Solid form of cyclic amine derivative, preparation method therefor, and pharmaceutical composition

Abstract

Provided in the present invention are a solid form of a cyclic amine derivative, a preparation method therefor, and a pharmaceutical composition, specifically relating to a solid form of a compound of formula I or a salt thereof, a preparation method therefor, and a pharmaceutical composition. The compound of formula I or the salt thereof provided by the present invention has strong binding ability to apo(a) and high stability, and can be better used in clinical practice.

Description

Solid form of a cyclic amine derivative, preparation method and pharmaceutical composition TECHNICAL FIELD

[0001] The present application belongs to the technical field of drugs, and relates to a solid form of a cyclic amine derivative, a preparation method and a pharmaceutical composition, in particular to a solid form of a compound of formula I or a salt thereof, a preparation method and a pharmaceutical composition. BACKGROUND

[0002] Patent PCT / CN2024 / 082950 discloses a cyclic amine derivative, wherein one example is a hydrochloride salt of a compound of formula I, which exhibits strong Apo(a) binding capacity, can effectively reduce Lp(a) level, and is a cyclic amine derivative with low toxicity and side effects, and can be used for preparing a drug for cardiovascular diseases.

[0003] For a pharmaceutical composition, the pharmaceutical active ingredient existing in the composition exhibits appropriate physicochemical properties, for example, stability, solubility and bioavailability of the pharmaceutical active ingredient. The form of the pharmaceutical active ingredient greatly affects its properties, and developing a suitable form of the pharmaceutical active ingredient to meet the quality requirements of the marketed drug is a technical problem to be solved in the process of developing a new drug. SUMMARY

[0004] The present application provides a solid form of a cyclic amine derivative, a preparation method and a pharmaceutical composition.

[0005] Patent WO2024217537A1 discloses a tertiary amine compound, a preparation method and medical use thereof, patent WO2024240056A1 discloses a sulfonamide compound, a preparation method and medical use thereof, and patent CN119490445A discloses an acyl compound, a preparation method and medical use thereof. The above patents also disclose some compounds in the prior art, activities and PK data of the compounds, but the data is not good. The full texts of patents WO2024217537A1, WO2024240056A1 and CN119490445A are incorporated into the present application.

[0006] The present application provides a salt of a compound of formula I:

[0007] The salt is an organic acid salt or an inorganic acid salt; the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, citric acid, gluconic acid, L-lactic acid, D-lactic acid, D / L-lactic acid, malic acid, aspartic acid, glutamic acid or cinnamic acid; and the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid or phosphoric acid.

[0008] The present application provides a solid form of a compound of Formula I, or a salt thereof, comprising one or more of amorphous and crystalline forms.

[0009] In some embodiments, the solid form of a compound of Formula I, or a salt thereof, is amorphous.

[0010] The amorphous form of a compound of Formula I, or a salt thereof, can be an amorphous form of a compound of Formula I free base, or can be an amorphous form of a salt of a compound of Formula I, or can be a combination of an amorphous form of a compound of Formula I free base and an amorphous form of a salt of a compound of Formula I.

[0011] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base. The X-ray powder diffraction pattern of the amorphous form of a compound of Formula I free base is substantially as shown in FIG. 1.

[0012] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base. The DSC pattern of the amorphous form of a compound of Formula I free base has an endothermic event in the range of 20 °C to 330 °C. Endothermic transitions occur at 70 °C to 80 °C and 260 °C to 270 °C.

[0013] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base. The DSC pattern of the amorphous form of a compound of Formula I free base has endothermic peaks at 75.74 ± 5 °C and 267.39 ± 5 °C.

[0014] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base. The DSC pattern of the amorphous form of a compound of Formula I free base is substantially as shown in FIG. 2.

[0015] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base. The TG pattern of the amorphous form of a compound of Formula I free base has a weight loss in the range of room temperature to 160 °C.

[0016] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base. The TG pattern of the amorphous form of a compound of Formula I free base has a weight loss of 4.1 ± 1% in the range of room temperature to 160 °C.

[0017] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base. The TG pattern of the amorphous form of a compound of Formula I free base is substantially as shown in FIG. 3.

[0018] In some embodiments, the present application provides an amorphous form of a compound of Formula I free base having an X-ray powder diffraction pattern substantially as shown in FIG. 4.

[0019] In some embodiments, the solid form of the compound of Formula I or salt thereof comprises a crystalline form. The crystalline form of the compound of Formula I or salt thereof can be a crystalline form of the free base of the compound of Formula I, or a crystalline form of a salt of the compound of Formula I, or a combination of a crystalline form of the free base of the compound of Formula I and a crystalline form of a salt of the compound of Formula I.

[0020] In some embodiments, the present application provides a crystalline form of the free base of the compound of Formula I, Form A. The X-ray powder diffraction pattern of the crystalline form of the free base of the compound of Formula I, Form A, has characteristic peaks at more than three of 7.78 ± 0.2°, 9.34 ± 0.2°, 10.90 ± 0.2°, 14.82 ± 0.2°, 15.64 ± 0.2°, 16.92 ± 0.2°, 18.02 ± 0.2°, 19.70 ± 0.2°, 20.46 ± 0.2°, 20.90 ± 0.2°, and 21.86 ± 0.2° in terms of 2Θ.

[0021] Optionally, the X-ray powder diffraction pattern of the crystalline form of the free base of the compound of Formula I, Form A, further has characteristic peaks at at least one of 11.70 ± 0.2°, 14.14 ± 0.2°, 14.46 ± 0.2°, 15.06 ± 0.2°, 17.10 ± 0.2°, 17.50 ± 0.2°, 18.80 ± 0.2°, 19.00 ± 0.2°, 20.16 ± 0.2°, 22.48 ± 0.2°, and 22.84 ± 0.2° in terms of 2Θ.

[0022] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of the free base of the compound of Formula I, Form A, has characteristic peaks at 7.78 ± 0.2°, 16.92 ± 0.2°, and 20.90° ± 0.2° in terms of 2Θ, optionally further comprising characteristic peaks at 9.34 ± 0.2°, 10.90 ± 0.2°, 14.82 ± 0.2°, 15.64 ± 0.2°, 18.02 ± 0.2°, 19.70 ± 0.2°, 20.46 ± 0.2°, and 21.86 ± 0.2° in terms of 2Θ.

[0023] Alternatively, the X-ray powder diffraction pattern of the crystalline form of the free base of the compound of Formula I, Form A, has characteristic peaks at 7.78 ± 0.2°, 20.90 ± 0.2°, and 21.86° ± 0.2° in terms of 2Θ, optionally further comprising characteristic peaks at 9.34 ± 0.2°, 10.90 ± 0.2°, 14.82 ± 0.2°, 15.64 ± 0.2°, 16.92 ± 0.2°, 18.02 ± 0.2°, 19.70 ± 0.2°, and 20.46 ± 0.2° in terms of 2Θ.

[0024] For example, the X-ray powder diffraction pattern of the crystalline form of the free base of the compound of Formula I, Form A, optionally has characteristic peaks at 2Θ of:

[0025] 7.78±0.2°、16.92±0.2°、20.90±0.2°；

[0026] 7.78±0.2°、20.90±0.2°、21.86°±0.2°；

[0027] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86±0.2°；

[0028] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86±0.2°、9.34±0.2°；

[0029] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86±0.2°、10.90±0.2°；

[0030] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86±0.2°、14.82±0.2°；

[0031] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86±0.2°、15.64±0.2°；

[0032] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86±0.2°、18.02±0.2°；

[0033] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、19.70±0.2°；

[0034] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、20.46±0.2°；

[0035] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、21.86°±0.2°；

[0036] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、9.34±0.2°；

[0037] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、10.90±0.2°；

[0038] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、14.82±0.2°；

[0039] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、18.02±0.2°；

[0040] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、19.70±0.2°；

[0041] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、20.46±0.2°；

[0042] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、21.86±0.2°；

[0043] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、18.02±0.2°、9.34±0.2°；

[0044] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、18.02±0.2°、10.90±0.2°；

[0045] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、15.64±0.2°、18.02±0.2°、14.82±0.2°；

[0046] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、14.82±0.2°、15.64±0.2°、18.02±0.2°、9.34±0.2°；

[0047] 7.78±0.2°、16.92±0.2°、20.90±0.2°、21.86°±0.2°、14.82±0.2°、15.64±0.2°、18.02±0.2°、10.90±0.2°；

[0048] 7.78 ± 0.2°, 16.92 ± 0.2°, 20.90 ± 0.2°, 21.86° ± 0.2°, 14.82 ± 0.2°, 15.64 ± 0.2°, 18.02 ± 0.2°, 9.34 ± 0.2°, 10.90 ± 0.2°;

[0049] 7.78 ± 0.2°, 9.34 ± 0.2°, 10.90 ± 0.2°, 14.82 ± 0.2°, 15.64 ± 0.2°, 16.92 ± 0.2°, 18.02 ± 0.2°, 19.70 ± 0.2°, 20.46 ± 0.2°, 20.90° ± 0.2° and 21.86° ± 0.2°.

[0050] In some embodiments, the X-ray powder diffraction pattern of the compound of Formula I, free base Form A, is substantially as shown in FIG. 5.

[0051] In some embodiments, the X-ray powder diffraction pattern of the compound of Formula I, free base Form A, is substantially as shown in FIG. 5.

[0052] Table 1. Free base Form A data for the compound of Formula I

[0053] In some embodiments, the DSC pattern of the compound of Formula I, free base Form A, has an endothermic event in the range of 20 °C to 300 °C.

[0054] In some embodiments, the DSC pattern of the compound of Formula I, free base Form A, has endothermic peaks at 82.00 ± 5 °C and 280.50 ± 5 °C.

[0055] In some embodiments, the DSC pattern of the compound of Formula I, free base Form A, is substantially as shown in FIG. 6.

[0056] In some embodiments, the TG pattern of the compound of Formula I, free base Form A, has a weight loss in the range of room temperature to 120 °C.

[0057] In some embodiments, the TG pattern of the compound of Formula I, free base Form A, has a weight loss of 8.7 ± 1% in the range of room temperature to 120 °C.

[0058] In some embodiments, the TG pattern of the compound of Formula I, free base Form A, is substantially as shown in FIG. 7.

[0059] The present application provides a compound of Formula I hydrochloride salt, having the structure shown below:

[0060] wherein n is selected from 1, 2, or 3, etc. The solid form of the compound of Formula I hydrochloride salt is amorphous or crystalline.

[0061] In some embodiments, the compound of Formula I hydrochloride salt has the following structure, and the solid form thereof is amorphous;

[0062] The X-ray powder diffraction pattern of the amorphous form of the compound of Formula I hydrochloride salt is substantially as shown in Figure 8.

[0063] In some embodiments, the amorphous form of the compound of Formula I hydrochloride salt contains water, and the content of water in the amorphous form of the compound of Formula I hydrochloride salt is about 0-3%. The content of water in the amorphous form of the compound of Formula I hydrochloride salt is 0%, 0.2%, 0.5%, 0.6%, 0.8%, 1.0%, 1.5%, 1.8%, 2.0%, 2.5%, or 3.0%, etc.

[0064] The present application provides a preparation method of the amorphous form of the compound of Formula I free base, which comprises:

[0065] Step 1, treating a solution containing the compound of Formula I free base to obtain the amorphous form of the compound of Formula I free base, the treatment is selected from one or more of freeze-drying treatment or spray drying, and the X-ray powder diffraction pattern of the obtained amorphous form of the compound of Formula I free base is substantially as shown in Figure 1.

[0066] In some embodiments, before treating the solution containing the compound of Formula I free base, the method further comprises:

[0067] obtaining a solution containing an acid salt of the compound of Formula I;

[0068] adding a base to the solution containing the acid salt of the compound of Formula I, and using the base to react with the acid salt of the compound of Formula I to obtain a solution containing the compound of Formula I free base.

[0069] The acid salt can be selected from one or more of inorganic acid salts and organic acid salts. The inorganic acid salt can be selected from one or more of hydrochloride, sulfate, hydrobromide, nitrate, and phosphate; the organic acid salt can be selected from one or more of acetate, maleate, fumarate, tartrate, benzoate, ascorbate, succinate, oxalate, methanesulfonate, benzenesulfonate, salicylate, citrate, gluconate, L-lactate, D-lactate, D / L-lactate, malate, aspartate, glutamate, and cinnamate.

[0070] The base can be selected from one or more of triethylamine, sodium hydroxide, sodium carbonate, and sodium bicarbonate.

[0071] In some embodiments, after obtaining the amorphous of the compound of formula I free base, the method further comprises: purifying the compound of formula I free base.

[0072] The purifying the compound of formula I free base can comprise: adding the compound of formula I free base into an organic solvent, stirring, suction filtering, and drying.

[0073] The drying can be selected from vacuum drying, and the vacuum drying temperature can be selected from 30-70℃, preferably 50-60℃. The vacuum drying temperature can be selected from 50℃, 55℃, or 60℃, etc.

[0074] The stirring temperature can be selected from 5-30℃, preferably 10-20℃. The stirring temperature can be selected from 10℃, 15℃, or 20℃, etc.

[0075] The organic solvent can be selected from alcohols. The organic solvent can be selected from one or more of methanol, ethanol, and isopropanol, etc., preferably methanol.

[0076] In some embodiments, in step 1, the freeze-drying treatment of the solution containing the compound of formula I free base can specifically comprise: freeze-drying treatment of the solution containing the compound of formula I free base under low-temperature vacuum conditions of-30~-60℃, preferably freeze-drying treatment of the solution containing the compound of formula I free base under low-temperature vacuum conditions of-40℃~-50℃, and the low-temperature vacuum drying temperature can be selected from-40℃, -45℃, or 50℃, etc.

[0077] The present application provides a preparation method of an amorphous of a compound of formula I free base, the preparation method comprising:

[0078] Step (1), dissolving the amorphous of the compound of formula I free base prepared in step 1 or step 2 above in a solvent to obtain a solution;

[0079] Step (2), treating the solution to obtain the amorphous of the compound of formula I free base, and the treatment is selected from one or more of freeze-drying treatment or spray drying, and the obtained X-ray powder diffraction pattern of another amorphous of the compound of formula I free base is substantially as shown in Figure 4.

[0080] In some embodiments, in step (1), the amorphous of the compound of formula I free base prepared in step 1 or step 2 above can be dissolved in a solvent to obtain a solution.

[0081] In some embodiments, in step (1), the solvent is selected from water.

[0082] In some embodiments, in step (1), the weight (g) of the compound of formula I to the volume (mL) of the solvent is 1:6-1:15.

[0083] In some embodiments, the freeze-drying treatment on the solution in step (2) can specifically include: freeze-drying treatment on the solution under low-temperature vacuum condition at-30 to-60℃, preferably freeze-drying treatment on the solution under low-temperature vacuum condition at-40 to-50℃, and the low-temperature vacuum drying temperature can be selected from-40℃, -45℃ or 50℃, etc.

[0084] The present application provides a preparation method of a free base crystal form of a compound of formula I, which comprises:

[0085] Step one, dissolving the free base of the compound of formula I in solvent 1 to obtain a solution;

[0086] Step two, cooling the obtained solution, stirring to crystallize, separating, and drying to obtain the free base crystal form of the compound of formula I, and the X-ray powder diffraction pattern thereof is substantially as shown in Figure 5.

[0087] In some embodiments, in step one, the solvent 1 is selected from one or more of water and organic solvents.

[0088] In some embodiments, in step two, after cooling the obtained solution, the method further comprises: adding solvent 2 to the cooled solution. Then stirring to crystallize, separating, and drying to obtain the free base crystal form of the compound of formula I. The solvent 2 is selected from one or more of water and organic solvents.

[0089] In some embodiments, the above-mentioned organic solvent is selected from one or more of ketone solvents and ether solvents. The ketone solvent can be selected from one or more of acetone and methyl isobutyl ketone; the ether solvent can be selected from one or more of tetrahydrofuran and methyl tetrahydrofuran.

[0090] The solvent 1 is water, or the solvent 1 is a combination of water and an organic solvent. The organic solvent can be selected from one or more of acetone and tetrahydrofuran.

[0091] The solvent 2 is selected from an organic solvent. The organic solvent can be selected from one or more of acetone and tetrahydrofuran.

[0092] In some embodiments, when solvent 1 is used without solvent 2, and solvent 1 includes an organic solvent and water, the volume ratio of the organic solvent and water is selected from 1:1 to 3:1. For example, the volume ratio of the organic solvent and water is selected from 1:1, 1.5:1, 2:1, 2.5:1 or 3:1, etc.

[0093] When solvent 1 and solvent 2 are used, the total composition of solvent 1 and solvent 2 includes organic solvent and water, the volume ratio of organic solvent and water is selected from 1:1 to 3:1. For example, the volume ratio of organic solvent and water is selected from 1:1, 1.5:1, 2:1, 2.5:1 or 3:1, etc.

[0094] In some embodiments, in step one, the weight (g) of the amorphous free base of the compound of formula I to the volume (mL) of solvent 1 is selected from 1:1 to 1:20. The weight (g) of the amorphous free base of the compound of formula I to the volume (mL) of solvent 1 can be selected from 1:1, 1:2, 1:5, 1:8, 1:10, 1:12, 1:15, 1:16, 1:18 or 1:20, etc.

[0095] In some embodiments, in step one, dissolving the free base of the compound of formula I in solvent 1 to obtain a solution includes: dissolving the amorphous free base of the compound of formula I prepared in step 1 or step 2 above in solvent 1 to obtain a solution.

[0096] In some embodiments, in step one, after dissolving the free base of the compound of formula I in solvent 1, heating to dissolve the free base of the compound of formula I to obtain a solution.

[0097] The heating temperature can be selected from 50-70℃. The heating temperature can be selected from 50℃, 52℃, 55℃, 60℃, 65℃ or 70℃, etc.

[0098] In some embodiments, in step two, the stirring temperature can be selected from 15-25℃. The stirring temperature can be selected from 15℃, 18℃, 20℃ or 25℃, etc.

[0099] In some embodiments, in step two, the stirring time can be selected from 5h-72h, preferably 10h-50h, more preferably 12h-24h. The stirring time can be selected from 12h, 15h, 18h, 20h, 25h or 30h, etc.

[0100] In some embodiments, in step two, the separation is selected from filtration, centrifugation or other processes.

[0101] The present application provides a pharmaceutical composition, which includes the salt of the compound of formula I provided above in the present application;

[0102] The salt is an organic acid salt or an inorganic acid salt; the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, citric acid, gluconic acid, L-lactic acid, D-lactic acid, D / L-lactic acid, malic acid, aspartic acid, glutamic acid or cinnamic acid; the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid or phosphoric acid.

[0103] The present application provides a pharmaceutical composition comprising the compound of formula I having a solid form as provided above or a salt thereof.

[0104] The present application also provides a use of a salt of the compound of formula I in the preparation of a medicament for reducing Lp(a) level.

[0105] The present application also provides a use of a salt of the compound of formula I in the preparation of a medicament for treating cardiovascular diseases.

[0106] The present application also provides a use of a salt of the compound of formula I in the preparation of a medicament for treating hyperlipidemia related disorders.

[0107] The present application also provides a use of the compound of formula I having a solid form or a salt thereof in the preparation of a medicament for reducing Lp(a) level.

[0108] The present application also provides a use of the compound of formula I having a solid form or a salt thereof in the preparation of a medicament for treating cardiovascular diseases.

[0109] The present application also provides a use of the compound of formula I having a solid form or a salt thereof in the preparation of a medicament for treating hyperlipidemia related disorders.

[0110] The present application also provides a method for diagnosing or treating a disease, comprising administering to an animal or human subject with overexpression of apolipoprotein A (apo(a)) an effective amount of a salt of the compound of formula I, or an effective amount of the compound of formula I having a solid form or a salt thereof. Overexpression of apo(a) leads to elevated Lp(a) level, resulting in disorders such as cardiovascular diseases. BRIEF DESCRIPTION OF DRAWINGS

[0111] Figure 1 is an X-ray powder diffraction pattern of the compound of formula I free base amorphous, wherein the abscissa is the angle 2 theta (°) and the ordinate is the intensity (CPS);

[0112] Figure 2 is a DSC graph of the compound of formula I free base amorphous, wherein the abscissa is the temperature (in degrees Celsius) and the ordinate is the heat flow (W / g);

[0113] Figure 3 is a TGA plot of the amorphous form of the compound of Formula I free base, wherein the abscissa is temperature (°C) and the ordinate is percent weight loss (%).

[0114] Figure 4 is an X-ray powder diffraction pattern of the amorphous form of the compound of Formula I free base, wherein the abscissa is angle 2 theta (°) and the ordinate is intensity (CPS).

[0115] Figure 5 is an X-ray powder diffraction pattern of the Form A of the compound of Formula I free base, wherein the abscissa is angle 2 theta (°) and the ordinate is intensity (CPS).

[0116] Figure 6 is a DSC plot of the Form A of the compound of Formula I free base, wherein the abscissa is temperature (°C) and the ordinate is heat flow (W / g).

[0117] Figure 7 is a TGA plot of the Form A of the compound of Formula I free base, wherein the abscissa is temperature (°C) and the ordinate is percent weight loss (%).

[0118] Figure 8 is an X-ray powder diffraction pattern of the amorphous form of the compound of Formula I hydrochloride salt, wherein the abscissa is angle 2 theta (°) and the ordinate is intensity (CPS). DETAILED DESCRIPTION

[0119] The present application is further illustrated by the following examples, which in no way should be construed as limiting the scope of the present application. The experimental methods in the following examples, where no specific conditions are indicated, were carried out in accordance with standard methods and conditions, or as specified in the commercial instructions.

[0120] The information of the testing instruments and the testing methods used in the following examples are as follows:

[0121] (1) Powder X-ray Diffraction:

[0122] Instrument: Rigaku SmatLab, Cu-Ka radiation, power 40 kV x 180 mA, scanning range 3-50°, step width 0.02°, scanning speed 5° / min. The amorphous form of the compound of Formula I free base prepared in Example 1 was tested by X-ray powder diffraction using this testing condition.

[0123] Instrument: PANalytica! Empyrean, Cu-Ka radiation, power 45 kV x 40 mA, scanning range 3-40°, step width 0.0167°, scanning time per step 33 seconds. The amorphous form of the compound of Formula I free base prepared in Example 3 was tested by X-ray powder diffraction using this testing condition.

[0124] (2) Differential Scanning Calorimetry:

[0125] Instrument: TA DSC Q100, purge gas: nitrogen 50 mL / min, heating rate: 10 °C / min.

[0126] (3) Thermal gravimetric analysis (TG) characterization:

[0127] Instrument: TA SDT Q600, purge gas: nitrogen 120 ml / min, heating rate: 10 °C / min.

[0128] Example 1, preparation of amorphous hydrochloride salt of compound of formula I

[0129] First step: Reactant 1 (5 g, 12.39 mmol) was added to a stirred solution of tert-butyl alcohol (50 mL), water (50 mL), NaClO2(11.21 g, 123.91 mmol), NaH2PO4(8.92 g, 74.35 mmol) and 2-methyl-2-butene (10 mL) at 25 °C and stirred overnight. The solvent was removed by rotary evaporation, EtOAc (80 mL) was added, the mixture was partitioned, the aqueous phase was extracted once with EtOAc (40 mL) and the combined organic phases were washed with saturated NaCl solution (40 mL), partitioned and the organic phase was dried. The filtrate was concentrated by rotary evaporation, the sample was mixed with silica gel and purified by column chromatography (EtOAc / PE 0-50%) and concentrated by rotary evaporation to give compound 2 (4.3 g, yield 82.72%).

[0130] MS m / z (ESI): 320.3 [M-100+H] + .

[0131] Second step: Reactant 2 (700 mg, 1.67 mmol) was dissolved in DMF (5 mL), HATU (1008 mg, 2.65 mmol) and DIEA (685 mg, 5.3 mmol) were added and the mixture was stirred at room temperature for 15 min, then a solution of 3 (1400 mg, 1.77 mmol) in DMF (5 mL) was added and the mixture was stirred at 30 °C overnight. Water was added, the mixture was extracted with EtOAc, the aqueous phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The solid 4 (1.5 g, yield 75.32%) was obtained by reverse phase preparative purification (methanol / water).

[0132] MS m / z (ESI): 497.4 [M / 2-100] + .

[0133] Step 3: Compound 4 (770 mg, 0.645 mmol) was dissolved in 4 M HCl / EtOAc at 40 °C overnight. Water was added, and EtOAc was washed twice. The aqueous phase was lyophilized to obtain compound 5 (510 mg, yield 94.76 %), which was an amorphous hydrochloride salt of the compound of formula I, and its X-ray powder diffraction pattern was substantially as shown in Figure 8.

[0134] MS m / z (ESI): 726.5 [M+H] + .

[0135] Example 2, Preparation of amorphous free base of the compound of formula I

[0136] Compound 4 (20 g) prepared in Example 1 was added to 60 mL of toluene, and the temperature was lowered to 10-20 °C. Concentrated hydrochloric acid 70 mL was added dropwise, and the reaction was stirred for 4 h after the dropwise addition was completed. The solution was allowed to stand and separate into layers, and the aqueous phase was obtained.

[0137] The aqueous phase was concentrated at 30-40 °C, and then the temperature was lowered to 10-20 °C. Water 300 mL was added, and triethylamine was added dropwise. The solution was passed through a nanofiltration membrane to obtain a filtrate.

[0138] The filtrate was concentrated to about 100 mL, and the concentrated solution was freeze-dried under low-temperature vacuum conditions at -40 to -50 °C to obtain a solid.

[0139] The obtained solid was added to 210 mL of methanol, and stirred at 10-20 °C for 3 h. Filtration was performed, and the filter cake was rinsed and dried under vacuum at 60 °C to obtain the amorphous free base of the compound of formula I, and its X-ray powder diffraction pattern was substantially as shown in Figure 1.

[0140] Example 3, Preparation of amorphous free base of the compound of formula I

[0141] The amorphous free base of the compound of formula I 1 g prepared in Example 2 was dissolved in 10 mL of water, and the obtained solution was freeze-dried to obtain the amorphous free base of the compound of formula I, and its X-ray powder diffraction pattern was substantially as shown in Figure 4.

[0142] Example 4, Preparation of crystalline form A of the free base of the compound of formula I

[0143] The amorphous free base of the compound of formula I 1 g prepared in Example 2 was dissolved in 3 mL of water, and the obtained solution was heated to 70 °C until it became clear. After the temperature was lowered to room temperature, the solution was stirred for 70 h, and then filtration was performed. The filter cake was dried at 40 °C to obtain the crystalline form A of the free base of the compound of formula I, and its X-ray powder diffraction pattern was substantially as shown in Figure 5.

[0144] Example 5, Preparation of crystalline form B of the free base of the compound of formula I

[0145] The compound of formula I free base amorphous 1 g prepared in Example 2 was dissolved in 4 mL of water, heated to 70 °C, dissolved, cooled to room temperature, then 2 mL of acetone was added, stirred for 18 h, suction filtered, dried at 40 °C to obtain the compound of formula I free base crystal form, whose X-ray powder diffraction pattern is substantially consistent with that of Figure 5.

[0146] Example 6, preparation of the compound of formula I free base crystal form

[0147] The compound of formula I free base amorphous 1 g prepared in Example 2 was dissolved in 5 mL of water, heated to 70 °C, dissolved, cooled to room temperature, then 5 mL of tetrahydrofuran was added, stirred for 24 h, suction filtered, dried at 40 °C to obtain the compound of formula I free base crystal form, whose X-ray powder diffraction pattern is substantially consistent with that of Figure 5.

[0148] Example 7, stability experiment

[0149] 50 mg of the compound of formula I hydrochloride amorphous prepared in Example 1 and 50 mg of the compound of formula I free base amorphous prepared in Example 2 were weighed into dry and clean glass bottles respectively, spread into a thin layer as the test sample. The glass bottles were placed at high temperature 60 °C with the opening exposed, the compound in the bottle was observed and the related substances were determined after 10 days and 30 days of placement respectively, the purity change of the compound after 10 days and the purity change of the compound after 30 days were analyzed to investigate the stability. The stability study data is shown in Table 2.

[0150] Table 2. Stability study data

[0151] The experimental data shows that under high temperature conditions, the compound of formula I free base amorphous, the compound of formula I free base crystal form and the compound of formula I hydrochloride amorphous all show high stability and are basically not degraded under high temperature conditions. Among them, the compound of formula I free base amorphous and the compound of formula I free base crystal form have higher stability.

[0152] Example 8, stability experiment

[0153] 50 mg of the compound of formula I hydrochloride amorphous prepared in Example 1 and 50 mg of the compound of formula I free base amorphous prepared in Example 2 were weighed into PE self-sealing bags respectively, sealed with an aluminum foil bag, placed under accelerated test conditions (40 °C / 75%) for 30 days, the compound was observed and the related substances were determined, the purity change of the compound after 30 days was analyzed to investigate the stability. The stability study data is shown in Table 3.

[0154] Table 3. Stability study data

[0155] The experimental data show that under accelerated conditions, the free base amorphous form of the compound of formula I, the free base crystalline form of the compound of formula I and the hydrochloride salt amorphous form of the compound of formula I all exhibit high stability, and there is essentially no degradation under accelerated conditions. Among them, the stability of the free base amorphous form of the compound of formula I and the free base crystalline form of the compound of formula I is higher.

[0156] Example 9

[0157] This example synthesizes 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzoyl)azanediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxyl)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate), i.e. compound 4 in this application, according to the steps A and B in CN119490445A Example 1, or by other synthesis methods in the prior art.

[0158] Then, at room temperature, compound 4 (49 mg, 0.041 mmol), dioxane (2.0 mL) and concentrated hydrochloric acid (0.5 mL) were added, and the reaction was carried out at 45°C for 5 hours. After the reaction was completed, it was concentrated to dryness, and the residue was purified by reverse phase preparation, and dried by rotary evaporation to obtain a sticky substance (not solid, 15 mg).

[0159] MS (ESI) m / z = 363.3 [(M+2) / 2] + .

[0160] Comparative Example 1

[0161] Comparative compound 1 can be synthesized with reference to patent WO2020 / 247429A1.

[0162] Biological test evaluation

[0163] Test Example 1: BLI detection of the affinity of the compound of the application to Apo(a)

[0164] 1. Purpose of the experiment: The purpose of this test is to test the affinity of the compound of the application to Apo(a).

[0165] 2. Experimental instruments and reagents:

[0166] Molecular interaction analyzer (ForteBio Octet red 96e);

[0167] SA sensor (ForteBio);

[0168] 96-well plates were purchased from Greine.

[0169] 3. Experimental method:

[0170] Two 96-well plates were prepared, one as a sample plate and one as a pre-wetting plate, 200 μL was added to each well of the pre-wetting plate with solidification buffer, and the SA sensor was pre-wetted for at least ten minutes. All reagents and samples were added to another black sample plate, and after the addition was completed, the sensor disk and sample plate were placed in the ForteBio Octet red 96e instrument. The program detection was set in order. The experimental temperature was set to 30℃, and the collection frequency was set to 5.0HZ. The biosensor was run in 1×PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA for 60s in the first column, which was the baseline step. The biotin-labeled apolipoprotein (a) was diluted to 40 μg / mL with 1×PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA, and added to the second column, and the column was run for a period of time until the solidification amount on the sensor reached 2.0nm. The biosensor was run in 1×PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA for 60s in the third column, which was the baseline step. The compound was diluted to 100nM with 1×PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA, and added to the fourth column, and the sensor was run in the column for 60s. The sensor was run in 1×PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA for 120s in the third column, and in the process the compound was dissociated from the sensor. The affinity constant KD reflects the size of the binding ability of the interaction, and when the concentration of the analyte is KD, the equilibrium signal Req is half of Rmax. The results show that the compound of the present application has strong binding force with human Apo(a) protein.

[0171] Test example 2: In vivo Lp(a) inhibition in cynomolgus monkeys

[0172] 1. Purpose of the experiment: The purpose of this test is to test the inhibitory effect of the compound of the present application on Lp(a) in cynomolgus monkeys.

[0173] 2. Experimental instruments and reagents:

[0174] Automatic biochemical analyzer (Hitachi 7600 type).

[0175] 3. Experimental method:

[0176] Cynomolgus monkeys were housed under standard light cycle (12 hours light / 12 hours dark), at room temperature 18-26 °C and 40-70% relative humidity, with 24 hours of uninterrupted access to drinking water, and the animals were provided with feed twice daily, in the morning (approximately 10:30) and in the afternoon (approximately 15:00). Cynomolgus monkeys were randomized (n=3 / group) for the study by body weight and baseline serum Lp(a) concentration 5 days prior to the study. The dosing volume was calculated based on the animal body weight on the day of the first dose, and the dosing volume was 5 mL / kg, with a dose of 3 mg / kg, administered orally by gavage once daily for 5 consecutive days, and the vehicle was 1% HEC, 0.25% Tween 80. Blood samples of 1 mL were collected from the cephalic or saphenous vein during the acclimation period (after an overnight fast), prior to dosing on Day 1, and 8 hours post-dose on Day 5. The serum was separated by centrifugation at 4 °C for 10 min at 3500 rpm after the whole blood was allowed to stand at room temperature for 30 min. Serum Lp(a) levels were measured using a fully automated biochemical analyzer. The percent reduction of Lp(a) for each group was determined by setting the mean Lp(a) level prior to dosing as 0% inhibition. The results confirmed that the compounds of the present application have a good effect on reducing the plasma Lp(a) level in vivo. The in vivo Lp(a) inhibition rate of the compounds of the present application in cynomolgus monkeys is shown in the following table:

[0177] Test Example 3: In vivo exposure determination in beagle dogs

[0178] 1. Purpose of the experiment: The purpose of this test was to determine the exposure of the compound in beagle dogs.

[0179] 2. Experimental method:

[0180] Beagle dogs were housed under standard light cycle (12 hours light / 12 hours dark), at room temperature 18-26 °C and 40-70% relative humidity, with free access to water and normal diet. Beagle dogs were randomized for the study by body weight 5 days prior to the study, with the oral dosing group (n=3 / group). The dosing volume was calculated based on the animal body weight on the day of the dose, and the dosing volume was 5 mL / kg, with a single oral gavage dose of 4.5 mg / kg, and the vehicle was 1% HEC, 0.25% Tween 80 in Water. Blood samples of approximately 1 mL were collected from the forelimb vein or other suitable vein at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h and 96 h post-dose. Each sample was collected into K2-EDTA tubes, placed on ice immediately after collection, and centrifuged (2200 g, 10 min, 2-8 °C) within 1 hour to separate plasma for drug concentration determination. The exposure in beagle dogs was calculated, and the results are shown in the following table:

[0181] Test Example 4: In vivo bioavailability determination in cynomolgus monkeys

[0182] 1. Experimental Purpose: The purpose of this test is to determine the bioavailability of the compound in cynomolgus monkeys.

[0183] 2. Experimental Method:

[0184] Cynomolgus monkeys were housed under standard photoperiod (12 hours light / 12 hours dark), at room temperature 18-26 °C and 40-70% relative humidity, with free access to water and normal diet. Cynomolgus monkeys were randomized by body weight 5 days prior to the study into intravenous and oral groups (n=2 / group) for study. The dosing volume was calculated based on animal body weight on the day of dosing, the dosing volume was 2 mL / kg, single intravenous dose, the dose was 1 mg / kg, the vehicle was 5% DMSO, 5% Solutol, 90% Saline. Blood samples were collected from the forelimb vein or other appropriate vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h and 72 h post-dose. The dosing volume was calculated based on animal body weight on the day of dosing, the dosing volume was 5 mL / kg, single oral gavage dose, the dose was 7.5 mg / kg, the vehicle was 1% HEC, 0.25% Tween 80 in Water. Blood samples were collected from the forelimb vein or other appropriate vein at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h and 72 h post-dose. Approximately 1 mL of each sample was collected, K2-EDTA anticoagulated, placed on ice after collection, and centrifuged for plasma separation (centrifugation conditions: 2200 g, 10 minutes, 2-8 °C) within 1 hour for blood concentration determination. The bioavailability F was calculated as shown in the table below:

[0185] Test Example 5: hERG test

[0186] 1. Experimental Purpose: The purpose of this test is to determine the inhibition rate of the compound on hERG potassium channel.

[0187] 2. Experimental Method:

[0188] The hERG current was recorded by whole-cell patch clamp technique. The HEK-293-hERG cell suspension was taken into a small culture dish and placed on the inverted microscope stage. After the cells adhered, they were perfused with extracellular fluid at a flow rate of 1-2 mL / min. The glass microelectrode was two-step drawn by a microelectrode puller, and after being filled with the electrode internal solution, its water resistance value was 2-5 MΩ. After establishing the whole-cell recording mode, the clamping potential was maintained at -80 mV. A depolarization voltage of +60 mV was given for 850 ms, and then repolarization to -50 mV was maintained for 1275 ms to induce hERG tail current. This set of pulse programs was repeated every 15 seconds throughout the experiment. After the current was stable, the drug was administered by continuous perfusion of the extracellular fluid from low concentration to high concentration. Starting from low concentration, continuous perfusion was performed until the drug effect was stable, and then the next concentration was perfused. The inhibition rate of the compound on the hERG potassium channel was calculated as shown in the following table:

[0189] Test Example 6: Salmonella typhimurium reverse mutation test

[0190] The recovered strain or single colony on the master plate was inoculated into broth, 100-120 rpm, 37±1°C constant temperature air bath shaker for 10-16 hours, and labeled for standby. The bottom agar medium (containing appropriate amount of agar, Vogel-Bonner buffer, 20% glucose solution and 20% magnesium sulfate solution) was poured into a six-well plate, about 20 mL-25 mL per well, and naturally cooled and solidified, and each well was labeled for standby. Each group had 3 holes for parallel test. The top agar medium was sterilized by high pressure and kept at about 65°C. In each test tube, 0.1 mL of negative control (DMSO) or positive control or test sample, 0.1 mL of bacterial solution, 0.5 mL of phosphate buffer (0.2M PBS) (-S9) or 0.5 mL of S9 mixture (+S9) and 2.5 mL of top medium were added, vortexed and uniformly spread on the culture dish with bottom agar medium. After natural cooling and solidification, the culture dishes were placed in a 37°C incubator for 48-72 hours. The culture dishes after 48-72 hours of culture were taken out, and the number of revertant colonies was counted, and the growth background was observed under a microscope to determine whether there was bacteriostasis or sterilization, and the test results were recorded. The mutagenicity of the compounds of the present application in each strain is shown in the following table: Note: In the "metabolic activation" column: + indicates the addition of S9 mixture; - indicates no addition of S9 mixture. In the "mutagenicity" column: + indicates mutagenic positive; - indicates mutagenic negative.

Claims

1. A solid form of a compound of Formula I: ###0001### or a salt thereof, characterized by, The solid forms include one or more of amorphous and crystalline forms; 2. The solid form of claim 1, wherein, The solid forms include the amorphous.

3. The solid form of claim 2, wherein, The X-ray powder diffraction pattern of the amorphous form of the compound of Formula I free base is substantially as shown in Figure 1.

4. The solid form of claim 2, wherein, The DSC pattern of the amorphous form of the compound of Formula I free base has an endothermic event in the range of 20 °C to 330 °C.

5. The solid form of claim 3, wherein, The DSC pattern of the amorphous form of the compound of Formula I free base has endothermic transitions at 70 °C to 80 °C and 260 °C to 270 °C.

6. The solid form of claim 2, wherein, The TG pattern of the amorphous form of the compound of Formula I free base has a weight loss in the range of room temperature to 160 °C.

7. The solid form of claim 6, wherein, The TG pattern of the amorphous form of the compound of Formula I free base has a weight loss of 4.1 ± 1% in the range of room temperature to 160 °C.

8. The solid form of claim 1, wherein, The solid form of the compound of Formula I free base is Form A, and the X-ray powder diffraction pattern of the compound of Formula I free base Form A has characteristic peaks at more than three of 7.78 ± 0.2°, 9.34 ± 0.2, 10.90 ± 0.2, 14.82 ± 0.2°, 15.64 ± 0.2°, 16.92 ± 0.2°, 18.02 ± 0.2°, 19.70 ± 0.2°, 20.46 ± 0.2°, 20.90° ± 0.2°, and 21.86° ± 0.2° in terms of 2-theta.

9. The solid form of claim 8, wherein, The X-ray powder diffraction pattern of the compound of Formula I free base Form A has characteristic peaks at 7.78 ± 0.2°, 16.92 ± 0.2°, and 20.90° ± 0.2° in terms of 2-theta, and optionally further comprising characteristic peaks at 9.34 ± 0.2°, 10.90 ± 0.2°, 14.82 ± 0.2°, 15.64 ± 0.2°, 18.02 ± 0.2°, 19.70 ± 0.2°, 20.46 ± 0.2°, and 21.86° ± 0.2° in terms of 2-theta.

10. The solid form of claim 8, wherein, The X-ray powder diffraction pattern of the compound of Formula I free base Form A has characteristic peaks at 7.78 ± 0.2°, 20.90° ± 0.2°, and 21.86° ± 0.2° in terms of 2-theta, and optionally further comprising characteristic peaks at 9.34 ± 0.2°, 10.90 ± 0.2°, 14.82 ± 0.2°, 15.64 ± 0.2°, 16.92 ± 0.2°, 18.02 ± 0.2°, 19.70 ± 0.2°, and 20.46 ± 0.2° in terms of 2-theta.

11. A process for the preparation of the amorphous free base of a compound of formula I according to any one of claims 1 to 7, characterized in that, Comprising: treating a solution comprising the compound of Formula I free base to obtain the amorphous form of the compound of Formula I free base, the treatment selected from one or more of lyophilization and spray drying.

12. A pharmaceutical composition, characterized by, A solid form of the compound of Formula I or a salt thereof according to any one of claims 1-10, the solid form comprising one or more of an amorphous form and a crystalline form.

13. A salt of a compound of formula I, characterized in that, the salt is an organic acid salt or an inorganic acid salt; the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, citric acid, gluconic acid, L-lactic acid, D-lactic acid, D / L-lactic acid, malic acid, aspartic acid, glutamic acid, or cinnamic acid; the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, or phosphoric acid;

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