Pharmaceutically acceptable salt of dihydropyridopyrimidine derivative, and crystal form and use thereof

Abstract

The present disclosure relates to a pharmaceutically acceptable salt of a dihydropyridopyrimidine derivative, and a crystal form and the use thereof. Specifically, provided in the present disclosure are a pharmaceutically acceptable salt of (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide, and a crystal form thereof and a preparation method therefor. The corresponding crystal form has a good stability and can be better used in clinical treatment.

Description

A pharmaceutically acceptable salt, crystalline form, and uses of a dihydropyridine-pyrimidine derivative. Technical Field

[0001] This disclosure pertains to the field of pharmaceutical technology and relates to a pharmaceutically acceptable salt of a dihydropyridinidine derivative, its crystalline form, and its uses. Background Technology

[0002] Cyclin-dependent kinase 7 (CDK7) is a unique member of the CDK family with dual functions in cell division and transcription regulation. CDK7 binds to cyclin H and MAT1 to form a trimerized cyclin-activated kinase (CAK). This kinase regulates the cell cycle by activating the activity of relevant CDK kinases (including CDK1, CDK2, CDK4, and CDK6) through phosphorylation. CDK7 also participates in the auxiliary regulation of transcription as a component of common transcription factor II H (TFIIH). It is involved in transcription initiation through phosphorylation of the Rbp1 subunit of RNA polymerase II (RNAPII) and then regulates transcription elongation through phosphorylation of the CDK9 complex.

[0003] PCT / CN2023 / 126415 provides a CDK7 inhibitor with the chemical name (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide, having the structure shown in Formula 1.

[0004] Salt formation can improve certain undesirable physicochemical or biological properties of drugs. Developing salts with superior physicochemical or pharmaceutical properties compared to (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide is of great significance. The crystal form of a pharmaceutically active ingredient often affects its chemical stability; different crystallization and storage conditions can lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other crystal forms. Given the importance of solid drug crystal forms and their stability in clinical treatment, in-depth research on the pharmaceutically acceptable salts and polymorphs of compound (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide is of great significance for developing drugs suitable for industrial production and with good biological activity. Summary of the Invention

[0005] This disclosure provides a pharmaceutically acceptable salt of the compound (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide, wherein the pharmaceutically acceptable salt is selected from hydrochloride, phosphate, sulfate, oxalate, hydrobromide, methanesulfonate, malate, citrate, tartrate, succinate, benzoate, benzenesulfonate, mandelate, hippurate, 2-hydroxyethylsulfonate, and p-aminobenzoate.

[0006] This disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of formula 1, comprising the step of reacting the compound of formula 1 with an acid selected from hydrochloric acid, phosphoric acid, sulfuric acid, oxalic acid, hydrobromic acid, methanesulfonic acid, malic acid, citric acid, tartaric acid, succinic acid, benzoic acid, benzenesulfonic acid, mandelic acid, hippuric acid, 2-hydroxyethylsulfonic acid, and p-aminobenzoic acid.

[0007] The solvents used in the salt formation of this disclosure are selected from, but are not limited to, acetone, ethyl acetate, n-hexane, ethanol, acetonitrile, isopropyl ether, and isopropanol.

[0008] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically usable salt also includes steps such as crystallization, filtration, washing, or drying.

[0009] In an optional embodiment, the chemical ratio of the compound of Formula 1 to the acid is 3:1 to 1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0010] In another embodiment, the chemical ratio of the compound of Formula 1 to the acid is 2:1 to 1:2.

[0011] In an optional embodiment, the chemical ratio of the compound of Formula 1 to hydrochloric acid is 1:1.

[0012] In an optional embodiment, the chemical ratio of the compound of Formula 1 to phosphoric acid is 1:3.

[0013] In an optional embodiment, the chemical ratio of the compound of Formula 1 to methanesulfonic acid is 1:1.

[0014] In an optional embodiment, the chemical ratio of the compound of Formula 1 to succinic acid is 1:1.

[0015] In an optional embodiment, the chemical ratio of the compound of Formula 1 to malic acid is 1:1.5.

[0016] In an optional embodiment, the chemical ratio of the compound of Formula 1 to benzoic acid is 1:1.

[0017] In some embodiments, the hydrochloride salt of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0018] This disclosure also provides a method for preparing the amorphous hydrochloride salt of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding hydrochloric acid and slurrying, and then adding n-hexane and slurrying.

[0019] In some embodiments, the phosphate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0020] This disclosure also provides a method for preparing the amorphous phosphate of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in ethyl acetate and adding phosphoric acid to slurry.

[0021] In some embodiments, the methanesulfonate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0022] This disclosure also provides a method for preparing the amorphous methanesulfonate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, adding methanesulfonic acid and slurrying, and then adding n-hexane and slurrying.

[0023] In some embodiments, the malate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0024] This disclosure also provides a method for preparing the amorphous malate of the compound of Formula 1, comprising dissolving the compound of Formula 1 in acetonitrile and adding malic acid to form a slurry.

[0025] In some embodiments, the citrate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0026] This disclosure also provides a method for preparing the amorphous citrate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in ethanol and adding citric acid to form a slurry.

[0027] In some embodiments, the tartrate salt of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0028] This disclosure also provides a method for preparing the amorphous tartrate salt of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in ethanol, adding tartaric acid and slurrying, and then adding n-hexane and slurrying.

[0029] In some embodiments, the succinate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0030] This disclosure also provides a method for preparing the amorphous succinate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in acetone, adding succinic acid and slurrying, and then adding n-hexane and slurrying.

[0031] In some embodiments, the benzoate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0032] This disclosure also provides a method for preparing the amorphous benzoate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding benzoic acid and slurrying, and then adding n-hexane and slurrying.

[0033] In some embodiments, the sulfate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0034] This disclosure also provides a method for preparing the amorphous sulfate of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in isopropyl ether and adding sulfuric acid to form a slurry.

[0035] In some embodiments, the hydrobromide of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0036] This disclosure also provides a method for preparing the amorphous hydrobromide of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in isopropyl ether and adding hydrobromic acid to form a slurry.

[0037] In some embodiments, the benzenesulfonate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0038] This disclosure also provides a method for preparing the amorphous benzenesulfonate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in isopropyl ether and adding benzenesulfonic acid to form a slurry.

[0039] In some embodiments, the 2-hydroxyethyl sulfonate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 3-50° at the diffraction angle 2θ.

[0040] This disclosure also provides a method for preparing the amorphous form of the compound 2-hydroxyethylsulfonate of Formula 1, comprising dissolving the compound of Formula 1 in isopropyl ether and adding 2-hydroxyethylsulfonic acid to form a slurry.

[0041] In some embodiments, the mandelate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0042] This disclosure also provides a method for preparing the amorphous mandelate of the compound shown in Formula 1, comprising the steps of dissolving the compound of Formula 1 in isopropyl ether and adding mandelic acid to form a slurry.

[0043] In some embodiments, the oxalate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0044] This disclosure also provides a method for preparing the amorphous oxalate of the compound of Formula 1, comprising the steps of dissolving the compound of Formula 1 in 95% acetone / isopropanol and adding oxalic acid to form a slurry.

[0045] In some embodiments, the p-aminobenzoate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0046] This disclosure also provides a method for preparing the amorphous form of p-aminobenzoic acid salt of the compound shown in Formula 1, comprising dissolving the compound of Formula 1 in 95% acetone / isopropanol and adding p-aminobenzoic acid to form a slurry.

[0047] In some embodiments, the hippurate of the compound of Formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 3-50°.

[0048] This disclosure also provides a method for preparing the amorphous hippurate of the compound of Formula 1, comprising dissolving the compound of Formula 1 in 95% acetone / isopropanol and adding hippuric acid to form a slurry.

[0049] The crystal form A of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.358, 7.726, 11.055, 15.606, 17.947, and 20.837 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0050] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.226, 7.358, 7.726, 8.567, 11.055, 14.763, 15.606, 17.947, 19.492, 20.837, and 22.276.

[0051] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.226, 7.358, 7.726, 8.567, 11.055, 14.763, 15.606, 16.509, 17.947, 19.492, 20.837, 22.276, 22.925, 25.245, and 25.983.

[0052] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 1.

[0053] This disclosure also provides a method for preparing crystal form A of the compound shown in Formula 1, wherein the method is selected from any of the following methods:

[0054] Method 1: Dissolve the compound of Formula 1 in solvent I and stir; the solvent I is selected from one or more of cyclohexane, ethyl acetate, tetrahydrofuran, and acetone;

[0055] Method 2: Dissolve the compound of Formula 1 in ethyl acetate, add cyclohexane, then add 20% ethyl acetate / cyclohexane (v / v) solvent and stir.

[0056] The crystal form B of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 7.706, 10.933, 15.423, 17.823, 19.635, and 21.235 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0057] In some embodiments, the X-ray powder diffraction pattern of crystal form B of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 7.706, 8.379, 10.933, 15.423, 17.823, 19.635, 20.479, 21.235, 23.392, and 25.302.

[0058] In some embodiments, the X-ray powder diffraction pattern of crystal form B of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 2.

[0059] This disclosure also provides a method for preparing crystal form B of the compound shown in Formula 1, the method comprising dissolving the compound of Formula 1 in a 20% tetrahydrofuran / petroleum ether (v / v) solvent and stirring.

[0060] The X-ray powder diffraction pattern of the compound of Formula 1 shown in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 8.195, 11.077, 12.296, 17.991, 20.875, and 24.904.

[0061] In some embodiments, the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 7.074, 8.195, 9.639, 11.077, 12.296, 14.027, 15.158, 17.991, 20.875, and 24.904.

[0062] In some embodiments, the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 7.074, 8.195, 9.639, 11.077, 12.296, 14.027, 15.158, 17.991, 18.959, 20.112, 20.875, 23.151, and 24.904.

[0063] In some embodiments, the X-ray powder diffraction pattern of the crystal form C of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 3.

[0064] This disclosure also provides a method for preparing crystal form C of the compound shown in Formula 1, wherein the method is selected from any of the following methods:

[0065] Method 1: Dissolve the compound of Formula 1 in solvent II and stir. Solvent II is selected from one or more of isopropyl ether, methyl tert-butyl ether, n-heptane, cyclohexane, isopropanol, acetone, tetrahydrofuran, ethyl acetate, dioxane, and dichloromethane.

[0066] Method 2: Add crystal form A of compound 1 to 5% acetone / n-heptane (v / v) and stir;

[0067] Method 3: Dry the crystal form B of compound 1 at 40°C;

[0068] Method 4: Add the compound of Formula 1 to solvent III and stir. Solvent III is selected from one or more of cyclohexane, cyclopentane, methylcyclopentane, ethyl acetate, tetrahydrofuran, acetone, toluene, and 2-methyltetrahydrofuran.

[0069] The crystal form D of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.257, 6.789, 7.485, 8.739, 11.254, 15.165, 15.993, and 20.249 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0070] In some embodiments, the X-ray powder diffraction pattern of the crystal form D of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 4.

[0071] This disclosure also provides a method for preparing the crystal form D of the compound shown in Formula 1, the method comprising dissolving the compound of Formula 1 in methyl tert-butyl ether and stirring at -6°C.

[0072] The crystal form E of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.157, 10.305, 14.405, 20.516, 21.345, and 21.754 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0073] In some embodiments, the crystal form E of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 5.165, 7.157, 10.305, 14.405, 18.355, 18.766, 20.516, 21.345, and 21.754.

[0074] In some embodiments, the X-ray powder diffraction pattern of the crystal form E of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 5.

[0075] This disclosure also provides a method for preparing crystal form E of the compound shown in Formula 1, the method comprising dissolving the compound of Formula 1 in 20% acetone / n-heptane (v / v) and stirring at -6°C.

[0076] The crystal form F of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.447, 9.194, 14.929, 18.001, 18.734, 20.862, and 22.409 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0077] In some embodiments, the X-ray powder diffraction pattern of the crystal form F of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 7.447, 9.194, 11.899, 13.350, 14.929, 18.001, 18.734, 20.862, and 22.409.

[0078] In some embodiments, the X-ray powder diffraction pattern of the crystal form F of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 6.

[0079] This disclosure also provides a method for preparing the crystal form F of the compound shown in Formula 1, the method comprising the steps of adding ethyl acetate of Formula 1 to cyclohexane and stirring, adding 5% acetone / n-heptane (v / v) and stirring.

[0080] The crystal form G of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 5.224, 7.888, 10.154, 14.794, and 18.854 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0081] In some embodiments, the X-ray powder diffraction pattern of the crystal form G of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 7.

[0082] This disclosure also provides a method for preparing the crystal form G of the compound shown in Formula 1, the method comprising the step of adding the compound of Formula 1 to 15% acetone / n-pentane (v / v) and stirring.

[0083] In some embodiments, this disclosure provides another method for preparing the crystal form G of the compound shown in Formula 1, the method comprising adding the compound of Formula 1 to 15% acetone / n-hexane and stirring.

[0084] The X-ray powder diffraction pattern of the compound of Formula 1 H provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 7.374, 10.348, 14.569, 18.854, 20.691, and 21.497.

[0085] In some embodiments, the crystal form H of the compound shown in Formula 1 has characteristic peaks at 5.257, 7.374, 10.348, 14.569, 16.277, 18.854, 20.691, and 21.497 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0086] In some embodiments, the X-ray powder diffraction pattern of the crystal form H of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 8.

[0087] This disclosure also provides a method for preparing the crystal form H of the compound shown in Formula 1, the method comprising the step of adding the compound of Formula 1 to 15% ethyl acetate / n-octane (v / v) and stirring.

[0088] In some embodiments, this disclosure also provides another method for preparing the crystal form H of the compound of Formula 1, the method comprising adding the compound of Formula 1 to 15% ethyl acetate / n-hexane (v / v) and stirring.

[0089] This disclosure also provides a pharmaceutical composition comprising any one of the aforementioned hydrochloride, phosphate, sulfate, oxalate, hydrobromide, methanesulfonate, malate, citrate, tartrate, succinate, benzoate, benzenesulfonate, mandelate, hippurate, 2-hydroxyethylsulfonate, or p-aminobenzoate or crystal form AH, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0090] This disclosure also provides a pharmaceutical composition prepared from any one of the aforementioned hydrochloride, phosphate, sulfate, oxalate, hydrobromide, methanesulfonate, malate, citrate, tartrate, succinate, benzoate, benzenesulfonate, mandelate, hippurate, 2-hydroxyethylsulfonate, or p-aminobenzoate or crystal form AH, and optionally a pharmaceutically acceptable excipient.

[0091] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing any one of the aforementioned hydrochloride, phosphate, sulfate, oxalate, hydrobromide, methanesulfonate, malate, citrate, tartrate, succinate, benzoate, benzenesulfonate, mandelate, hippurate, 2-hydroxyethylsulfonate, or p-aminobenzoate or any crystal form AH with a pharmaceutically acceptable excipient.

[0092] This disclosure also provides the use of the aforementioned hydrochloride, phosphate, sulfate, oxalate, hydrobromide, methanesulfonate, malate, citrate, tartrate, succinate, benzoate, benzenesulfonate, mandelate, hippurate, 2-hydroxyethylsulfonate, or p-aminobenzoate or any crystal form AH, or the aforementioned composition, in the preparation for the prevention and / or treatment of cancer.

[0093] The uses described in this disclosure, wherein the cancer is selected from chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer; preferably, the breast cancer is triple-negative breast cancer or ER / PR+HER2- breast cancer, more preferably, the ER / PR+HER2- breast cancer is ER / PR+HER2- breast cancer resistant to CDK4 / 6 inhibitors; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer; and the colorectal cancer is selected from colon cancer or rectal cancer.

[0094] The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0095] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0096] The starting material used in the crystal form preparation method disclosed herein can be any form of compound, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0097] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0098] The crystallization methods described in this disclosure include room temperature crystallization, cooling crystallization, solvent evaporation crystallization, and seed crystallization induction. The cooling temperature is selected from below 65°C, preferably from -10°C to 60°C. Stirring can also be performed during the crystallization process.

[0099] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0100] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guiding Principles on Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0101] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0102] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0103] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0104] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0105] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0106] The “excipients” described in this disclosure include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock. Attached Figure Description

[0107] Figure 1 shows the XRPD spectrum of crystal form A of compound 1.

[0108] Figure 2 shows the XRPD spectrum of crystal form B of compound 1.

[0109] Figure 3 shows the XRPD spectrum of crystal form C of compound 1.

[0110] Figure 4 shows the XRPD spectrum of crystal form D of compound 1.

[0111] Figure 5 shows the XRPD spectrum of crystal form E of compound 1.

[0112] Figure 6 shows the XRPD spectrum of crystal form F of compound 1.

[0113] Figure 7 shows the XRPD spectrum of crystal form G of compound 1.

[0114] Figure 8 shows the XRPD spectrum of crystal form H of compound 1.

[0115] Figure 9 shows the XRPD spectrum of compound 1 in its amorphous form. Detailed Implementation

[0116] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0117] Test conditions of the instruments used in the experiment:

[0118] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0119] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0120] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0121] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0122] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0123] XRPD (X-ray Powder Diffraction) was used for analysis: measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data collected included: Cu anode (40 kV, 40 mA), Cu-Kα1 rays. Scanning mode: θ / 2θ, scanning range (2θ range): 3°~48°.

[0124] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10℃ / min. The specific temperature range was referenced from the corresponding spectra (mostly 25-160℃), and the nitrogen purging rate was 50mL / min.

[0125] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10℃ / min, and the specific temperature range was referenced from the corresponding spectrum (mostly 30-300℃). The nitrogen purging rate was 50mL / min.

[0126] DVS stands for Dynamic Moisture Adsorption: The detection method is SMSDVS Advantage, with humidity changes of 50%-95%-0%-95%-50% at 25℃, in 10% increments (5% in the final step) (specific parameters are subject to the corresponding chromatograms; the methods listed here are the most commonly used). The judgment criterion is that dm / dt is not greater than 0.002%.

[0127] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0128] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0129] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0130] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0131] Example 1: Preparation of Compound 1

[0132] (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide

[0133] first step

[0134] Preparation of compound 1c

[0135] At room temperature, 1a (500 mg, 1.753 mmol) and HBTU (1329 mg, 3.5 mmol) were dissolved in DCM (7 mL) and stirred for 5 minutes. K2CO3 (726 mg, 5.26 mmol) and 1b (134.4 mg, 2.63 mmol) were then added. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was extracted, concentrated, and dried to obtain a crude product. The crude product was purified by column chromatography to obtain compound 1c (900 mg, 2.83 mmol).

[0136] MS m / z(ESI): 319.2 [M+H] + .

[0137] Step 2

[0138] Compound 1d preparation

[0139] Under a hydrogen atmosphere, 10% palladium Pd / C was added to a 15 mL solution of compound 1c (900 mg, 2.83 mmol) in ethyl acetate. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to give crude product 1d (260 mg). This crude product (260 mg) could be used directly in the next reaction.

[0140] MS m / z (ESI): 185.1 [M+H] +

[0141] Step 3

[0142] Preparation of compound 1e

[0143] Under a nitrogen atmosphere, LiAlH4 (82.0 mg, 2.17 mmol) was added to anhydrous THF (5.0 mL). After cooling to -78 °C, a THF solution of compound 1d was added dropwise, and the mixture was stirred for 30 minutes. The reaction mixture was then heated to 50 °C and reacted for 2 hours, followed by quenching with ammonium chloride solution. The crude product was obtained by extraction, concentration, and drying. The crude product was purified by preparative HPLC to obtain compound 1e (40.0 mg, yield 21%).

[0144] MS m / z (ESI): 171.1 [M+H] +

[0145] Step 4

[0146] Preparation of compound 1l

[0147] At room temperature, DMF-DMA (12.3 g, 103 mmol, 13.7 mL, 2.00 eq) was slowly added dropwise to a DMF (50 mL) solution of compound 1k (11.0 g, 51.6 mmol, 1.00 eq). The reaction solution was heated to 90 °C and stirred for 18 hours. Water (150 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (100 mL x 3). The organic phases were combined and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 1 L (12 g).

[0148] MS m / z(ESI): 269.1 [M+H] + .

[0149] Step 5

[0150] Preparation of compound 1m

[0151] At room temperature, EtONa (6.69 g, 98.4 mmol) was slowly added to EtOH (200 mL) containing compound 1l (12.0 g, 44.7 mmol) and 2-methylisothiourea sulfate (24.9 g, 89.4 mmol, 2.00 eq). The reaction mixture was heated to 90 °C and stirred for 12 hours. After cooling to room temperature, H2O (150 mL) was added, and the mixture was extracted with EtOAc (60 mL x 5). The organic phases were combined and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether as the eluent: 10-30% ethyl acetate, to give compound 1m (6.20 g, 21.0 mmol, yield 46.9%). MS m / z (ESI): 296.1 [M+H] + .

[0152] Step 6

[0153] Preparation of intermediate 1n

[0154] At 0°C, m-CPBA (10.3 g, 50.7 mmol) was added to a DCM (100 mL) solution of compound 1m (5.00 g, 17.0 mmol), and the mixture was stirred for 2 hours. The reaction solution was then brought to room temperature and stirred for 10 hours. The mixture was cooled to 0°C, and Na2SO3 (10%, 40 mL) was added to the reaction solution. The mixture was extracted with DCM (30 mL x 3), and the organic phases were combined and washed once with saturated brine (50 mL). The mixture was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.

[0155] The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 10-30% ethyl acetate as the eluent, to give compound 1n (2.7 g, 8.25 mmol, yield 48.7%).

[0156] MS m / z(ESI): 328.1 [M+H] + .

[0157] 1H NMR(400MHz, CDCl3)δ8.59(s,1H),5.08,5.02(m,1H),4.82(s,1H),4.33-4.27 (m,1H),3.29(s,3H),3.13-3.06(m,1H),2.67-2.63(m,1H),1.45(s,9H),1.05 -1.03(m,3H).

[0158] Compound 1n was resolved by a chiral column (column: Chiralcel OD-3, 150×4.6mm ID, 3um) with mobile phases: A: supercritical CO2 fluid and B: methanol (0.1% IPAm, v / v) to give 1n-1 and 1n-2.

[0159] Compound 1n-1 (retention time 2.770 minutes)

[0160] MS m / z(ESI): 328.1 [M+H] + .

[0161] 1H NMR (400MHz, CDCl3) δ8.59 (s, 1H), 5.08-5.03 (m, 1H), 4.82 (br s,1H),4.32-4.27(m,1H),3.29(s,3H),3.13-3.06(m,1H),2.67-2.63(m,1H),1.43(s,9H),1.05 -1.03(m,3H)

[0162] Compound 1n-2 (retention time 2.469 minutes).

[0163] Step 7

[0164] Preparation of intermediate 1p

[0165] At room temperature, 1o (380 mg, 3.42 mmol) was added to a 2 mL solution of t-BuOH containing 140 mg (0.428 mmol). The reaction mixture was heated to 100 °C and stirred for 12 hours. The mixture was then concentrated under reduced pressure to obtain a crude product, which was purified by rapid column chromatography using silica gel chromatography with 1-5% ethyl acetate in petroleum ether as the eluent, yielding compound 1p (100 mg, 0.279 mmol, 45.7%).

[0166] MS m / z (ESI): 359.1 [M+H] + .

[0167] Step 8

[0168] Preparation of compound 1q

[0169] At room temperature, TFA (0.8 mL, 10.8 mmol) was added to a DCM solution of compound 1p (100 mg, 0.279 mmol), and the mixture was stirred for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to give crude product 1q (96.0 mg, 0.186 mmol, 66.6%).

[0170] MS(ESI): m / z = 259.1 [M+H] + .

[0171] Step 9

[0172] Preparation of Compound 1

[0173] Compound 1e (20.0 mg, 0.094 mmol) and CDI (30 mg, 0.188 mmol) were dissolved in DMF (1.0 mL). Et3N (0.039 mL, 0.282 mmol) was added to the solution, and the mixture was stirred at room temperature for 0.5 hours. Compound 1q (24.3 mg, 0.094 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was purified by preparative HPLC to obtain compound 1 (5.0 mg, 0.011 mmol). X-ray powder diffraction analysis showed that the product was in a free, amorphous state, and the XRPD pattern is shown in Figure 9.

[0174] MS m / z (ESI): 455.4 [M+H] + .

[0175] 1H NMR (400MHz, DMSO-d6): δ8.10(s,1H),7.53(s,1H),7.38–7.27(m,4H),7.24–7.16(m,2H),6.86(d,J=7.8Hz,1H),6.09(s,1H),4.93–4.84(m, 1H),4.73–4.55(m,2H),4.47–4.33(m,2H),3.97(d,J=18.6Hz,1H),3.7 6(s,3H),2.81–2.71(m,2H),2.45–2.39(m,2H),0.93(d,J=6.7Hz,3H).

[0176] Test Example 1: Inhibitory activity test of compound 1 against ovarian cancer cells (OVCAR3)

[0177] Experimental steps

[0178] Ovarian cancer cells (OVCAR3) were cultured in RPMI 1640 with 10% FBS in a 37% CO2 incubator. On day one, cells were plated in 96-well plates at a concentration of 2500 cells / well and cultured overnight. On day two, cells were treated with compounds at a maximum concentration of 10 μM, diluted 3-fold, resulting in 9 concentrations, with a final DMSO concentration of 0.1%. After 5 days of continued culture, cell viability was assessed using the Celltiter Glo assay kit (Promega), following the instructions provided with the kit. Data were processed and IC50 was calculated using a GraphPad Prism 8.

[0179] The calculation formula is Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0180] X: Logarithm of compound concentration; Y: % inhibition.

[0181] Table 1

[0182] Test Example 2: Test of the inhibitory activity of compound 1 on tumor cells

[0183] Experimental steps

[0184] Breast cancer cells MCF7 (ATCC#HTB-22) and T47D (ATCC#HTB-133), and pancreatic cancer cells PANC-1 (ATCC#CRL-1469) were purchased from ATCC. Breast cancer cells MDA-MB-231 (Kebai#CBP60382), HCC1806 (Kebai#CBP60373), and MDA-MB-468 (Kebai#CBP60387), colorectal cancer cells HCT-116 (Kebai#CBP60028), and leukemia cells OCI-AML-3 (Kebai#CBP60817) and MV-4-11 (Kebai#CBP60522) were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0185] OCI-AML-3 was cultured in RPMI 1640 medium with 20% FBS; HCC1806 and T47D were cultured in RPMI 1640 medium with 10% FBS; MCF7, MDA-MB-231, MDA-MB-468 and PANC-1 were cultured in DMEM medium with 10% FBS; MV-4-11 was cultured in IMDM medium with 20% FBS; and HCT-116 was cultured in MC'5A medium with 10% FBS.

[0186] Palbociclib-resistant cells were constructed on MCF7 parental cells and labeled MCF7Palbo-R. Culture conditions were identical to those for the parental cells. All tumor cells were cultured in a 37°C, 5% CO2 incubator. Cells were seeded in 384-well plates at the following densities: 600 cells / well for MDA-MB-231; 500 cells / well for MDA-MB-468, PANC-1, and HCT-116; 200 cells / well for MCF7 and HCC1806; 800 cells / well for MCF7Palbo-R; and 3000 cells / well for OCI-AML-3 and MV-4-11. Cells were cultured overnight. The next day, the cells were treated with the compound at a maximum concentration of 10 μM, 3-fold diluted, with 9 concentrations, each in duplicate. The final concentration of DMSO was 0.1%. Cells were cultured in an incubator for 5 days with MDA-MB-231, PANC-1, MDA-MB-468, OCI-AML-3, and MV-4-11; and for 7 days with HCC1806, MCF7, MCF7Palbo-R, and HCT116. Cell viability was assessed using the Celltiter Glo assay kit (Promega), following the instructions provided with the kit. Readings were taken using an Envision microplate reader. Data were processed and IC50 was calculated using a GraphPad Prism 8. 50 .

[0187] The calculation formula is Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)). 50 -X)*HillSlope)).

[0188] X: Logarithm of compound concentration; Y: % inhibition.

[0189] Table 2

[0190] Example 2: Preparation of free crystal form A

[0191] Approximately 5 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of 20% acetone / cyclohexane solvent (v / v). The mixture was stirred and the reaction solution was slurried at 25°C for 1 day. The solid was centrifuged to obtain the title product. X-ray powder diffraction analysis identified the product as free crystal form A. The XRPD spectrum is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 3.

[0192] Table 3

[0193] Example 3: Preparation of free crystal form A

[0194] Approximately 5 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of solvent (as shown in Table 4 below). The reaction solution was stirred at 25°C for 1 day. The solid was centrifuged to obtain the title product. X-ray powder diffraction analysis showed that the product was in a free crystalline form, A.

[0195] Table 4

[0196] Example 4: Preparation of free crystal form A

[0197] Weigh approximately 30 mg of the compound shown in Formula 1, dissolve it in 0.1 ml of ethyl acetate, add 0.1 ml of cyclohexane to crystallize, add 0.3 ml of 20% ethyl acetate / cyclohexane (v / v) solvent, and slurry the reaction solution at 25°C for 1 day to obtain a solid. X-ray powder diffraction analysis showed that the product was in a free crystalline form A.

[0198] Example 5: Preparation of free crystal form B

[0199] Approximately 5 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of 20% tetrahydrofuran / petroleum ether (v / v) solvent. The reaction solution was stirred at 25°C for 1 day, and the solid was obtained by centrifugation. X-ray powder diffraction analysis identified the product as free crystalline form B. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 5.

[0200] Table 5

[0201] Example 6: Preparation of free crystalline form C

[0202] Approximately 5 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of 5% isopropanol / cyclohexane (v / v) solvent with stirring. The reaction solution was slurried at 25°C for 1 day. The solid was centrifuged and dried to obtain the title product. X-ray powder diffraction analysis identified the product as free crystalline form C. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 6. The TGA spectrum showed a weight loss of 0.12% before 100°C. The DSC spectrum showed an endothermic peak at 72.23°C.

[0203] Table 6

[0204] Example 7: Preparation of free crystalline form C

[0205] Approximately 5 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of solvent (as shown in Table 7 below). The reaction solution was stirred at 25°C for 1 day. The solid was centrifuged and dried to obtain the title product. X-ray powder diffraction analysis showed that the product was in the free crystalline form C.

[0206] Table 7

[0207] Example 8: Preparation of free crystalline form C

[0208] Weigh approximately 30 mg of the compound shown in Formula 1, dissolve it in 0.1 ml of ethyl acetate, add 0.1 ml of cyclohexane to crystallize, add 0.3 ml of 20% ethyl acetate / cyclohexane (v / v) solvent, stir the reaction solution at 25°C for 1 day, add 0.3 ml of 5% acetone / n-heptane (v / v) to the solid, stir, centrifuge, and dry to obtain the title product.

[0209] Example 9: Preparation of free crystalline form C

[0210] The compound B shown in Formula 1 can be dried at 40°C to obtain the C crystal form.

[0211] Example 10: Preparation of free crystal form D

[0212] Approximately 5 mg of the compound shown in Formula 1 was weighed and dissolved in 0.05 ml of methyl tert-butyl ether. The reaction solution was stirred at -6°C for 1 day, and the solid was obtained by centrifugation. X-ray powder diffraction analysis determined that the product was defined as free crystal form D. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 8.

[0213] Table 8

[0214] Example 11: Preparation of free crystal form E

[0215] Weigh about 5 mg of the compound shown in Formula 1 and dissolve it in 0.05 ml of 20% acetone / n-heptane (v / v). The reaction solution was stirred at -6°C for 2 days. The solid was centrifuged and dried to obtain the title product.

[0216] X-ray powder diffraction analysis identified the product as free crystalline form E. The XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks are listed in Table 9. The TGA spectrum shows a weight loss of 2.32% before reaching 90℃. The DSC spectrum shows an endothermic peak at 67.72℃.

[0217] Table 9

[0218] Example 12: Preparation of free crystal form F

[0219] Approximately 600 mg of the compound shown in Formula 1 was weighed and dissolved in 2 ml of ethyl acetate. 1.6 ml of cyclohexane was added to induce crystallization. 6 ml of 5% acetone / n-heptane (v / v) was added and stirred for 24 h. The mixture was then centrifuged and dried to obtain the title solid. X-ray powder diffraction analysis identified the product as free crystalline form F. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 10. The TGA spectrum showed a weight loss of 2.91% before 85 °C. The DSC spectrum showed an endothermic peak at 64.44 °C.

[0220] Table 10

[0221] Example 13: Preparation of free crystal form G

[0222] Approximately 10 mg of compound E (formula 1) was weighed and added to 0.9 ml of 15% acetone / n-pentane (v / v). The reaction solution was stirred at 25°C for 2 days, and centrifuged to obtain the title solid. X-ray powder diffraction analysis identified the product as free crystal form G. The XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 11.

[0223] Table 11

[0224] Example 14: Preparation of free crystalline form H

[0225] Weigh approximately 10 mg of the compound E crystal form shown in Formula 1 and add it to 0.9 ml of 15% ethyl acetate / n-octane (v / v). The reaction solution is stirred at 25°C for 2 days. The solid is centrifuged to obtain the title product.

[0226] X-ray powder diffraction analysis revealed that the product was defined as free-state crystalline form H. The XRPD spectrum is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 12.

[0227] Table 12

[0228] Example 15: Preparation of hydrochloride

[0229] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 mL of ethyl acetate. Hydrochloric acid solution (2 mol / L, 10.5 μL) was added, and the mixture was stirred at 25°C for one day. Then, 0.2 mL of n-hexane was added, and the mixture was stirred for another day. The mixture was centrifuged and dried to obtain the title product. X-ray powder diffraction analysis showed that the product was an amorphous hydrochloride salt, and the XRPD spectrum showed no obvious characteristic peaks. Ion chromatography analysis revealed a chloride ion content of 7.5%.

[0230] Example 16: Preparation of Phosphate

[0231] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 mL of ethyl acetate. Phosphoric acid solution (2 mol / L, 10.5 μL) was added, and the mixture was stirred at 25 °C for one day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous phosphate, and no obvious characteristic peaks were observed in XRPD. Ion chromatography analysis revealed a phosphate ion content of 40.8%.

[0232] Example 17: Preparation of methanesulfonate

[0233] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 ml of acetone. Then, 10.5 μL of methanesulfonic acid solution (2 mol / L) was added, and the mixture was stirred at 25°C for one day. Next, 0.2 ml of n-hexane was added, and the mixture was stirred for another day. The mixture was then centrifuged and dried to obtain the title product. X-ray powder diffraction analysis showed that the product was an amorphous methanesulfonate, and the XRPD spectrum showed no obvious characteristic peaks. Ion chromatography analysis revealed that the methanesulfonate ion content was 15.6%.

[0234] Example 18: Preparation of malate

[0235] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 ml of acetonitrile. 3 mg of solid malic acid was added, and the mixture was stirred at 25°C for one day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous malate, and the XRPD spectrum showed no obvious characteristic peaks. Ion chromatography analysis revealed that the malate ion content was 30.8%.

[0236] Example 19: Preparation of Citrate

[0237] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 ml of ethanol. 4.2 mg of solid citric acid was added, and the mixture was stirred at 25°C for one day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous citrate salt, and the XRPD spectrum showed no obvious characteristic peaks.

[0238] Example 20: Preparation of tartrates

[0239] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 ml of ethanol. 3 mg of solid tartaric acid was added, and the mixture was stirred at 25°C for 1 day. Then, 0.2 ml of n-hexane was added and the mixture was stirred for another 1 day. The mixture was centrifuged and dried to obtain the title product. X-ray powder diffraction analysis showed that the product was an amorphous tartrate salt, and the XRPD spectrum showed no obvious characteristic peaks.

[0240] Example 21: Preparation of Succinate

[0241] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 ml of acetone. 2.9 mg of solid succinic acid was added, and the mixture was stirred at 25°C for one day. Then, 0.2 ml of n-hexane was added, and the mixture was stirred for another day. The mixture was centrifuged and dried to obtain the title product. X-ray powder diffraction analysis showed that the product was an amorphous succinate, and the XRPD spectrum showed no obvious characteristic peaks. Ion chromatography analysis revealed that the succinate ion content was 24.6%.

[0242] Example 22: Preparation of benzoate

[0243] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.066 ml of ethyl acetate. 2.5 mg of solid benzoic acid was added, and the mixture was stirred at 25°C for one day. Then, 0.2 ml of n-hexane was added, and the mixture was stirred for another day. The mixture was centrifuged and dried to obtain the title product. X-ray powder diffraction analysis showed that the product was an amorphous benzoate, and the XRPD spectrum showed no obvious characteristic peaks. Ion chromatography analysis revealed that the benzoate ion content was 20.7%.

[0244] Example 23: Preparation of Sulfate

[0245] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 mL of isopropyl ether. A sulfuric acid solution (2 mol / L, 5.25 μL) was added, and the mixture was stirred at 25 °C for one day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous sulfate, and the XRPD spectrum showed no obvious characteristic peaks.

[0246] Example 24: Preparation of hydrobromide

[0247] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 mL of isopropyl ether. Hydrobromic acid solution (2 mol / L, 10.5 μL) was added, and the mixture was stirred at 25 °C for 1 day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous hydrobromide, and the XRPD spectrum showed no obvious characteristic peaks.

[0248] Example 25: Preparation of benzenesulfonate

[0249] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of isopropyl ether. Then, 3.2 mg of solid benzenesulfonic acid was added, and the mixture was stirred at 25°C for 1 day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous benzenesulfonate, and the XRPD spectrum showed no obvious characteristic peaks.

[0250] Example 26: Preparation of 2-hydroxyethyl sulfonate

[0251] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 mL of isopropyl ether. Then, 10.5 μL of 2-hydroxyethylsulfonic acid solution (2 mol / L) was added, and the mixture was stirred at 25 °C for 1 day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous 2-hydroxyethylsulfonate, and the XRPD spectrum showed no obvious characteristic peaks.

[0252] Example 27: Preparation of Mandelate

[0253] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of isopropyl ether. 3 mg of solid mandelic acid was added, and the mixture was stirred at 25°C for 1 day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous mandelic acid salt, and the XRPD spectrum showed no obvious characteristic peaks.

[0254] Example 28: Preparation of oxalate

[0255] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of 95% acetone / isopropanol. 1.4 mg of solid oxalic acid was added, and the mixture was stirred at 25°C for 1 day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous oxalate, and the XRPD spectrum showed no obvious characteristic peaks.

[0256] Example 29: Preparation of p-aminobenzoate

[0257] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of 95% acetone / isopropanol. 2.1 mg of solid p-aminobenzoic acid was added, and the mixture was stirred at 25°C for 1 day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous p-aminobenzoate, and the XRPD spectrum showed no obvious characteristic peaks.

[0258] Example 30: Preparation of hippurate

[0259] Approximately 9 mg of the compound shown in Formula 1 was weighed and dissolved in 0.06 ml of 95% acetone / isopropanol. 2.7 mg of hippuric acid was added, and the mixture was stirred at 25°C for 1 day. After centrifugation and drying, the title product was obtained. X-ray powder diffraction analysis showed that the product was an amorphous hippurate, and the XRPD spectrum showed no obvious characteristic peaks.

[0260] Example 31: Preparation of free crystalline form C

[0261] Approximately 20 mg of the compound shown in Formula 1 was weighed and mixed with the solvents shown in Table 13. The mixture was then centrifuged and dried under vacuum at room temperature to obtain a solid product. X-ray powder diffraction analysis revealed that the product was in the free crystalline form C.

[0262] Table 13

Claims

1. A pharmaceutically acceptable salt of (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide as shown in Formula 1, said pharmaceutically acceptable salt being selected from hydrochloride, phosphate, sulfate, oxalate, hydrobromide, methanesulfonate, malate, citrate, tartrate, succinate, benzoate, benzenesulfonate, mandelate, hippurate, 2-hydroxyethylsulfonate, and p-aminobenzoate.

2. The medicinal salt according to claim 1, characterized in that, The chemical ratio of (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide to the acid is 3:1-1:3, preferably 2:1-1:2, more preferably 1:1 or 1:

2.

3. The method for preparing the pharmaceutically acceptable salt according to claim 1 or 2, comprising the step of reacting the compound of formula 1 with an acid, wherein the acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, oxalic acid, hydrobromic acid, methanesulfonic acid, malic acid, citric acid, tartaric acid, succinic acid, benzoic acid, benzenesulfonic acid, mandelic acid, hippuric acid, 2-hydroxyethylsulfonic acid, and p-aminobenzoic acid.

4. A crystal form A of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.358, 7.726, 11.055, 15.606, 17.947, and 20.837, with preferred peaks at 6.226, 7.358, 7.726, 8.567, 11.055, 14.763, 15.606, 17.947, and 19.

492. Characteristic peaks are found at 20.837 and 22.276, and more preferably at 6.226, 7.358, 7.726, 8.567, 11.055, 14.763, 15.606, 16.509, 17.947, 19.492, 20.837, 22.276, 22.925, 25.245, and 25.

983.

5. The crystal form A according to claim 4, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 1.

6. A method for preparing crystal form A as described in claim 4 or 5, wherein the method is selected from any of the following methods: Method 1: Dissolve the compound of Formula 1 in solvent I and stir; solvent I is selected from one or more of cyclohexane, ethyl acetate, tetrahydrofuran, and acetone; Method 2: Dissolve the compound of Formula 1 in ethyl acetate, add cyclohexane, then add 20% ethyl acetate / cyclohexane (v / v) and stir.

7. A crystal form C of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 8.195, 11.077, 12.296, 17.991, 20.875, and 24.904, preferably at 7.074, 8.195, 9.639, 11.077, 12.296, 14.027, 15.158, 17.991, 20.875, and 24.904, and more preferably at 7.074, 8.195, 9.639, 11.077, 12.296, 14.027, 15.158, 17.991, 18.959, 20.112, 20.875, 23.151, and 24.

904.

8. The crystal form C according to claim 7, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 3.

9. A method for preparing crystal form C as described in claim 7 or 8, wherein the method is selected from any of the following methods: Method 1: Dissolve the compound of Formula 1 in solvent II and stir. Solvent II is selected from one or more of isopropyl ether, methyl tert-butyl ether, n-heptane, cyclohexane, isopropanol, acetone, tetrahydrofuran, ethyl acetate, dioxane, and dichloromethane. Method 2: Add crystal form A of compound 1 to 5% acetone / n-heptane (v / v) and stir; Method 3: Dry the crystal form B of compound 1 at 40°C; Method 4: Add the compound of Formula 1 to solvent III and stir. Solvent III is selected from one or more of cyclohexane, cyclopentane, methylcyclopentane, ethyl acetate, tetrahydrofuran, acetone, toluene, and 2-methyltetrahydrofuran.

10. The crystal form according to any one of claims 4-5 and 7-8, wherein the 2θ angle error range is ±0.

20.

11. A pharmaceutical composition comprising a pharmaceutically acceptable salt of (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide as described in any one of claims 1-2, or the crystal form as described in any one of claims 4-5, 7-8, and optionally a pharmaceutically acceptable excipient.

12. A method for preparing a pharmaceutical composition, comprising the following steps: The step of mixing the pharmaceutically acceptable salt of (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide as described in any one of claims 1-2, or the crystal form and pharmaceutically acceptable excipient as described in any one of claims 4-5, 7-8.

13. Use of the salt of any one of claims 1-2, or the crystal form of any one of claims 4-5, 7-8, or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating and / or preventing diseases or conditions associated with abnormal activity of CDK7.

14. Use of the salt of any one of claims 1-2, or the crystal form of any one of claims 4-5, 7-8, or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is selected from breast cancer, colorectal cancer, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, and acute myeloid leukemia.

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