WO2023226630A1 - Polymorph of kras inhibitor or salt thereof and preparation of formulation of polymorph - Google Patents

Abstract

Provided is a polymorph of a cycloalkyl and heterocycloalkyl inhibitor or a salt thereof. Specifically, the present invention relates to a polymorph of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof, or a solvate thereof, i.e., a polymorph of a compound as represented by formula I or a salt thereof, or a solvate thereof. The polymorph is suitable for preparing a pharmaceutical composition of KRAS inhibitor.

Description

A polymorphic form of a KRAS inhibitor or salt thereof and preparation of its preparation Technical field

The present invention belongs to the field of medical technology. Specifically, it relates to a polymorphic form of cycloalkyl and heterocycloalkyl or their salts and their preparation. More specifically, it relates to (S)-2-(4- (7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrakis Hydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof, or a solvate thereof Crystalline form.

Background technique

(S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy)- 5,6,7,8-Tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile ((S)-2-( 4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile), the structure is shown in Formula I:

The molecular formula of the compound of formula I is C ₃₃ H ₃₆ ClF ₂ N ₇ O ₂ and the molecular weight is 636.14. The compound is a type of KRAS inhibitor and is suitable for preparing drugs for the treatment/prevention of cancer and other related diseases.

Because the different crystal forms and salt forms of the drug may affect its dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent, especially for some poorly soluble oral solid or semi-solid preparations, the crystal form The impact will be greater. There are currently no literature reports on the study of polymorphic forms of compounds of formula I, and no polymorphic forms of compounds of formula I have yet been developed.

Therefore, it is necessary to develop polymorphic forms of compounds of formula I.

Contents of the invention

The object of the present invention is to provide a polymorphic form of a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof.

A first aspect of the present invention provides a polymorph, which is a compound represented by formula I

Polymorphs of the free base or a pharmaceutically acceptable salt thereof or a solvate thereof,

In another preferred embodiment, the polymorphs are Form A, Form B, Form C, Form D, Form E, Form F, and Form G.

In another preferred embodiment, the polymorphs are Form A, Form B, and Form F.

In another preferred embodiment, the polymorph is Form B.

In another preferred embodiment, the polymorph is polymorph A of the compound represented by formula I, wherein the polymorph A has 3 or more X-rays selected from the group below Powder diffraction characteristic peaks: 6.91±0.2°, 7.99±0.2°, 13.54±0.2°, 14.19±0.2°, 21.09±0.2° and 24.12±0.2°.

In another preferred embodiment, the polymorph is polymorph B of the ethanol compound of the compound shown in formula I, wherein the polymorph B has X-ray powder diffraction characteristics selected from the following group Peaks: 6.35±0.2°, 8.05±0.2° and 20.53±0.2°.

In another preferred example, the polymorph B has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 6.35±0.2°, 8.05±0.2°, 9.90±0.2°, 15.83 ±0.2°, 19.81±0.2°, 20.53±0.2° and 22.48±0.2°.

In another preferred example, the polymorph B has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 6.35±0.2°, 6.77±0.2°, 8.05±0.2°, 9.90 ±0.2°, 12.65±0.2°, 14.35±0.2°, 15.83±0.2°, 18.12±0.2°, 19.81±0.2°, 20.53±0.2°, 21.18±0.2° and 22.48±0.2°.

In another preferred example, the polymorph is polymorph C of n-propanolate of the compound shown in formula I, wherein the polymorph C has 3 or more polymorphs selected from the following: The X-ray powder diffraction characteristic peaks of the group are: 5.93±0.2°, 6.13±0.2°, 15.54±0.2°, 16.33±0.2° and 24.03±0.2°.

In another preferred example, the polymorph is polymorph D of n-propanolate of the compound shown in formula I, wherein the polymorph D has 3 or more polymorphs selected from the following: The X-ray powder diffraction characteristic peaks of the group are: 5.93±0.2°, 7.16±0.2°, 8.85±0.2°, 16.39±0.2°, 20.01±0.2° and 23.23±0.2°.

In another preferred embodiment, the polymorph is polymorph E of the methanesulfonate salt of the compound represented by formula I, wherein the polymorph E has 3 or more polymorphs selected from the group consisting of: The X-ray powder diffraction characteristic peaks are: 13.85±0.2°, 14.80±0.2°, 16.06±0.2°, 19.79±0.2°, 20.47±0.2° and 27.10±0.2°.

In another preferred embodiment, the polymorph is polymorph F of the citrate salt of the compound shown in formula I, wherein the polymorph F has 3 or more selected from the group below X-ray powder diffraction characteristic peaks: 5.68±0.2°, 7.52±0.2°, 12.16±0.2°, 13.50±0.2°, 17.31±0.2°, 20.21±0.2°, 22.08±0.2°, 23.19±0.2°, 24.69± 0.2° and 29.07±0.2°.

In another preferred embodiment, the polymorph is polymorph G of the citrate salt of the compound shown in formula I, wherein the polymorph G has 3 or more selected from the group below X-ray powder diffraction characteristic peaks: 5.64±0.2°, 7.33±0.2°, 8.75±0.2°, 10.58±0.2°, 11.82±0.2°, 13.63±0.2°, 17.42±0.2°, 19.09±0.2°, 21.87± 0.2°, 22.53±0.2°, 23.35±0.2° and 24.98±0.2°.

A second aspect of the invention provides a use of the polymorph for preparing pharmaceutical compositions of KRAS inhibitors.

A third aspect of the invention provides a pharmaceutical composition comprising:

(a) The polymorph of any one of claims 1-10; and

(b) Pharmaceutically acceptable carrier.

The third aspect of the present invention provides a method for preparing the polymorph, including the steps of: crystallizing the compound represented by formula I and an acid in an inert solvent to form a salt, or crystallizing the compound represented by formula I or its pharmaceutical The above acceptable salt, or its solvate, is crystallized in an inert solvent to obtain the polymorph of any one of claims 1 to 8.

In another preferred example, the preparation method of polymorph A of the compound represented by formula I includes three steps: step (1) suspending polymorph B of the ethanolate of the compound represented by formula I in a specific volume in water; step (2) stir at a specific temperature for a specific time; step (3) filter and dry to obtain polymorph A.

In another preferred example, in the preparation method of polymorph A of the compound represented by formula I, in step (1), the specific volume of water means that the volume of water used is 1 to 50 times the weight of polymorph B; preferably The preferred range is 2 to 20 times; the preferred range is 3 to 10 times.

In another preferred example, in the preparation method of polymorph A of the compound represented by formula I, in step (2), the specific temperature refers to a temperature of -10~105°C, and the preferred temperature is -5~100°C; especially The preferred temperature is 10 to 50°C.

In another preferred example, in the preparation method of polymorph A of the compound represented by formula I, in step (2), the specific stirring time is 1 to 48 hours; preferably 2 to 36 hours; particularly preferably 8 ~24 hours.

In another preferred example, the preparation method of polymorph B of the ethanolate of the compound represented by formula I includes three steps: step (1) dissolving the amorphous or polymorphic form of the compound represented by formula I in a specific into a volume of ethanol at a specific temperature; step (2) cool to a specific temperature and stir for a specific time; step (3) filter and dry to obtain polymorph B.

In another preferred example, in the preparation method of polymorph B of the ethanol compound of the compound represented by formula I, in step (1), the volume of ethanol used is 1 to 50 times the weight of polymorph B; preferably 2 to 20 times; particularly preferably 3 to 15 times.

In another preferred example, the preparation method of polymorph B of the ethanolate of the compound represented by formula I, step (1) , the specific temperature refers to a temperature of 0 to 85°C; the preferred temperature is 30 to 80°C; the particularly preferred temperature is 50 to 75°C.

In another preferred example, in the preparation method of polymorph B of the ethanolate of the compound represented by formula I, in step (2), cooling to a specific temperature means that the temperature is -50~80°C; the preferred temperature is -10 to 50°C; a particularly preferred temperature is -5 to 30°C.

In another preferred example, in the preparation method of polymorph B of the ethanolate of the compound represented by formula I, in step (2), the specific stirring time refers to 1 to 48 hours; preferably 2 to 24 hours; Particularly preferred is 5-16 hours.

In another preferred example, the preparation method of polymorph E of the citrate salt of the compound represented by formula I includes four steps: step (1) dissolving the amorphous or polymorphic form of the compound represented by formula I in a specific into a solvent with a specific volume and temperature; step (2) add a certain amount of anhydrous citric acid or citric acid monohydrate; step (3) slowly cool down to a specific temperature and stir for a specific time; step (4) filter and dry. Polymorph E was obtained.

In another preferred example, the preparation method of polymorph E of the citrate salt of the compound represented by formula I, in step (1), the solvent used is selected from the group consisting of ethyl acetate, isopropyl acetate, dichloromethane, 1, 2-Dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, diethyl ether, methyl ethyl ether, dioxane, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, methylcyclohexane, ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, methanol, ethanol, isopropyl alcohol, tert-butanol, n- Propanol, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol di Methyl ether (DME), or combinations thereof; preferred solvents are ethyl acetate, isopropyl acetate, methylene chloride, acetonitrile, acetone, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, dioxane, Petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, methylcyclohexane, ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, methanol, ethanol, isopropanol, tert-butyl Alcohol, n-propanol, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), or combinations thereof; particularly preferred solvents are ethyl acetate, isopropyl acetate , acetonitrile, acetone, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, ethanol, isopropanol, tert-butanol, n-propanol, or combinations thereof.

In another preferred embodiment, the method for preparing polymorph E of the citrate salt of the compound represented by Formula I, in step (1), the specific volume means that the usage volume of the solvent is 1 to 50% of the weight of the compound represented by Formula I. times; preferably 2 to 20 times; particularly preferably 3 to 15 times.

In another preferred example, in the preparation method of polymorph E of the citrate salt of the compound represented by formula I, in step (1), the specific temperature refers to a temperature of -10~105°C, and the preferred temperature is -5~ 100°C; a particularly preferred temperature is 40 to 90°C.

In another preferred embodiment, in the method for preparing polymorph E of the citrate salt of the compound represented by formula I, in step (2), a certain equivalent refers to the molar equivalent of anhydrous citric acid or citric acid monohydrate. 0.5 to 10 equivalents of the compound represented by formula I; preferably 1 to 5 equivalents; particularly preferably 1 to 3 equivalents.

In another preferred example, the preparation method of polymorph E of the citrate salt of the compound represented by formula I, step (3) , the specific temperature refers to a temperature of -50 to 80°C; the preferred temperature is -10 to 50°C; the particularly preferred temperature is -5 to 30°C.

In another preferred example, in the preparation method of polymorph E of the citrate salt of the compound represented by formula I, in step (3), the specific stirring time refers to 1 to 48 hours; the preferred time is 2 to 24 hours ;A particularly preferred time is 2-10 hours.

The fourth aspect of the present invention provides the use of the polymorph for preparing tablets containing the compound represented by formula I.

In another preferred embodiment, the tablet consists of the following components: tablet core and coating material.

In another preferred embodiment, the tablet and tablet core include the polymorphs A to G, fillers, disintegrants, binders and lubricants.

In another preferred embodiment, the tablet and filler are selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, sorbitol, anhydrous calcium hydrogen phosphate, starch, and sucrose.

In another preferred embodiment, the tablet and the disintegrating agent are selected from one or more of crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose.

In another preferred embodiment, the tablet and the binder are selected from one or more of hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose, and copovidone.

In another preferred embodiment, the tablet and lubricant are selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate.

In another preferred embodiment, the tablet and coating material are selected from one or more of Opadry, Opadry II, and Opadry amb II.

In another preferred embodiment of the tablet, the mass percentage of polymorphs A to G in the tablet core is 5.0%-90.0%, preferably 30.0%-80.0%, and more preferably 50.0-70.0% .

In another preferred example, the mass percentage of filler in the tablet core is 10.0-60.0%, preferably 20.0-50.0%, and more preferably 25.0-35.0%.

In another preferred embodiment of the tablet, the mass percentage of the disintegrant in the tablet core is 0.5-25.0%, preferably 2.0-15.0%, and more preferably 4.0-12.0%.

In another preferred embodiment of the tablet, the mass percentage of the binder in the tablet core is 1.0-6.0%, preferably 1.0-4.0%, and more preferably 1.0-2.0%.

In another preferred embodiment, the mass percentage of lubricant in the tablet core is 0.25-5.0%, preferably Preferably it is 0.5-3.0%, more preferably 0.5-1.5%.

In another preferred embodiment, for the tablets, the coating material is prepared with pure water into a coating liquid, and the tablet core is coated so that the weight of the tablet core coating increases by 3.0-6.0%, preferably 3.0-3.0%. 5.0%, more preferably 3.0-4.0%.

In another preferred embodiment, the preparation method of the tablet includes the following steps:

a. Pretreatment: sieve all components and pretreat;

b. Preparation of adhesive solution: Prepare the adhesive solution with pure water and set aside;

c. Wet granulation: Add polymorphs A to G, fillers and internal disintegrants into the wet granulator, stir and mix evenly, and then spray the binder solution to make a suitable soft material. Granulating, drying, whole graining, adding disintegrant, mixing evenly, adding lubricant, mixing evenly, and tableting;

d. Coating: Use pure water to prepare the coating material into a coating liquid, and then coat;

e. Packaging: aluminum packaging, outer packaging, warehousing.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.

Description of the drawings

Figure la shows the X-ray powder diffraction pattern of polymorph A.

Figure 1b shows a differential scanning calorimetry plot of Polymorph A.

Figure 1c shows the ¹ H NMR pattern of polymorph A.

Figure 2a shows the X-ray powder diffraction pattern of Polymorph B.

Figure 2b shows the differential scanning calorimetry plot of polymorph B.

Figure 2c shows the ¹ H NMR pattern of polymorph B.

Figure 3a shows the X-ray powder diffraction pattern of polymorph C.

Figure 3b shows the differential scanning calorimetry plot of polymorph C.

Figure 3c shows the ¹ H NMR pattern of polymorph C.

Figure 4a shows the X-ray powder diffraction pattern of polymorph D.

Figure 4b shows the differential scanning calorimetry plot of polymorph D.

Figure 4c shows the ¹ H NMR pattern of polymorph D.

Figure 5a shows the X-ray powder diffraction pattern of polymorph E.

Figure 5b shows the differential scanning calorimetry plot of polymorph E.

Figure 5c shows the ¹ H NMR pattern of polymorph E.

Figure 6a shows the X-ray powder diffraction pattern of polymorph F.

Figure 6b shows a differential scanning calorimetry plot of polymorph F.

Figure 6c shows the ¹ H NMR pattern of polymorph F.

Figure 7a shows the X-ray powder diffraction pattern of polymorph G.

Figure 7b shows a differential scanning calorimetry plot of polymorph G.

Figure 7c shows the ¹ H NMR pattern of polymorph G.

Figure 8 shows the change curve of blood drug concentration with time.

Detailed ways

Through long-term and in-depth research, the inventor unexpectedly discovered multiple polymorphic forms of the compound of formula I or its pharmaceutically acceptable salt, or its solvate, which polymorphic forms have better pharmaceutical properties. Bioavailability, and the polymorph has high purity and is very stable, and is suitable for preparing pharmaceutical compositions of KRAS inhibitors, thereby being more conducive to the prevention and treatment of cancer and other diseases. In addition, the polymorph of the present invention is not easy to rise during the pharmaceutical manufacturing process such as dispensing, is easy to collect, is not prone to waste, and helps protect the health of operators. On this basis, the inventor completed the present invention.

the term

Compounds of formula I

As used herein, "compound of formula I" refers to (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1- ((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoropropene Acyl)piperazin-2-yl)acetonitrile.

inert solvent

As used herein, "inert solvent" is methanol, ethanol, isopropanol, n-propanol, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetone, Acetonitrile, acetic acid, formic acid, n-hexane, n-heptane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, methylene chloride, chloroform, n-heptane, cyclohexane, n-hexane , methylcyclohexane, pentane, petroleum ether, dioxane, methyl tert-butyl ether, water or a mixture of the above solvents.

(S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy)- Solvate of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

(S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl) of the present invention) Methoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Compounds include various solvate forms of compounds of formula I.

For example, (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile ethanolate; ( S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy)-5 ,6,7,8-Tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile n-propanolate; (S )-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy)-5, 6,7,8-Tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile N,N-dimethylformamide compound.

Preferably, (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy base)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile ethanolate, It refers to the solvate in which the molar ratio of the compound of formula I to ethanol is 1:1.

polymorph

Solids exist in either amorphous or crystalline form. In the case of the crystalline form, the molecules are positioned within a three-dimensional lattice site. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are known as Called "polymorph". Different polymorphs of a given substance may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystalline form, packing pattern, flowability, and/or solid state stability.

crystallization

Production-scale crystallization can be accomplished by manipulating the solution so that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, such as dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Or reduce the liquid volume by boiling, normal pressure evaporation, vacuum drying or other methods. The solubility of a compound of interest can be reduced by adding an antisolvent or a solvent or a mixture of such solvents in which the compound has low solubility. Another option is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, 3rd Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

If it is desired that salt formation occurs simultaneously with crystallization, then the addition of an appropriate acid or base can lead to direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Likewise, completion of the synthesis reaction allows direct crystallization of the final product in a medium in which the final desired form is less soluble than the reactants.

Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. Additionally, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperatures and then add an appropriate volume of antisolvent in a controlled manner so that the system is just at saturation. and below the level. At this point, the desired form of seed crystal can be added (and the integrity of the seed crystal maintained), and the system is cooled to complete crystallization.

As used herein, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

Polymorphs of the invention

As used herein, the term "polymorphs of the present invention" includes polymorphs of a compound of Formula I, or a pharmaceutically acceptable salt thereof (eg, citrate), or various solvates thereof.

Preferred polymorphs of the present invention include (but are not limited to):

Polymorph A of the compound of formula I;

Polymorph B of the ethanolate of the compound of formula I;

Polymorph C of n-propanolate of the compound of formula I;

Polymorph D of n-propanolate of the compound of formula I;

Polymorph E of methanesulfonic acid, the compound of formula I;

Polymorph F of the compound of formula I, citric acid;

Polymorph G of the compound of formula I, citric acid.

Wherein, in the polymorph B, the molar ratio of the compound of formula I and ethanol is 1:1; in the polymorph C, the molar ratio of the compound of formula I and n-propanol is 1:1; In the crystal form D, the molar ratio of the compound of formula I and n-propanol is 1:0.5; in the polymorph E, the molar ratio of the compound of formula I and methanesulfonic acid is 1:2; the polymorph In F and G, the molar ratio of the compound of formula I and citric acid is 1:1.

Identification and characterization of polymorphs

After preparing the polymorph of the compound of formula I, the present invention uses the following various methods and instruments to study its properties.

X-ray powder diffraction

The solid samples obtained from the experiment were analyzed using an X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2θ scanning angle is from 3° to 45° (or 60°), the scanning step is 0.02°, and the exposure time is 0.12 seconds. When testing the sample, the light tube voltage and current are 40kV and 40mA respectively, and the sample disk is a zero-background sample disk.

The polymorph of the compound of formula I of the present invention has a specific crystal form and has specific characteristic peaks in an X-ray powder diffraction (XRPD) pattern. The following are preferred:

(1)Polymorph A

The polymorph A has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 6.91±0.2°, 7.99±0.2°, 13.54±0.2°, 14.19±0.2°, 21.09±0.2 ° and 24.12±0.2°.

In another preferred example, the polymorph A has X-ray powder diffraction characteristic peaks selected from the following group: 7.15±0.2°, 10.18±0.2°, 12.02±0.2°, 19.51±0.2°, 20.48± 0.2° and 26.33±0.2°.

In another preferred embodiment, the polymorph A has an X-ray powder diffraction pattern substantially as shown in Figure 1a.

(2)Polymorph B

The polymorph B has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 6.35±0.2°, 6.77±0.2°, 8.05±0.2°, 9.90±0.2°, 12.65±0.2 °, 15.83±0.2°, 19.81±0.2° and 20.53±0.2°.

In another preferred example, the polymorph B has X-ray powder diffraction characteristic peaks selected from the following group: 10.93±0.2°, 14.35±0.2°, 18.12±0.2°, 18.63±0.2°, 22.48± 0.2°, 23.03±0.2° and 24.33±0.2°.

In another preferred embodiment, the polymorph B has an X-ray powder diffraction pattern substantially as shown in Figure 2a.

(3)Polymorph C

The polymorph C has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 5.93±0.2°, 6.13±0.2°, 15.54±0.2°, 16.33±0.2° and 24.03±0.2 °.

In another preferred embodiment, the polymorph C has X-ray powder diffraction characteristic peaks selected from the following group: 7.92±0.2°, 12.48±0.2°, 2.10±0.2° and 22.49±0.2°.

In another preferred embodiment, the polymorph C has an X-ray powder diffraction pattern substantially as shown in Figure 3a.

(4)Polymorph D

The polymorph D has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 5.93±0.2°, 7.16±0.2°, 8.85±0.2°, 16.39±0.2°, 20.01±0.2 ° and 23.23±0.2°.

In another preferred example, the polymorph D has X-ray powder diffraction characteristic peaks selected from the following group: 9.57±0.2°, 11.94±0.2°, 12.31±0.2°, 17.29±0.2° and 17.83± 0.2°.

In another preferred embodiment, the polymorph D has an X-ray powder diffraction pattern substantially as shown in Figure 4a.

(5)Polymorph E

The polymorph E has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 13.85±0.2°, 14.80±0.2°, 16.06±0.2°, 19.79±0.2°, 20.47±0.2 ° and 27.10±0.2°.

In another preferred embodiment, the polymorph E has X-ray powder diffraction characteristic peaks selected from the following group: 9.37±0.2°, 13.16±0.2°, 19.21±0.2°, 25.02±0.2° and 26.11± 0.2°.

In another preferred embodiment, the polymorph E has an X-ray powder diffraction pattern substantially as shown in Figure 5a.

(6)Polymorph F

The polymorph F has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 5.68±0.2°, 7.52±0.2°, 12.16±0.2°, 13.50±0.2°, 17.31±0.2 °, 20.21±0.2°, 22.08±0.2°, 23.19±0.2°, 24.69±0.2° and 29.07±0.2°.

In another preferred example, the polymorph F has X-ray powder diffraction characteristic peaks selected from the following group: 8.60±0.2°, 10.85±0.2°, 14.11±0.2°, 18.98±0.2°, 26.78± 0.2° and 3±0.2°.

In another preferred embodiment, the polymorph F has an X-ray powder diffraction pattern substantially as shown in Figure 6a.

(7)Polymorph G

The polymorph G has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 5.64±0.2°, 7.33±0.2°, 8.75±0.2°, 10.58±0.2°, 11.82±0.2 °, 13.63±0.2°, 17.42±0.2°, 19.09±0.2°, 21.87±0.2°, 22.53±0.2°, 23.35±0.2° and 24.98±0.2°.

In another preferred embodiment, the polymorph F has X-ray powder diffraction characteristic peaks selected from the following group: 13.16±0.2°, 18.32±0.2°, 20.34±0.2° and 29.28±0.2°.

In another preferred embodiment, the polymorph G has an X-ray powder diffraction pattern substantially as shown in Figure 7a.

Differential Scanning Calorimetry

Also known as "differential calorimetric scanning analysis" (DSC), it is a technology that measures the relationship between the energy difference and temperature between the substance being measured and the reference substance during the heating process. The peak position, shape and number of peaks on the DSC spectrum are related to the properties of the substance, so they can be used to identify the substance qualitatively. This method is commonly used in this field to detect various parameters such as phase transition temperature, glass transition temperature, heat of reaction, etc. of substances.

DSC assay methods are known in the art. For example, NETZSCH DSC 204F1 differential scanning calorimeter can be used to increase the temperature from 25°C to 300°C at a heating rate of 10°C per minute to obtain the DSC scanning spectrum of the crystal form.

The polymorphic form of the compound of formula I of the present invention has specific characteristic peaks in a differential calorimetric scanning analysis (DSC) chart.

(1)Polymorph A

The differential scanning calorimetry spectrum of polymorph A has a maximum peak at 109.99°C ±2°C (or ±1°C, or ±0.5°C).

In another preferred embodiment, the polymorph A has a differential scanning calorimetry pattern (DSC) substantially as shown in Figure 1b.

(2)Polymorph B

The differential scanning calorimetry spectrum of polymorph B has a maximum peak at 99.46°C ±2°C (or ±1°C, or ±0.5°C).

In another preferred embodiment, the polymorph B has a differential scanning calorimetry pattern (DSC) substantially as shown in Figure 2b.

(3)Polymorph C

The differential scanning calorimetry spectrum of the polymorph C has a value at 79.06°C±2°C (or ±1°C, or ±0.5°C) maximum peak value.

In another preferred embodiment, the polymorph C has a differential scanning calorimetry pattern substantially as shown in Figure 3b.

(4)Polymorph D

The differential scanning calorimetry spectrum of polymorph D has a maximum peak at 88.3°C ±2°C (or ±1°C, or ±0.5°C).

In another preferred embodiment, the polymorph D has a differential scanning calorimetry pattern substantially as shown in Figure 4b.

(5)Polymorph E

The differential scanning calorimetry spectrum of polymorph E has a maximum peak at 190.5°C ±2°C (or ±1°C, or ±0.5°C).

In another preferred embodiment, the polymorph E has a differential scanning calorimetry pattern substantially as shown in Figure 5b.

(6)Polymorph F

The differential scanning calorimetry spectrum of polymorph F is at 142.96°C±2°C (or ±1°C, or ±0.5°C) or 187.°C±2°C (or ±1°C, or ±0.5°C) There is a maximum peak value.

In another preferred embodiment, the polymorph F has a differential scanning calorimetry pattern substantially as shown in Figure 6b.

(7)Polymorph G

The differential scanning calorimetry spectrum of polymorph G has a maximum peak at 136.2°C ±2°C (or ±1°C, or ±0.5°C).

In another preferred embodiment, the polymorph G has a differential scanning calorimetry pattern substantially as shown in Figure 7b.

Nuclear magnetic resonance (NMR) can also be used to assist in determining the crystalline structure, and methods for its determination are known in the art. The present invention preferably uses Bruker Avance III plus-400MHz.

active ingredients

As used herein, the term "active ingredient" or "active compound" refers to a polymorph of the present invention, i.e., a polymorph of a compound of Formula I or a pharmaceutically acceptable salt thereof (such as the hydrochloride salt thereof), or a solvate thereof type object.

Pharmaceutical compositions and methods of administration

Since the polymorph of the present invention has KRAS inhibitor activity, the polymorph of the present invention and pharmaceutical compositions containing the polymorph of the present invention as the main active ingredient can be used to treat, prevent and alleviate KRAS target mediation. induced diseases. According to the existing technology, the polymorphs of the present invention can be used to prevent or treat diseases such as cancer.

The pharmaceutical composition of the present invention contains the polymorph of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.

Among them, "safe and effective dose" refers to the amount of compound (or polymorph) sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the polymorph of the invention per dose, more preferably, 100-1000 mg of the polymorph of the invention per dose. Preferably, the "dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility" here refers to the ability of each component of the composition to be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The administration mode of the polymorph or pharmaceutical composition of the present invention is not particularly limited. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) a filler or compatibilizer, for example, Microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; ( c) Humectants, for example, glycerin; (d) Disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, cross-linked povidone, cross-linked Sodium carboxymethylcellulose; (e) retarder, such as paraffin; (f) absorption accelerator, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) Adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active ingredient can also be in the form of microcapsules with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups Or tincture. In addition to the active ingredients, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.

Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of polymorphs of the present invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

The polymorphs of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using a pharmaceutical composition, a safe and effective amount of the polymorph of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage during administration is a pharmaceutically effective dosage, for a person weighing 60 kg In terms of dosage, the daily dosage is usually 1 to 2000 mg, preferably 100 to 1500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.

A tablet containing polymorphs A to G, characterized in that it consists of the following components in mass percentage:

Polymorphs A to G, fillers, disintegrants, binders, lubricants, and coating materials.

Among them, the polymorph A～G in the tablet core is 5.0%-90.0%, preferably 30.0%-80.0%, and more preferably 50.0-70.0%;

The filler in the tablet core is 10.0-60.0%, preferably 20.0-50.0%, and more preferably 25.0-35.0%;

The disintegrant in the tablet core is 0.5-25.0%, preferably 2.0-15.0%, and more preferably 4.0-12.0%;

The binder in the tablet core is 1.0-6.0%, preferably 1.0-4.0%, more preferably 1.0-2.0%;

The lubricant in the tablet core is 0.25-5.0%, preferably 0.5-3.0%, and more preferably 0.5-1.5%;

The coating material is prepared into a coating liquid with pure water, and the tablet core is coated to increase the weight of the tablet core coating. 3.0-6.0%, preferably 3.0-5.0%, more preferably 3.0-4.0%.

The preparation method of the tablets containing polymorphs A to G of the present invention includes the following steps:

a. Pretreatment: sieve all components and pretreat;

b. Preparation of adhesive solution: Prepare the adhesive solution with pure water and set aside;

c. Wet granulation: Add polymorphs A to G, fillers and internal disintegrants into the wet granulator.

Stir and mix evenly, then spray into the binder solution to make a suitable soft material, granulate, dry, and granulate.

Add external disintegrant, mix evenly, add lubricant, mix evenly, and press into tablets;

d. Coating: Use pure water to prepare the coating material into a coating liquid, and then coat;

e. Packaging: aluminum packaging, outer packaging, warehousing.

The main advantages of the present invention include:

1. Provides a series of novel (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)) ring Propyl)methoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Or a pharmaceutically acceptable salt thereof, or a polymorphic form of a solvate thereof. The polymorphs of the present invention include polymorphs A to G, all of which have good stability, low hygroscopicity, and high bioavailability.

2. It also provides the use of multiple polymorphs, which can be used to prepare pharmaceutical compositions of KRAS inhibitors for the prevention and treatment of cancer and other diseases.

The present invention will be further described below in conjunction with specific implementations. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless otherwise specified, all quantities including quantities, percentages, fractions and ratios are understood to be modified by the word "about" and the quantities are not intended to represent significant figures.

Example 1 Preparation of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methyl Polymorphs of oxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Object A

Suspend the ethanol compound of I in water and suspend and stir at 30-40°C for 24 hours. Filter, wash with water, and vacuum dry the solid at 40±5°C to constant weight to obtain a white solid (yield 90%).

The sample was tested by ¹ H NMR, X-ray powder diffraction, DSC, etc. and proved to be the title crystalline compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.03-7.99(m,1H),7.79-7.77(m,1H),7.61-7.50(m,2H),7.45-7.38(m,1H),5.42 -5.22(m,2H),4.80(br,1H),4.19-3.73(m,7H),3.47-2.90(m,9H),2.20(s,2H),2.15(s,6H),0.57(m ,2H),0.37(m,2H).

The X-ray powder diffraction pattern is shown in Figure 1a, and the parameters of each peak are shown in Table 1. Differential scanning calorimetry The chart (DSC) is shown in Figure 1b, and the ¹ H NMR chart is shown in 1c.

Table 1

Example 2 Preparation of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methyl Polymorphs of oxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Object B

Suspend the amorphous material of I in ethanol, stir at 60-80°C until dissolved, slowly cool to 0-10°C, continue stirring for 3-4 hours, filter, wash with ethanol, and vacuum dry the solid at 30±5°C to constant temperature. Heavy to obtain a white solid (yield 80%).

The sample was tested by ¹ H NMR, X-ray powder diffraction, DSC, etc. and proved to be the title crystalline compound.

¹ H NMR (400MHz, CDCl ₃ ) δ7.74-7.70(m,1H),7.59-7.56(m,1H),7.43-7.39(m,1H),7.31-7.22(m,2H),5.44-5.20 (m,2H),4.80(br,1H),4.41-2.55(m,18H),2.38-2.24(m,9H),1.20(t,J＝6.8Hz,3H),0.64(m,2H), 0.44(m,2H).

The X-ray powder diffraction pattern is shown in Figure 2a, the parameters of each peak are shown in Table 2, the differential scanning calorimetry (DSC) pattern is shown in Figure 2b, and ^{the 1} H NMR pattern is shown in 2c.

Table 2

Example 3: Preparation of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl) Polycrystalline of methoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Type C

Dissolve the amorphous substance I in n-propanol, add n-heptane at 25-30°C, precipitate the solid, and centrifuge to obtain a white solid.

The sample was tested by ¹ H NMR, X-ray powder diffraction, DSC, etc. and proved to be the title crystalline compound.

¹ H NMR (400MHz, DMSO-d6) δ8.03-7.99(m,1H),7.79-7.77(m,1H),7.61-7.49(m,2H),7.43-7.38(m,1H),5.42- 5.21(m,2H),4.80(br,1H),4.36(t,J＝6.8Hz,1H),4.17-3.72(m,7H),3.46-2.67(m,11H),2.19(s,2H) ,2.14(s,6H),1.45-1.36(m,2H),0.82(t,J＝7.6Hz,3H),0.56(m,2H),0.36(m,2H).

The X-ray powder diffraction pattern is shown in Figure 3a, the parameters of each peak are shown in Table 3, the differential scanning calorimetry (DSC) pattern is shown in Figure 3b, and ^{the 1} H NMR pattern is shown in 3c.

table 3

Example 4 Preparation of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methyl Polymorphs of oxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Object D

Take the amorphous substance I in n-propanol and water solvent system, suspend and stir at 50°C for 24 hours, and centrifuge to obtain a white solid.

The sample was tested by ¹ H NMR, X-ray powder diffraction, DSC, etc. and proved to be the title crystalline compound.

¹ H NMR (400MHz, DMSO-d6) δ8.03-7.99(m,1H),7.79-7.77(m,1H),7.61-7.49(m,2H),7.43-7.38(m,1H),5.41- 5.20(m,2H),4.80(br,1H),4.36(t,J＝6.8Hz,1H),4.17-3.72(m,7H),3.46-2.67(m,10H),2.19(s,2H) ,2.13(s,6H),1.45-1.36(m,1H),0.82(t,J＝7.6Hz,1.5H),0.56(m,2H),0.36(m,2H).

The X-ray powder diffraction pattern is shown in Figure 4a, the parameters of each peak are shown in Table 4, the differential scanning calorimetry (DSC) pattern is shown in Figure 4b, and ^{the 1} H NMR pattern is shown in 4c.

Table 4

Example 5 Preparation of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methyl Oxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile methanesulfonic acid Salt Polymorph E

Add the amorphous substance of I (1.0eq) and methanesulfonic acid (1.0eq) to acetone. When a solid appears, stir at 20-30°C for 2-4 days, and centrifuge to obtain a white solid.

The sample was tested by ¹ H NMR, X-ray powder diffraction, DSC, etc. and proved to be the title crystalline compound.

¹ H NMR (400MHz, DMSO-d6) δ9.19(br,1H),8.05-8.01(m,1H),7.81-7.79(m,1H),7.62-7.51(m,2H),7.45-7.39( m,1H),5.42-5.21(m,2H),4.80(br,1H),4.19-3.72(m,7H),3.51-2.87(m,17H),2.83(s,6H),0.81-0.73( m,4H).

The X-ray powder diffraction pattern is shown in Figure 5a, the parameters of each peak are shown in Table 5, the differential scanning calorimetry (DSC) pattern is shown in Figure 5b, and ^{the 1} H NMR pattern is shown in 5c.

table 5

Example 6 Preparation of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methyl Oxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile citrate Polymorph F

Suspend the amorphous substance of I (1.0eq) in ethanol, add citric acid monohydrate (1.1eq) at 60-80°C, slowly lower the temperature to 20-25°C, stir for 3-4 hours, and centrifuge to obtain a white solid. .

The sample was tested by ¹ H NMR, X-ray powder diffraction, DSC, etc. and proved to be the title crystalline compound.

¹ H NMR (400MHz, DMSO-d6) δ10.90(br,3H),8.04-8.01(m,1H),7.81-7.78(m,1H),7.62-7.51(m,2H),7.45-7.39( m,1H),5.43-5.22(m,2H),4.80(br,1H),4.19-3.74(m,7H),3.49-2.91(m,11H),2.66(s,6H),2.63-2.50( m,4H),0.74(m,2H),0.66(m,2H).

The X-ray powder diffraction pattern is shown in Figure 6a, the parameters of each peak are shown in Table 6, the differential scanning calorimetry (DSC) pattern is shown in Figure 6b, and ^{the 1} H NMR pattern is shown in 6c.

Table 6

Example 7 Preparation of (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methyl Oxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile citrate Polymorph G

Take polymorph F (1.0 eq) of I and suspend it in ethyl acetate, methyl tert-butyl ether, toluene or n-heptane at 20-30°C, stir for 10 days, and centrifuge to obtain a white solid.

The sample was tested by ¹ H NMR, X-ray powder diffraction, DSC, etc. and proved to be the title crystalline compound.

¹ H NMR (400MHz, DMSO-d6) δ10.90(br,3H),8.06-8.02(m,1H),7.82-7.79(m,1H),7.63-7.54(m,2H),7.45-7.39( m,1H),5.43-5.22(m,2H),4.80(br,1H),4.19-3.74(m,7H),3.49-2.91(m,11H),2.66(s,6H),2.63-2.50( m,4H),0.73(m,2H),0.64(m,2H).

The X-ray powder diffraction pattern is shown in Figure 7a, the parameters of each peak are shown in Table 7, the differential scanning calorimetry (DSC) pattern is shown in Figure 7b, and ^{the 1} H NMR pattern is shown in 7c.

Table 7

Example 8 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy Polymorphs of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile A's stability

After 6 months of accelerated testing (test conditions 40±2℃, 75%±5%RH), the results show that the crystal form of polymorph A is very stable, and is more stable than the newly prepared one (0 months) As for polymorph A, the purity of polymorph A has basically remained unchanged, always above 99%, and no obvious degradation impurities have been found.

Example 9 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy Polymorphs of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile B’s stability

After 6 months of accelerated testing (test conditions 40±2℃, 75%±5%RH), the results show that the crystal form of polymorph B is very stable, and is more stable than the newly prepared one (0 months) As for polymorph B, the purity of polymorph B has basically remained unchanged, always above 99%, and no obvious degradation impurities have been found.

Example 10 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy Polymorphs of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Stability of C

After 6 months of accelerated testing (test conditions 40±2℃, 75%±5%RH), the results show that the crystal form of polymorph C is very stable, and is more stable than the newly prepared one (0 months) As for the polymorph C, the purity of the polymorph C has basically not changed and is always above 99%, with no obvious degradation impurities.

Example 11 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy Polymorphs of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile D's stability

After 6 months of accelerated testing (test conditions 40±2℃, 75%±5%RH), the results show that the crystal form of polymorph D is very stable, and is more stable than the newly prepared one (0 months) As for polymorph D, the purity of polymorph D has basically remained unchanged, always above 99%, and no obvious degradation impurities have been found.

Example 12 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy Polymorphs of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Stability of E

After 6 months of accelerated testing (test conditions 40±2℃, 75%±5%RH), the results show that the crystal form of polymorph E is very stable, and is more stable than the newly prepared one (0 months) As for the polymorph E, the purity of the polymorph E has basically not changed and is always above 99%, with no obvious degradation impurities.

Example 13 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy Polymorphs of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Stability of F

After 6 months of accelerated testing (test conditions 40±2℃, 75%±5%RH), the results show that the crystal form of polymorph E is very stable, and is more stable than the newly prepared one (0 months) As for the polymorph F, the purity of the polymorph F has basically not changed and is always above 99%, with no obvious degradation impurities.

Example 14 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(1-((dimethylamino)methyl)cyclopropyl)methoxy Polymorphs of 5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Stability of G

After 6 months of accelerated testing (test conditions 40±2℃, 75%±5%RH), the results show that the crystal form of polymorph G is very stable, and is more stable than the newly prepared one (0 months) As for polymorph G, the purity of polymorph G has basically remained unchanged, always above 99%, and no obvious degradation impurities have been found.

Example 15 Saturated solubility test

Place the fixed vertical mixer in a 37°C thermostat with a rotation speed of 60 rpm. After the temperature stabilizes, add preheated media to a 50ml plastic centrifuge tube: pH 1.2 hydrochloric acid, pH 4.5 acetate. Buffer and pH 6.8 phosphate buffer solution, then add excess sample, shake well, place on the mixer, take samples at 6 hours and 24 hours respectively, take about 2ml of suspension each time, and pass through 0.45μm while hot Membrane filtration, take an appropriate amount of the filtrate, dilute it to an appropriate multiple with acetonitrile: water (1:1), and then perform HPLC measurement to obtain the saturated solubility.

Example 16 Pharmaceutical Composition

Each 1000 tablets consists of the following components:

The preparation method includes the following steps:

a. Pretreatment: sieve all components and pretreat;

b. Preparation of adhesive solution: Prepare the adhesive solution with pure water and set aside;

c. Wet granulation: Add polymorphs A to G, fillers and internal disintegrants into the wet granulator, stir and mix evenly, and then spray the binder solution to make a suitable soft material. Granulating, drying, whole graining, adding disintegrant, mixing evenly, adding lubricant, mixing evenly, and tableting;

d. Coating: Use pure water to prepare the coating material into a coating liquid, and then coat;

e. Packaging: aluminum packaging, outer packaging, warehousing

Example 17 Pharmaceutical Composition

Each 1000 tablets consists of the following components:

The preparation method includes the following steps:

a. Pretreatment: sieve all components and pretreat;

b. Preparation of adhesive solution: Prepare the adhesive solution with pure water and set aside;

c. Wet granulation: Add polymorphs A to G, fillers and internal disintegrants into the wet granulator, stir and mix evenly, and then spray the binder solution to make a suitable soft material. Granulating, drying, whole graining, adding disintegrant, mixing evenly, adding lubricant, mixing evenly, and tableting;

d. Coating: Use pure water to prepare the coating material into a coating liquid, and then coat;

e. Packaging: aluminum packaging, outer packaging, warehousing.

Comparative Example 1 Pharmaceutical Composition

Each 1000 tablets consists of the following components:

The preparation method includes the following steps:

a. Pretreatment: sieve all components and pretreat;

b. Preparation of adhesive solution: Prepare the adhesive solution with pure water and set aside;

c. Wet granulation: Add polymorphs A to G, fillers and internal disintegrants into the wet granulator, stir and mix evenly, and then spray the binder solution to make a suitable soft material. Granulating, drying, whole graining, adding disintegrant, mixing evenly, adding lubricant, mixing evenly, and tableting;

d. Coating: Use pure water to prepare the coating material into a coating liquid, and then coat;

e. Packaging: aluminum packaging, outer packaging, warehousing.

Comparative Example 2 Pharmaceutical Composition

Each 1000 tablets consists of the following components:

The preparation method includes the following steps:

a. Pretreatment: sieve all components and pretreat;

b. Preparation of adhesive solution: Prepare the adhesive solution with pure water and set aside;

c. Wet granulation: Add polymorphs A to G, fillers and internal disintegrants into the wet granulator, stir and mix evenly, and then spray the binder solution to make a suitable soft material. Granulating, drying, whole graining, adding disintegrant, mixing evenly, adding lubricant, mixing evenly, and tableting;

d. Coating: Use pure water to prepare the coating material into a coating liquid, and then coat;

e. Packaging: aluminum packaging, outer packaging, warehousing.

Experimental Example 18: Polymorphic hygroscopicity test

Carry out in accordance with the guiding principles for drug hygroscopicity testing (Chinese Pharmacopoeia 2010 Edition, Part II, Appendix XIX J).

1. Take 4 dry glass weighing bottles with lids (outer diameter 60mm, height 30mm), place them in a constant temperature and humidity box at 25℃±1℃ the day before the test, and place a saturated ammonium sulfate solution in the lower part. In a glass dryer ("constant temperature and humidity dryer").

2. After each empty weighing bottle and its cap are placed in a "constant temperature and humidity dryer" for 24 hours, its weight is accurately stabilized in units of sets (weighing bottle + cap), and is counted as m1.

3. Take an appropriate amount of polymorph II sample, place it flatly in a weighed glass weighing bottle (sample thickness is about 1mm), close the cap, and accurately weigh each weighing bottle at this time (weighing bottle + cap + sample) weight, measured as m2.

3. After each sample is placed in the "constant temperature and humidity dryer" for 24 hours, the weight of each weighing bottle (weighing bottle + cap + sample) at this time is accurately measured, and it is calculated as m3.

4. Calculate the moisture attraction weight gain percentage of each sample (the calculation formula is as follows). When the moisture attraction weight gain percentage is less than 0.2%, it is defined as no or almost no moisture attraction; the moisture attraction weight gain percentage is greater than or equal to 0.2%, but less than 2.0%. When the weight gain of moisture is less than 15% but not less than 2%, it is defined as being hygroscopic; if the weight gain of moisture is not less than 15%, it is defined as extremely hygroscopic; it absorbs enough water to form a liquid , defined as deliquescence.

Weight gain percentage=[(m3-m2)/(m2-m1)]×100%

According to the above steps, the hygroscopicity of polymorph II of the present invention was measured. The results showed that the weight gain percentage of polymorph B [(35.2816-35.2801)/(35.2801-34.2536)]×100%=0.15%. It can be seen that polymorph B has no or almost no hygroscopicity.

Repeat the operation of Example 18, except that polymorphs A, C to G according to the invention are used instead of polymorph B. As a result, it is found that the various polymorphs according to the invention are very stable and basically There is no hygroscopicity, only polymorph A has slight hygroscopicity.

Therefore, the polymorphs of the present invention are very suitable for use in pharmaceutical compositions. Moreover, the polymorph of the present invention is not easy to rise during the pharmaceutical manufacturing process such as dispensing, is easy to collect, is not easy to cause waste, and helps protect the health of operators.

Experimental Example 19 Pharmacokinetic Testing of Different Polymorphs

Male beagle dogs, weighing about 8-10Kg, were given 30 mg/kg capsules of the compound of the present invention by gavage without fasting. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24 hours after administration of Compound I, Polymorph B of Example 2, and Polymorph F of Example 6, respectively, and measured by LC/MS/MS. Concentrations of compounds of the invention or control compounds in plasma.

Table 8 Summary of pharmacokinetic parameters: (n=4, mean)

It can be seen from Table 8 and Figure 8 that compared to the control compound I, the compounds of the present invention Example 2 and Example 6 exhibit better metabolic properties, maximum blood concentration (Cmax) and plasma exposure in beagle dogs The AUC is higher. The results show that the polymorphs of Example 2 and Example 6 have better bioavailability and efficacy.

Experimental Example 20 Tablet Quality Research Experiment

Dissolution testing

According to the second method of the four general chapters "0931 Dissolution and Release Measurement Method" of the 2020 edition of the "Chinese Pharmacopoeia", use pH 5.8 disodium hydrogen phosphate-citrate buffer as the dissolution medium, with a rotation speed of 75 rpm, respectively. Take samples for measurement at 5min, 10min, 15min, 30min, 45min and 60min.

Experimental results:

The tablets of Example 16 and Comparative Example 1 were tested separately and quality research was conducted to examine the dissolution of the tablets. The results are shown in Table 9:

Table 9: Disintegration time and dissolution data of tablets of Example 16 and Comparative Example 1

The dissolution data of Example 16 and Comparative Example 1 show that the cumulative dissolution of the tablets of Example 16 at 60 minutes is greater than 95%, and the dissolution of the tablets of Comparative Example 1 at 60 minutes is less than 80%, indicating that the cumulative dissolution of Example 16 Higher than Comparative Example 1. Therefore, for the tablets containing polymorphs A to G of the present invention, the use of crospovidone as the disintegrant is superior to the use of croscarmellose sodium as the disintegrant.

The tablets of Example 17 and Comparative Example 2 were tested and quality studied respectively, and the dissolution rate of the tablets was examined. The results are shown in Table 10:

Table 10: Disintegration time limit and dissolution data of tablets of Example 17 and Comparative Example 2

The cumulative dissolution rate of the tablets of Example 17 at 60 minutes was greater than 95%, and the dissolution rate of the tablets of Comparative Example 2 at 60 minutes was less than 90%, indicating that the cumulative dissolution rate of Example 17 was higher than that of Comparative Example 2. Therefore, in the tablets containing polymorphs A to G of the present invention, microcrystalline cellulose is used as a filler rather than lactose.

All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (13)

1. A polymorphic form, characterized in that the polymorphic form is a polymorphic form of the compound represented by formula I or a pharmaceutically acceptable salt thereof or a solvate thereof,
   
2. The polymorph of claim 1, wherein the polymorph is polymorph A of the compound represented by formula I, wherein the polymorph A has 3 or 3 The above X-ray powder diffraction characteristic peaks are selected from the following group: 6.91±0.2°, 7.99±0.2°, 13.54±0.2°, 14.19±0.2°, 21.09±0.2° and 24.12±0.2°.
3. The polymorph of claim 1, wherein the polymorph is polymorph B of the ethanolate of the compound represented by formula I, wherein the polymorph B has a polymorph selected from the group consisting of: The X-ray powder diffraction characteristic peaks of the lower group are: 6.35±0.2°, 8.05±0.2° and 20.53±0.2°.
4. The polymorph of claim 1, wherein the polymorph is polymorph C of n-propanolate of the compound represented by formula I, wherein the polymorph C has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 5.93±0.2°, 6.13±0.2°, 15.54±0.2°, 16.33±0.2° and 24.03±0.2°.
5. The polymorph of claim 1, wherein the polymorph is polymorph D of n-propanolate of the compound of formula I, wherein the polymorph D has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 5.93±0.2°, 7.16±0.2°, 8.85±0.2°, 16.39±0.2°, 20.01±0.2° and 23.23±0.2°.
6. The polymorph of claim 1, wherein the polymorph is polymorph E of the methanesulfonate salt of the compound represented by formula I, wherein the polymorph E has 3 One or more X-ray powder diffraction characteristic peaks selected from the following group: 13.85±0.2°, 14.80±0.2°, 16.06±0.2°, 19.79±0.2°, 20.47±0.2° and 27.10±0.2°.
7. The polymorph of claim 1, wherein the polymorph is polymorph F of the citrate salt of the compound represented by formula I, wherein the polymorph F has 3 Or more than 3 X-ray powder diffraction characteristic peaks selected from the following group: 5.68±0.2°, 7.52±0.2°, 12.16±0.2°, 13.50±0.2°, 17.31±0.2°, 20.21±0.2°, 22.08±0.2 °, 23.19±0.2°, 24.69±0.2° and 29.07±0.2°.
8. The polymorph of claim 1, wherein the polymorph is polymorph G of the citrate salt of the compound represented by formula I, wherein the polymorph G has 3 Or 3 or more selected from the group below Characteristic peaks of X-ray powder diffraction: 5.64±0.2°, 7.33±0.2°, 8.75±0.2°, 10.58±0.2°, 11.82±0.2°, 13.63±0.2°, 17.42±0.2°, 19.09±0.2°, 21.87 ±0.2°, 22.53±0.2°, 23.35±0.2° and 24.98±0.2°.
9. A use of the polymorph according to any one of claims 1 to 10, characterized in that it is used to prepare a pharmaceutical composition of a KRAS inhibitor.
10. A pharmaceutical composition, characterized in that it contains:

    (a) The polymorph of any one of claims 1-10; and

    (b) Pharmaceutically acceptable carrier.
11. A method for preparing polymorphs according to any one of claims 1 to 10, characterized in that it includes the steps of: crystallizing the compound of formula I and an acid in an inert solvent to form a salt, or crystallizing the compound of formula I The compound shown, a pharmaceutically acceptable salt thereof, or a solvate thereof is crystallized in an inert solvent, thereby obtaining the polymorph described in any one of claims 1 to 8.
12. The use of the polymorph according to claim 1, characterized in that it is used to prepare tablets containing the compound represented by formula I.
13. The tablet as claimed in claim 12, its preparation method includes the following steps:

    a. Pretreatment: sieve all components and pretreat;

    b. Preparation of adhesive solution: Prepare the adhesive solution with pure water and set aside;

    c. Wet granulation: Add polymorphs A to G, fillers and internal disintegrants into the wet granulator, stir and mix evenly, and then spray the binder solution to make a suitable soft material. Granulating, drying, whole graining, adding disintegrant, mixing evenly, adding lubricant, mixing evenly, and tableting;

    d. Coating: Use pure water to prepare the coating material into a coating liquid, and then coat;

    e. Packaging: aluminum packaging, outer packaging, warehousing.