阅读说明：本技术 一种fgfr4抑制剂的制剂组合物、制备方法及其用途 (FGFR4 inhibitor preparation composition, preparation method and application thereof ) 是由 霍志强 黄巧萍 姜玉岗 柏小娟 唐睿 戴信敏 于 2020-12-29 设计创作，主要内容包括：本发明属于药物领域,尤其涉及一种FGFR4抑制剂的制剂组合物、制备方法及其用途,以所述FGFR4抑制剂的制剂组合物的总质量为100％计,所述FGFR4抑制剂的制剂组合物的质量百分含量的成分为：活性成分1-15％,药学上可接受的辅料85％～99％,所述活性成分为具有式I结构的化合物或其药学上可接受的盐：本发明开发了一种以具有式Ⅰ结构的化合物或其药学上可接受的盐为活性成分的FGFR4抑制剂的制剂组合物,具有良好的抗癌药物耐药性能,有助于提高癌症的治疗水平。(The invention belongs to the field of medicines, and particularly relates to a preparation composition of an FGFR4 inhibitor, a preparation method and application thereof, wherein the total mass of the preparation composition of the FGFR4 inhibitor is 100%, and the preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass: 1-15% of active ingredient and 85-99% of pharmaceutically acceptable auxiliary materials, wherein the active ingredient is a compound with a structure shown in formula I or pharmaceutically acceptable salt thereof:)

1. The preparation composition of the FGFR4 inhibitor is characterized by comprising the following components in percentage by mass based on 100% of the total mass of the preparation composition of the FGFR4 inhibitor:

1-15% of active ingredients;

85-99% of pharmaceutically acceptable auxiliary materials;

the active ingredient is a compound having the structure of formula I:

wherein R is₁Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group, R₂Represents H, F, Cl, Br, MeO, CN, CONH₂And n is 1 or 2.

2. The formulation composition of FGFR4 inhibitor according to claim 1, wherein the active ingredient is at least one of the following compounds:

3. the preparation composition of the FGFR4 inhibitor according to claim 1 or 2, wherein the preparation composition comprises the following components in percentage by mass based on 100% of the total mass of the preparation composition:

4. the formulation composition of claim 3, wherein the filler comprises at least one of pregelatinized starch, microcrystalline cellulose, starch, and lactose.

5. The formulation composition of FGFR4 inhibitor according to claim 3, wherein the disintegrant comprises at least one of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose.

6. The formulation composition of FGFR4 inhibitor according to claim 3, wherein the binder comprises at least one of hydroxypropyl cellulose, hypromellose, povidone, and gelatin.

7. The formulation composition of an FGFR4 inhibitor according to claim 3, wherein the lubricant comprises at least one of sodium stearyl fumarate, magnesium stearate, aerosil and talc.

8. The formulation composition of FGFR4 inhibitor according to any one of claims 1 or 2, wherein the formulation composition is a plain tablet, a dispersible tablet, a chewable tablet, a dry suspension, a granule, a coated formulation or a capsule.

9. A method of preparing a formulated composition of FGFR4 inhibitor according to any of claims 1 or 2, comprising the steps of:

crushing the active ingredients, and sieving with a sieve with a first mesh number to obtain the active ingredients meeting the requirement of particle size;

weighing the active ingredients meeting the particle size requirement and pharmaceutically acceptable auxiliary materials according to the formula ratio, and uniformly mixing to obtain a first mixture;

compressing the first mixture into a tablet or granulate to obtain a formulation composition of the FGFR4 inhibitor.

10. Use of a formulated composition of an FGFR4 inhibitor according to any one of claims 1 or 2 for the preparation of a medicament for the prevention and/or treatment of tumors.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a preparation composition of an FGFR4 inhibitor, a preparation method and application thereof.

Background

Cancer is one of the major diseases threatening human health, and the main treatment modalities of cancer at present include drug therapy, surgical therapy, radiation therapy, etc., wherein drug therapy is one of the most common treatment modalities. The traditional cytotoxic drugs can not distinguish tumor cells from normal cells, so that serious side effects are often caused, and the targeted drugs take the tumor cells as specific targets, can accurately act on tumors, can greatly improve the treatment level of cancers and can effectively reduce the adverse reaction rate.

FGFR (Fibroblast Growth Factors) belongs to Receptor protein tyrosine kinase, and the family mainly comprises FGFR1, FGFR2, FGFR3 and FGFR 4. FGFR participates in many processes such as cell proliferation, apoptosis, migration, and neovascularization. Researches find that FGFR activation is related to liver cancer, bladder cancer, lung cancer, breast cancer and the like, and plays an important role in the processes of tumor angiogenesis, tumor invasion and metastasis and the like, so that FGFR can be used as an important target for tumor treatment.

FGFR4 is a member of the FGFR receptor family, and forms dimers on the cell membrane by binding to fibroblast growth factor 19(FGF19), a ligand of these dimers, which causes phosphorylation of key tyrosine residues within the FGFR4 itself, thereby activating multiple downstream signaling pathways within the cell that play important roles in cell proliferation, survival, and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant tumor invasion. Decreasing and decreasing FGFR4 expression reduces cell proliferation and promotes apoptosis. Recent studies have shown that about one-third of the FGF19/FGFR4 signaling pathways in liver cancer patients are continuously activated and are the main carcinogenic factor in liver cancer development in this subset of patients. Meanwhile, the expression or high expression of the FGFR4 is closely related to other tumors, such as gastric cancer, prostatic cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.

Therefore, the inhibition effect on FGFR4 is improved, the treatment level of cancer is improved, and the adverse reaction rate of cancer is effectively reduced, so that the drug resistance of the existing anticancer drug is improved, and the targeting effect of the drug is improved.

Disclosure of Invention

The invention provides a preparation composition of an FGFR4 inhibitor, a preparation method and application thereof, which are beneficial to improving the treatment level of cancer and effectively reducing the adverse reaction rate of the cancer, thereby solving the problem of drug resistance of the existing anticancer drugs and improving the targeting effect of the drugs.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the invention provides a preparation composition of an FGFR4 inhibitor, wherein the preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass based on the total mass of the preparation composition of the FGFR4 inhibitor as 100 percent:

1-15% of active ingredients;

85-99% of pharmaceutically acceptable auxiliary materials;

the active ingredient is a compound having the structure of formula I:

wherein R is₁Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group, R₂Represents H, F, Cl, Br, MeO, CN, CONH₂And n is 1 or 2.

It should be noted that: (1) "phenyl" refers to a group having a benzene ring as a functional group. (2) "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. When the ring-constituting atoms contain at least one hetero atom in addition to carbon atoms, an aromatic heterocyclic group is used. (3) "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, malonic acid, or the like; preferably hydrochloric acid or (L) -malic acid; or when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base, a salt is formed; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

In one embodiment, the active ingredient is at least one of the following compounds:

in one embodiment, the preparation composition comprises the following components in percentage by mass based on 100% of the total mass of the preparation composition:

in one embodiment, the filler comprises at least one of pregelatinized starch, microcrystalline cellulose, starch, and lactose.

In one embodiment, the disintegrant comprises at least one of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose.

In one embodiment, the binder comprises at least one of hydroxypropyl cellulose, hypromellose, povidone, and gelatin.

In one embodiment, the lubricant comprises at least one of sodium stearyl fumarate, magnesium stearate, aerosil and talc.

In one embodiment, the formulation composition is a general tablet, a dispersible tablet, a chewable tablet, a dry suspension, a granule, a coated formulation or a capsule.

In a second aspect, the invention also provides a preparation method of the preparation composition of the FGFR4 inhibitor, which comprises the following steps:

crushing the active ingredients, and sieving with a sieve with a first mesh number to obtain the active ingredients meeting the requirement of particle size;

weighing the active ingredients meeting the particle size requirement and pharmaceutically acceptable auxiliary materials according to the formula ratio, and uniformly mixing to obtain a first mixture;

compressing the first mixture into a tablet or granulate to obtain a formulation composition of the FGFR4 inhibitor.

In a third aspect, the invention provides a use of the preparation composition of the FGFR4 inhibitor in the first aspect for preparing a medicament for preventing and/or treating tumors and/or viral diseases.

The invention discloses a preparation composition of an FGFR4 inhibitor, which takes a compound with a structure as shown in formula I or a pharmaceutically acceptable salt thereof as an active ingredient. The active ingredient is an FGFR4 inhibitor, has good FGFR4 activity inhibition capability, and is beneficial to improving the treatment effect of the medicament on cancer, reducing the adverse reaction rate of cancer and the targeting effect of the medicament, so the preparation composition has good anti-cancer medicament resistance and medicament targeting effect.

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

In a first aspect, the invention provides a preparation composition of an FGFR4 inhibitor, wherein the preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass based on the total mass of the preparation composition of the FGFR4 inhibitor as 100 percent:

1-15% of active ingredients;

85-99% of pharmaceutically acceptable auxiliary materials;

the active ingredient is a compound having the structure of formula I:

wherein R is₁Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group, R₂Represents H, F, Cl, Br, MeO, CN, CONH₂And n is 1 or 2.

The compound with the structure shown in the formula I or the pharmaceutically acceptable salt compound thereof is an FGFR4 inhibitor, has good FGFR4 activity inhibition capability, and is favorable for improving the treatment effect of the medicament on cancer, reducing the adverse reaction rate of the cancer and the targeting effect of the medicament. Therefore, the FGFR4 inhibitor preparation composition taking the compound with the structure of formula I or the pharmaceutically acceptable salt thereof as an active ingredient has good anticancer drug resistance and drug targeting effect.

Further, the active ingredient is at least one of the following compounds:

further, the preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass based on 100% of the total mass of the preparation composition:

further, the filler includes at least one of pregelatinized starch, microcrystalline cellulose, starch, and lactose, and the filler may be used to fill the weight or volume of the tablet to facilitate tableting.

Further, the disintegrating agent comprises at least one of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose, and can enable the tablet to be rapidly cracked into fine particles in gastrointestinal fluid, so that the functional ingredients are rapidly dissolved and absorbed to play a role of medicine, and meanwhile, the disintegrating agent can play a role in increasing the weight and the volume of the preparation.

Further, the adhesive comprises at least one of hydroxypropyl cellulose, hypromellose, povidone and gelatin, and has the functions of connecting active ingredients, a filling agent and a disintegrating agent, so that the granulation and the molding are facilitated.

Further, the lubricant comprises at least one of sodium stearyl fumarate, magnesium stearate, aerosil and talc.

Further, the preparation composition of the FGFR4 inhibitor is a common tablet, a dispersible tablet, a chewable tablet, a dry suspension, a granule or a capsule. The preparation composition provided by the embodiment of the invention can be prepared into different dosage forms according to clinical needs, such as common tablets, dispersible tablets, chewable tablets, dry suspensions, granules, coating preparations or capsules, and the like, and the active ingredients represented by the formula I can be contained in proper amount according to the use purpose, object, property and the like of the preparation composition.

Typical routes of administration of the formulation compositions of the embodiments of the present invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.

The pharmaceutically effective amount and the administration method or means of administration of the pharmaceutical composition of the embodiment of the present invention can be appropriately selected by those skilled in the art according to the severity of symptoms, the treatment regimen, the age, weight, sex, general health of the patient, and the background of the (genetic) race of the patient, and conventional methods in the art can be used for the preparation of the pharmaceutical composition. For example, when preparing a common tablet, a direct tabletting method can be adopted, namely, all the components are mixed and then tabletted; optionally granulating all the components and tabletting; optionally, a part of the ingredients can be granulated and mixed with the rest ingredients for tabletting. In addition, tablets may be coated by methods commonly used in the art.

Further, the preparation method of the active ingredient comprises the following steps:

(1) synthesis of intermediate IV:

dissolving a compound II with a structure of a formula II, a compound III with a structure of a formula III and a first base in a first reaction solvent at a first preset temperature to react to obtain an intermediate IV with a structure of a formula IV;

(2) synthesis of Compound I:

and dissolving the intermediate IV, the compound V with the structure of the formula V, a catalyst, a ligand and a second base in a second reaction solvent at a second preset temperature to react to obtain the compound I with the structure of the formula I.

Further, in the step (1), the first base is at least one selected from the group consisting of triethylamine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydroxide, lithium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, and lithium hexamethylamide.

Further, in the step (1), the first reaction solvent is at least one of dichloromethane, acetonitrile, tetrahydrofuran, dioxane, toluene and N, N-dimethylformamide.

Further, in the step (1), the first preset temperature is 0 ℃ to 80 ℃, for example, the reaction temperature may be 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.

Further, in the step (2), the second base is at least one selected from cesium carbonate, sodium tert-butoxide, potassium tert-butoxide and potassium carbonate.

Further, in the step (2), the second reaction solvent is at least one of dioxane, N-dimethylformamide, and toluene.

Further, in the step (2), the catalyst is selected from at least one of palladium acetate, tris (dibenzylideneacetone) dipalladium, and 1,1' - [ bis (diphenylphosphino) ferrocene ] dichloropalladium.

Further, in the step (2), the ligand is selected from at least one of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, and 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene.

Further, in the step (2), the second preset temperature is 80 ℃ to 120 ℃, for example, the reaction temperature may be 80 ℃, 90 ℃, 100 ℃, 110 ℃ or 120 ℃.

In a second aspect, the invention also provides a preparation method of the preparation composition of the FGFR4 inhibitor, which comprises the following steps:

step S10, crushing the active ingredients, and sieving the crushed active ingredients with a first mesh to obtain the active ingredients meeting the requirement of the particle size;

step S20, weighing the active ingredients meeting the particle size requirement and pharmaceutically acceptable auxiliary materials according to the formula ratio, and uniformly mixing to obtain a first mixture;

step S30, compressing the first mixture into a tablet or granulate to obtain a formulation composition of the FGFR4 inhibitor.

Further, in step S30, the granulating is performed by dry granulation or wet granulation, the first mixture is granulated to obtain broken dry granules, and the dry granules are granulated by a screen to obtain the first granules.

Further, mixing the first granules with a lubricant to obtain second granules, and subpackaging or putting the second granules into a coating machine for coating or filling capsules to obtain a granular preparation composition or a coated preparation composition or a capsule preparation composition.

Further, in obtaining the coating preparation composition, it is necessary to coat the second granules with a film coating powder, which is various commercially available film coating powders, such as the opadry series film coating powder of the kallikc company.

In a third aspect, the embodiments of the present invention provide a use of a formulation composition of the FGFR4 inhibitor according to the first aspect for the preparation of a medicament for the prevention and/or treatment of tumors.

Further, the tumor is selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, fibrosarcoma.

The invention discloses a preparation composition of an FGFR4 inhibitor, which takes a compound with a structure as shown in formula I or a pharmaceutically acceptable salt thereof as an active ingredient. The active ingredient is an FGFR4 inhibitor, has good FGFR4 activity inhibition capability, and is beneficial to improving the treatment effect of the medicament on cancer, reducing the adverse reaction rate of cancer and the targeting effect of the medicament, so the preparation composition has good anti-cancer medicament resistance and medicament targeting effect.

The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.

Example 1

The preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass:

name (R)	Weight ratio (%)	Function of
			FGFR4 inhibitors	2.5％	Active ingredient
Microcrystalline cellulose	83％	Filler
			Cross-linked polyvidone	12％	Disintegrating agent
Hydroxypropyl cellulose	1.5％	Adhesive agent
			Magnesium stearate	1％	Lubricant agent

The active ingredient is 1- (4- (3- (2, 6-dichlorophenyl) -1-methylureido) pyridin-2-yl) indoline-6-formamide, namely the compound 4.

The preparation process comprises the following steps:

step S1, synthesis of compound 1 c:

dissolving compound 1a (37.4g, 200.0mmol), 1b (37.2g, 200.0mmol) and potassium carbonate (41.4g, 300.0mmol) in acetonitrile (500mL), reacting at room temperature for 10 hours, monitoring the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain off-white compound (compound 1c)58.3g with a yield of 78.3%;

synthesis of Compound 4:

compound 1c (3.7g, 10.0mmol), compound 4a (1.6g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd2(dba)3(458mg, 0.5mmol), Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL), stirred to react at 100 ℃ for 6 hours, monitored by TLC, quenched after the reaction by addition of water, extracted twice with ethyl acetate (50mL each), the organic layer was concentrated, and column chromatographed to give 3.1g of a pale yellow solid (compound 4), yield 68.1%, ESI (+) m/z ═ 456.1 (compound 4 is active ingredient).

And step S2, crushing the active ingredient obtained in the step S1, and sieving the crushed active ingredient with a 60-mesh sieve to obtain the active ingredient meeting the particle size requirement.

And step S3, weighing the active ingredient, the filler, the disintegrant and the adhesive obtained in the step S2 according to the prescription amount, and putting the active ingredient, the filler, the disintegrant and the adhesive into a three-dimensional mixer to mix for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain the first medicine.

And step S4, adding the first medicine and the lubricant obtained in the step S3 into a three-dimensional mixer, and mixing for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain a second medicine.

And S5, compressing the second medicament obtained in the step S4 by using a rotary tablet press to obtain a plain tablet.

And step S6, packaging the plain tablets obtained in the step S5 by aluminum plastic to obtain the preparation composition of the FGFR4 inhibitor.

The tablets of the FGFR4 inhibitor obtained in example 1 were subjected to a dissolution test (the test conditions were the same as in the effect example), and the dissolution rate of the tablets at 45min was found to be 96.6%.

Example 2

The preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass:

name (R)	Weight ratio (%)	Function of
			FGFR4 inhibitors	11％	Active ingredient
Starch	78％	Filler
			Croscarmellose sodium	8％	Disintegrating agent
Povidone	2％	Adhesive agent
			Magnesium stearate	1％	Lubricant agent

The active ingredient is 1- (2- (6-cyanoindolin-1-yl) pyridin-4-yl) -3- (2, 6-dichlorophenyl) -1-methylurea, namely compound 5.

The preparation process comprises the following steps:

step S1, synthesis of compound 1 c:

dissolving compound 1a (37.4g, 200.0mmol), 1b (37.2g, 200.0mmol) and potassium carbonate (41.4g, 300.0mmol) in acetonitrile (500mL), reacting at room temperature for 10 hours, monitoring the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain off-white compound (compound 1c)58.3g with a yield of 78.3%;

synthesis of Compound 5:

compound 1c (3.7g, 10.0mmol), compound 5a (1.4g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd₂(dba)₃Dissolving 458mg, 0.5mmol) and Xantphos (578mg, 1.0mmol) in DMF (50mL), heating to 100 ℃, stirring for reaction for 6 hours, monitoring the reaction by TLC, adding water after the reaction is finished, quenching the reaction, extracting twice by ethyl acetate (50mL each time), concentrating an organic layer, and separating by column chromatography to obtain 2.5g of light yellow solid (compound 5) with the yield of 57.2%. ESI (+) m/z-438.1 (compound 5 as active ingredient).

And step S2, crushing the active ingredient obtained in the step S1, and sieving the crushed active ingredient with a 60-mesh sieve to obtain the active ingredient meeting the particle size requirement.

Step S3, weighing the active ingredients, the filling agent and the disintegrating agent obtained in the step S2 according to the prescription amount, adding the active ingredients, the filling agent and the disintegrating agent into a wet mixing granulator, and mixing to obtain a first mixed material.

Step S4, granulating the first mixed material and the binder obtained in step S3 with a wet mixing granulator to obtain first wet granules.

And S5, putting the first wet granules obtained in the step S4 into a fluidized bed for drying, wherein the air inlet temperature in the fluidized bed is 50-70 ℃, the material temperature is kept at 30-40 ℃, the first medicine is obtained, and the water content of the first medicine is controlled to be 2-4% by mass.

And step S6, adding the first medicine and the lubricant obtained in the step S5 into a three-dimensional mixer, and mixing for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain a second medicine.

And S7, compressing the second medicament obtained in the step S6 by using a rotary tablet press to obtain a plain tablet.

And step S8, adding the plain tablets and the film coating powder obtained in the step S7 into a high-efficiency coating machine for coating to obtain the preparation composition of the FGFR4 inhibitor.

The dissolution test (same test conditions as the effect example) was performed on the capsule of the FGFR4 inhibitor obtained in example 2, and the dissolution of the capsule at 45min was found to be 94.1%.

Example 3

The preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass:

name (R)	Weight ratio (%)	Function of
			FGFR4 inhibitors	5％	Active ingredient
Starch	83.5％	Filler
			Sodium carboxymethyl starch	9％	Disintegrating agent
Povidone	2％	Adhesive agent
			Talcum powder	0.5％	Lubricant agent

The active ingredient is 3- (2-chloro-6-fluorophenyl) -1- (2- (8-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) pyridin-4-yl) -1-methylurea, i.e., compound 8.

The preparation process comprises the following steps:

step S1, synthesis of compound 6 b:

dissolving compound 6a (17.1g, 100.0mmol), 1b (18.6g, 100.0mmol) and potassium carbonate (20.7g, 150.0mmol) in acetonitrile (300mL), reacting at room temperature for 10 hours, monitoring the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain off-white compound 6b (25.4 g) with yield of 71.1%;

synthesis of compound 8:

compound 6b (3.6g, 10.0mmol), compound 8a (1.5g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd₂(dba)₃(458mg, 0.5mmol) and Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL), the reaction was stirred at 100 ℃ for 6 hours, monitored by TLC, and after the reaction was completed, water was added to quench the reaction, ethyl acetate (50mL each) was extracted twice, the organic layer was concentrated, and column chromatography was performed to give 3.1g of off-white solid (Compound 8), yield 69.8%, ESI (+) m/z ═ 445.1 (Compound 8 is active ingredient).

And step S2, crushing the active ingredient obtained in the step S1, and sieving the crushed active ingredient with a 60-mesh sieve to obtain the active ingredient meeting the particle size requirement.

And S3, weighing the active ingredients, the filling agent and the disintegrating agent obtained in the step S2 according to the prescription amount, adding the active ingredients, the filling agent and the disintegrating agent into a high-efficiency wet granulator, and mixing to obtain a second mixed material.

And S4, granulating the second mixed material and the adhesive obtained in the step S3 by using a wet mixing granulator to obtain second wet granules.

And step S5, putting the second wet granules obtained in the step S4 into a fluidized bed for drying and granulating to obtain the first medicament, wherein the water content of the first medicament is controlled to be 2-3% by mass.

And step S6, adding the first medicine and the lubricant obtained in the step S5 into a three-dimensional mixer, and mixing for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain a second medicine.

And step S7, putting the second medicine obtained in the step S6 into a capsule filling machine for filling to obtain capsules.

And step S8, carrying out aluminum plastic packaging on the capsule obtained in the step S7 to obtain the preparation composition of the FGFR4 inhibitor.

The dissolution test (same test conditions as the effect example) was performed on the capsules of the FGFR4 inhibitor obtained in example 3, and the dissolution rate of the capsules at 45min was found to be 94.9%.

Example 4

The preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass:

name (R)	Weight ratio (%)	Function of
			FGFR4 inhibitors	12％	Active ingredient
Microcrystalline cellulose	74.5％	Filler
			Croscarmellose sodium	11％	Disintegrating agent
Povidone	1.5％	Adhesive agent
			Magnesium stearate	1％	Lubricant agent

The active ingredient is 3- (3, 5-dichloropyridin-4-yl) -1- (2- (6-fluoroindolin-1-yl) pyridin-4-yl) -1-methylurea, namely the compound 12.

The preparation process comprises the following steps:

step S1, synthesis of compound 11 b:

dissolving compound 11a (18.8g, 100.0mmol), 1b (18.6g, 100.0mmol) and potassium carbonate (20.7g, 150.0mmol) in acetonitrile (300mL), reacting at room temperature for 10 hours, monitoring the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain off-white compound (compound 11b)27.1g with a yield of 72.7%;

synthesis of compound 12:

compound 11b (3.7g, 10.0mmol), compound 2a (1.4g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd₂(dba)₃(458mg, 0.5mmol) and Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL), the reaction was stirred at 100 ℃ for 6 hours, monitored by TLC, and after the reaction was completed, water was added to quench the reaction, ethyl acetate (50mL each) was extracted twice, the organic layer was concentrated, and column chromatography was performed to give 2.6g of off-white solid (Compound 12) in 60.3% yield (ESI (+) m/z: 432.1 (Compound 12 is active ingredient).

And step S2, crushing the active ingredient obtained in the step S1, and sieving the crushed active ingredient with a 60-mesh sieve to obtain the active ingredient meeting the particle size requirement.

Step S3, adding the active ingredients, the filling agent and the disintegrating agent obtained in the step S3 according to the prescription amount into a high-efficiency wet granulator for mixing to obtain a second mixed material.

And S4, granulating the second mixed material and the adhesive obtained in the step S3 by using a wet mixing granulator to obtain second wet granules.

And step S5, putting the second wet granules obtained in the step S4 into a fluidized bed for drying and granulating to obtain the first medicament, wherein the water content of the first medicament is controlled to be 2-3% by mass.

And step S6, adding the first medicine and the lubricant obtained in the step S5 into a three-dimensional mixer, and mixing for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain a second medicine.

And step S7, putting the second medicine obtained in the step S6 into a capsule filling machine for filling to obtain capsules.

And step S8, carrying out aluminum plastic packaging on the capsule obtained in the step S7 to obtain the preparation composition of the FGFR4 inhibitor.

Example 5

The preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass:

name (R)	Weight ratio (%)	Function of
			FGFR4 inhibitors	6％	Active ingredient
Lactose	75％	Filler
			Low-substituted hydroxypropyl cellulose	15％	Disintegrating agent
Gelatin	2.5％	Adhesive agent
			Talcum powder	1.5％	Lubricant agent

The active ingredient is 3- (3, 5-dichloropyridin-4-yl) -1- (2- (6-fluoroindolin-1-yl) pyridin-4-yl) -1-methylurea, namely compound 17.

The preparation process comprises the following steps:

synthesis of compound 16 b:

dissolving compound 16a (17.2g, 100.0mmol), 1b (18.6g, 100.0mmol) and potassium carbonate (20.7g, 150.0mmol) in acetonitrile (300mL), reacting at room temperature for 10 hours, monitoring the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain off-white compound (compound 16b)24.5g with a yield of 68.4%;

synthesis of compound 17:

compound 16b (3.6g, 10.0mmol), compound 7a (1.5g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd₂(dba)₃(458mg, 0.5mmol) and Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL) and the reaction was stirred at 100 ℃After completion of the reaction, the reaction was quenched with water, extracted twice with ethyl acetate (50mL each), the organic layer was concentrated, and separated by column chromatography to give 2.9g of an off-white solid (compound 17) in 65.2% yield and ESI (+) m/z was 446.1 (compound 18 was active ingredient).

And step S2, crushing the active ingredient obtained in the step S1, and sieving the crushed active ingredient with a 80-mesh sieve to obtain the active ingredient meeting the particle size requirement.

And step S3, weighing the active ingredient, the filler, the disintegrant and the adhesive obtained in the step S2 according to the prescription amount, and putting the active ingredient, the filler, the disintegrant and the adhesive into a three-dimensional mixer to mix for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain the first medicine.

And step S4, adding the first medicine and the lubricant obtained in the step S3 into a three-dimensional mixer, and mixing for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain a second medicine.

And S5, compressing the second medicament obtained in the step S4 by using a rotary tablet press to obtain a plain tablet.

And step S6, packaging the plain tablets obtained in the step S5 by aluminum plastic to obtain the preparation composition of the FGFR4 inhibitor.

Example 6

The preparation composition of the FGFR4 inhibitor comprises the following components in percentage by mass:

the active ingredient is 3- (3, 5-dichloropyridin-4-yl) -1- (2- (6-fluoroindolin-1-yl) pyridin-4-yl) -1-methylurea, namely compound 18.

The preparation process comprises the following steps:

synthesis of compound 16 b:

dissolving compound 16a (17.2g, 100.0mmol), 1b (18.6g, 100.0mmol) and potassium carbonate (20.7g, 150.0mmol) in acetonitrile (300mL), reacting at room temperature for 10 hours, monitoring the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain off-white compound (compound 16b)24.5g with a yield of 68.4%;

synthesis of compound 18:

compound 16b (3.6g, 10.0mmol), compound 8a (1.5g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd2(dba)3(458mg, 0.5mmol), Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL), stirred to react at 100 ℃ for 6 hours, monitored by TLC, quenched after the reaction by addition of water, extracted twice with ethyl acetate (50mL each), the organic layer was concentrated, and column chromatography gave 2.1g of off-white solid (compound 18) in 47.2% yield and ESI (+) m/z 446.1 (compound 18 is the active ingredient).

And step S2, crushing the active ingredient obtained in the step S1, and sieving the crushed active ingredient with a 60-mesh sieve to obtain the active ingredient meeting the particle size requirement.

Step S3, weighing the active ingredients, the filling agent and the disintegrating agent obtained in the step S2 according to the prescription amount, adding the active ingredients, the filling agent and the disintegrating agent into a wet mixing granulator, and mixing to obtain a first mixed material.

Step S4, granulating the first mixed material and the binder obtained in step S3 with a wet mixing granulator to obtain first wet granules.

And S5, putting the first wet granules obtained in the step S4 into a fluidized bed for drying, wherein the air inlet temperature in the fluidized bed is 50-70 ℃, the material temperature is kept at 30-40 ℃, the first medicine is obtained, and the water content of the first medicine is controlled to be 2-4% by mass.

And step S6, adding the first medicine and the lubricant obtained in the step S5 into a three-dimensional mixer, and mixing for 30min, wherein the rotating speed of the three-dimensional mixer is 10 revolutions per minute, so as to obtain a second medicine.

And S7, compressing the second medicament obtained in the step S6 by using a rotary tablet press to obtain a plain tablet.

And step S8, adding the plain tablets and the film coating powder obtained in the step S7 into a high-efficiency coating machine for coating to obtain the preparation composition of the FGFR4 inhibitor.

Examples of effects

Dissolution tests were performed on the formulation compositions of FGFR4 inhibitor obtained in example 1, example 2, example 3 and example 4, respectively.

The test method comprises the following steps: referring to a determination method of dissolution rate and release rate (0931 first method in the four-part general rules of the Chinese pharmacopoeia 2020 version);

the instrument comprises the following steps: an ultraviolet spectrophotometer and a dissolution tester;

dissolution medium: hydrochloric acid solution with pH of 1.0; volume of dissolution medium: 500 mL; rotating speed: 50 revolutions per minute;

sampling time: 5min, 10min, 15min, 30min, 45 min.

The following test results were obtained:

time (min)	5min	10min	15min	30min	45min
						Example 1 dissolution (%)	22.5	42.1	65.1	86.6	96.6
Example 2 dissolution (%)	10.2	33.2	52.1	88.2	94.1
						Example 3 dissolution (%)	13.4	30.2	48.5	80.2	94.9
Example 4 dissolution (%)	31.2	52.1	71.8	87.5	96.9

And (4) conclusion: when the dissolution time of the preparation composition of the FGFR4 inhibitor prepared by the preparation method of the embodiment 1-4 is 45min, the in vitro cumulative dissolution rate can reach more than 85%. The cumulative dissolution of the formulation compositions according to examples 1-4 at different times can be obtained: the FGFR4 inhibitor preparation composition prepared by adopting the formula and the preparation method of the FGFR4 inhibitor preparation composition has better dissolution rate and faster dissolution speed.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.