R ³ Is H, R ¹ Is represented by one or more R ^1-1 Substituted C _1-6 An alkyl group; preferably R ² And R ³ Is H, R ¹ Is composed of

(2)R ¹ And R ² Is H, R ³ Is represented by one or more R ^1-1 Substituted C _1-6 An alkyl group; preferably R ¹ And R ² Is H, R ³ Is composed of

4. The compound of formula I according to claim 1, wherein the compound of formula I is any one of the following compounds:

5. a pharmaceutical composition 1 comprising a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutical excipient.

6. A pharmaceutical composition 2 comprising a particulate material, said particulate material comprising the following components in mass fractions: 30-45% of a compound shown as a formula II or pharmaceutically acceptable salt thereof, 7-28% of copovidone, 25-48% of a filling agent, 1.0-8.0% of a disintegrating agent, 0.5-4.0% of a glidant and 0.5-4.0% of a lubricant;

the sum of the mass fractions of all the components in the particulate matter is 100%; the mass fraction is the mass percentage of the mass of each component in the particulate matter in the total mass of each component;

each R ^4-1 Are each independently-N (C) _1-6 Alkyl radical) ₂ And 1, 2 or 3 heteroatoms selected from N, O and S, the number of the heteroatoms is 1, 2 or 3 ", 4-6 membered heterocycloalkyl substituted with one or more R ^4-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms, or-SO ₂ -C _1-6 An alkyl group;

each R ^4-a Each independently is halogen or-N (C) _1-6 Alkyl radical) ₂ 。

7. The pharmaceutical composition 2 according to claim 6, which satisfies one or more of the following conditions:

(1) Each R ^4-1 Are each independently-N (C) _1-6 Alkyl radical) ₂ By one or more R ^4-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms, or-SO ₂ -C _1-6 An alkyl group;

(2) The R is ⁴ 、R ⁵ 、R ⁶ 、R ^4-1 And R ^4-a Said is "substituted by one or more R ^4-1 Substituted C _1-6 Alkyl', said "-SO ₂ -C _1-6 Alkyl "and said" -N (C) _1-6 Alkyl radical) ₂ "C in _1-6 Alkyl is independently from each other methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; preferably methyl;

(3) The R is ^4-1 Wherein said "heteroatom is selected from 1, 2 or 3 of N, O and S, 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms" and said "substituted with one or more R ^4-a The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom in the 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms is selected from 1, 2 or 3 of N, O and S, the 4-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms is independently N, and the heteroatom number is 1; preference is given to

(4) The R is ^4-a Wherein said halogen is fluorine, chlorine, bromine or iodine; preferably fluorine.

8. The pharmaceutical composition 2 according to claim 6, which satisfies one or more of the following conditions:

(1)R ⁵ and R ⁶ Is H, R ⁴ Is represented by one or more R ^4-1 Substituted C _1-6 An alkyl group; preferably R ⁵ And R ⁶ Is H, R ⁴ Is composed of

(2)R ⁴ And R ⁶ Is H, R ⁵ Is represented by one or more R ^4-1 Substituted C _1-6 An alkyl group; preferably R ⁴ And R ⁶ Is H, R ⁵ Is composed of

9. The pharmaceutical composition 2 according to claim 6, wherein the compound of formula II is any one of the following compounds:

10. the pharmaceutical composition 2 according to claim 6, which satisfies one or more of the following conditions:

(1) In the pharmaceutical composition, the pharmaceutically acceptable salt is a maleate salt of the compound shown as the formula II;

(2) In the pharmaceutical composition, the mass fraction of the compound shown in the formula II or the pharmaceutically acceptable salt thereof is 35-42%; preferably 36%;

(3) In the pharmaceutical composition, the mass fraction of the copovidone is 8-22%; preferably 21%;

(4) In the pharmaceutical composition, the filler is sugar alcohol and/or water-swelling additive; preferably mannitol and microcrystalline cellulose;

(5) In the pharmaceutical composition, the mass fraction of the filler is 34-45%; preferably 37%;

(6) In the pharmaceutical composition, the disintegrating agent is one or more of adipic acid, alginic acid, gelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydrated silicon dioxide, calcium citrate, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, corn starch, tragacanth powder, potato starch, hydroxyethyl methyl cellulose, hydroxypropyl starch, pregelatinized starch, monosodium fumarate, povidone, anhydrous citric acid, methyl cellulose and calcium dihydrogen phosphate; preferably crospovidone, more preferably crospovidone XL-10;

(7) In the pharmaceutical composition, the mass fraction of the disintegrant is 1.7-4.9%; preferably 2.0%;

(8) In the pharmaceutical composition, the glidant is one or more of colloidal silicon dioxide, gel silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talcum powder, corn starch and magnesium aluminum metasilicate; preferably colloidal silica or gel silica;

(9) The mass fraction of the glidant is 1.0-4.0%; preferably 2.0%;

(10) In the pharmaceutical composition, the lubricant is one or more of cocoa fat, carnauba wax, hydrated silicon dioxide (colloidal silicon dioxide), aluminum hydroxide xerogel, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium fumarate stearate, stearyl alcohol and polyethylene glycol 40 stearate; preferably sodium stearyl fumarate or magnesium stearate;

(11) In the pharmaceutical composition, the mass fraction of the lubricant can be 1.0-4.0%; preferably 2%;

(12) In the pharmaceutical composition, the pharmaceutically acceptable salt thereof exists in an anhydrous crystalline form or an amorphous form; preferably in the form of the anhydrous crystalline form.

11. The pharmaceutical composition 2 according to claim 6, comprising granules comprising the following components in mass fraction: 30-45% of anhydrous neratinib maleate, 7-28% of copovidone, 25-48% of filler, 1.0-8.0% of disintegrant, 0.5-4.0% of glidant and 0.5-4.0% of lubricant; the sum of the mass fractions of all the components in the particles is 100%.

12. The pharmaceutical composition 2 according to claim 11, wherein one or more of the following conditions are met:

(1) In the pharmaceutical composition 2, the anhydrous neratinib maleate is a crystal form of the anhydrous neratinib maleate, and an X-ray powder diffraction pattern represented by a diffraction angle of 2 theta has characteristic peaks at 6.0 +/-0.2 °, 7.3 +/-0.2 °, 10.1 +/-0.2 °, 12.1 +/-0.2 °, 15.6 +/-0.2 °, 17.3 +/-0.2 ° and 19.9 +/-0.2 °; preferably said crystalline form of neratinib maleate has an X-ray powder diffraction pattern substantially as shown in figure 1, 2 or 3;

(2) In the pharmaceutical composition 2, the anhydrous neratinib maleate has a mass fraction of 35-42%; preferably 36%;

(3) In the pharmaceutical composition 2, the mass fraction of the copovidone is 8-22%; preferably 21%;

(4) In the pharmaceutical composition 2, the filler is sugar alcohol and/or a water-swelling additive; preferably mannitol and microcrystalline cellulose;

(5) In the pharmaceutical composition 2, the mass fraction of the filler is 34-45%; preferably 37%;

(6) In the pharmaceutical composition 2, the disintegrating agent is one or more of adipic acid, alginic acid, gelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydrated silicon dioxide, calcium citrate, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, corn starch, tragacanth powder, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, pregelatinized starch, monosodium fumarate, povidone, anhydrous citric acid, methylcellulose, and calcium dihydrogen phosphate; preferably crospovidone, more preferably crospovidone XL-10;

(7) In the pharmaceutical composition 2, the mass fraction of the disintegrant is 1.7-4.9%; preferably 2.0%;

(8) In the pharmaceutical composition 2, the glidant is one or more of colloidal silicon dioxide, gel silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talcum powder, corn starch and magnesium aluminum metasilicate; preferably colloidal silica or gel silica;

(9) The mass fraction of the glidant is 1.0-4.0%; preferably 2.0%;

(10) In the pharmaceutical composition 2, the lubricant is one or more of cocoa fat, carnauba wax, hydrated silicon dioxide (colloidal silicon dioxide), aluminum hydroxide xerogel, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium fumarate stearate, stearyl alcohol and polyethylene glycol 40 stearate; preferably sodium stearyl fumarate or magnesium stearate;

(11) In the pharmaceutical composition 2, the mass fraction of the lubricant can be 1.0-4.0%, preferably 2%;

(12) The pharmaceutical composition 2 further comprises a coating agent; the coating agent is preferably one or more of hydroxypropyl methylcellulose, ethylcellulose, methylcellulose or hydroxypropyl cellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer dispersoid, sucrose, mannitol and Opadry, and more preferably Opadry; the mass ratio of the coating agent to the drug particles is preferably 0.01.

13. The pharmaceutical composition 2 according to claim 11, wherein the pharmaceutical composition 2 satisfies one or more of the following conditions: in the pharmaceutical composition 2, the components of the granules comprise an inner component of the granules and an outer component of the granules;

the inner component of the particulate matter: 30-45% of anhydrous neratinib maleate, 7-28% of copovidone, 25-48% of filler, 1.0-8.0% of disintegrant, 1.0-4.0% of glidant and 0.5-4.0% of lubricant;

the external component of the particulate matter: 0-2.5% of disintegrant and/or 0-1% of lubricant, and the disintegrant and the lubricant are not 0 at the same time;

the external component of the particulate matter: 1.0% magnesium stearate;

group (3): the inner component of the particulate matter: 36.1% anhydrous neratinib maleate, 27.1% mannitol, 8.6% microcrystalline cellulose, 22.4% copovidone, 1.7% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 1.0% magnesium stearate.

14. The pharmaceutical composition 2 of claim 13, wherein the pharmaceutical composition 2 consists of the following components of group (a), group (b), or group (c):

group (a): the mass ratio of the particle material to the Opadry is 0.03:1;

group (b): the mass ratio of the particle material to the Opadry is 0.034:1;

the inner component of the particulate matter: 42.3% anhydrous neratinib maleate, 31.7% dry dew alcohol, 13.1% microcrystalline cellulose, 8.0% copovidone, 2.0% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 1.0% magnesium stearate;

group (c): the mass ratio of the particle material to the Opadry is 0.036:1;

the inner component of the particulate matter: 36.1% anhydrous neratinib maleate, 27.1% dry dew alcohol, 8.6% microcrystalline cellulose, 22.4% copovidone, 1.7% crospovidone XL-10, 2.0% colloidal silicon dioxide, and 1.0% magnesium stearate;

the external component of the particulate matter: 1.0% magnesium stearate.

15. A process for the preparation of a pharmaceutical composition 2 according to any one of claims 11 to 14, comprising the steps of: granulating the following raw materials in parts by mass to obtain particles;

16. The method of claim 15, wherein the pharmaceutical composition 2 is prepared by a method that satisfies one or more of the following conditions:

(1) The neratinib maleate is anhydrous neratinib maleate, and the type and the content of the anhydrous neratinib maleate are as defined in any one of claims 11-14;

(2) The copovidone, the filler, the disintegrant, the glidant and the lubricant are all as described in any one of claims 11 to 14;

(3) The granulation method is dry granulation, and the dry granulation adopts a dry granulator.

17. The method of claim 16, wherein the pharmaceutical composition 2 is prepared by a method that satisfies one or more of the following conditions:

(1) The pressure of the compression roller of the dry granulator is 65-100bar, such as 80bar;

(2) The feeding speed of the dry-type granulator is preferably 40-50rpm;

(3) The press roll speed of the dry granulator is preferably 5-15rpm, for example 6rpm;

(4) The granulating speed of the dry granulator is preferably 50-500rpm, such as 100rpm;

(5) The preparation method of the pharmaceutical composition 2 further comprises a coating step; in the coating step, a coating machine is adopted for coating, and the parameters of the coating machine are as follows: the air inlet temperature of the coating machine is preferably 55-60 ℃; the atomization pressure of the coating machine is preferably 0.10-0.30MPa; the rotating speed of a peristaltic pump of the coating machine is preferably 2.0-12.0rpm; the air outlet temperature of the coating machine is preferably 35-42 ℃.

18. The method of preparing the pharmaceutical composition 2 according to claim 15, wherein the method of preparing the pharmaceutical composition 2 comprises the steps of:

step 2: tabletting the particles 1 and the outer material of the particles to obtain the particles:

19. A pharmaceutical composition 2 obtained by a process for the preparation of a pharmaceutical composition 2 according to any one of claims 11 to 14.

20. A pharmaceutical solid formulation comprising the pharmaceutical composition 2 of any one of claims 11-14 and 19 and a pharmaceutically acceptable excipient.

21. Use of substance a, which is a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, pharmaceutical composition 2 according to any one of claims 11 to 14 and 19 or a pharmaceutical solid preparation according to claim 20, for the manufacture of an EGFR inhibitor or a medicament for preventing or treating diseases associated with EGFR.

22. A pharmaceutical composition 3 comprising substance X and substance Y;

23. a pharmaceutical composition 4 comprising substance M and substance N;

24. use of the pharmaceutical composition 3 according to claim 22 or the pharmaceutical composition 4 according to claim 23 for the preparation of a medicament for the prevention or treatment of cholangiocarcinoma.