Crystal of 7h-pyrrolo[2,3-d]pyrimidine-4-amine derivative

Abstract

Provided is a crystal of a compound having EGFR inhibition ability or a salt thereof, said crystal being excellent in one or more characteristics of stability, hygroscopicity and oral absorbability. One aspect of the present invention provides a crystal form of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide the diffraction angle (2θ±0.2°) of which has a peak at a preset angle in the X-ray powder diffraction spectrum.

Description

[0089] Each crystal can also be produced by adding the crystal of interest as a seed crystal to a specific solvent. This specific solvent can be the same solvent used to obtain the crystals described above.

[0090] (Activities and uses) A crystal of Compound (1) according to an embodiment of the present invention has an excellent EGFR inhibitory activity. In particular, it has an excellent inhibitory activity against EGFR (Del19 / C797S), EGFR (L858R / C797S), EGFR (Del19 / T790M / C797S), and EGFR (L858R / T790M / C797S), and is useful as an antitumor agent. In addition, a crystal of Compound (1) according to an embodiment of the present invention has excellent selectivity for mutant EGFR and has the advantage of fewer side effects than those caused by wild-type EGFR and other kinases.

[0091] Herein, “wild-type EGFR” is represented, for example, by the amino acid sequence of GenBank accession number: NP 005219.2. “Exon 19” herein refers to the region 729-823 in the amino acid sequence of wild-type EGFR (e.g., GenBank accession number: NP 005219.2).

[0092] Herein, “Del19” refers to a mutation in which one or more amino acids are deleted in the exon 19 region of wild-type EGFR. Mutations including, in addition to the deletion in the region, insertion of any one or more amino acids are also included. The mutation of deletion in exon 19 include a mutation in which five amino acids spanning from glutamic acid at position 746 to alanine 750 at position 750 in the exon 19 region are deleted (Del E746-A750 (also referred to as d746-750)), a mutation in which deletion of seven amino acids spanning from leucine at position 747 to proline at position 753 in the exon 19 region is followed by insertion of serine (Del L747-P753insS), a mutation in which five amino acids spanning from leucine at position 747 to threonine at position 751 in the exon 19 region are deleted (Del L747-T751), and a mutation in which deletion of four amino acids spanning from leucine at position 747 to alanine at position 750 in the exon 19 region is followed by insertion of proline (Del L747-A750insP), etc. Preferably, it may be a mutation in which five amino acids spanning from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750).

[0093] The crystal of the present invention may be used in postoperative adjuvant chemotherapy that is given after surgical resection of a tumor to prevent recurrence, or in preoperative adjuvant chemotherapy given before surgical resection of a tumor.

[0094] While the tumor targeted by the present invention is not particularly limited, examples thereof include head and neck cancer, gastrointestinal cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, large bowel cancer (colorectal cancer, colon cancer, rectal cancer, anal cancer, etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, testicular mesothelioma, etc.)), breast cancer, genital cancer (ovarian cancer, vulvar cancer, uterine cancer (uterine cervical cancer, uterine body cancer, endometrial cancer, etc.), etc.), urogenital cancer (renal cancer, bladder cancer, prostate cancer, testicular tumor, urothelial cancer, renal pelvis cancer, urethral cancer, etc.), hematopoietic tumor (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, rhabdomyosarcoma, skin cancer, brain tumor, malignant schwannoma, neuroendocrine tumor, thyroid cancer, etc. Preferably, it is head and neck cancer, breast cancer, large bowel cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer, or brain tumor, and particularly preferably it is lung cancer. Here, cancers include not only their primary foci but also cancers that have metastasized to other organs (e.g., liver). Furthermore, a crystal of Compound (1) according to an embodiment of the present invention has an excellent inhibitory activity against mutant EGFR. Examples of such mutant EGFR include drug-resistant mutant EGFR and highly sensitive mutant EGFR. Therefore, the compound or a salt thereof of the present invention is also useful as an antitumor agent against the aforementioned malignant tumors with mutant EGFR.

[0095] As used herein, the term “effective amount” of a compound means the amount (therapeutically effective amount) of the compound of the present invention, which can cause a biological or medical response such as reduction or inhibition of enzyme and / or protein activity in a subject, which can ameliorate symptoms, alleviate conditions, slow or delay the progress of a disease, or the like. As used herein, the term “subject” encompasses mammals and non-mammals. According to an embodiment, the subject is a human, and may be a human who has been diagnosed as being in need of the treatment of a symptom, condition, or disease disclosed herein.

[0096] Crystals of Compound (1) or salts thereof, or co-crystals thereof can be used as medicines in various dosage forms depending on the purpose of treatment, with or without pulverizing the crystals, and can be used in formulations commonly used for pharmaceutical purposes. The dosage form may be, for example, either an oral dosage form such as a tablet, a capsule, granules, fine granules, powder, or a dry syrup; or a parenteral dosage form such as a suppository, an inhalant, a nasal spray, an ointment, a plaster, or an injection. Pharmaceutical compositions suitable for these dosage forms can be produced by formulation methods known and customary to those skilled in the art, using pharmacologically acceptable carriers.

[0097] An embodiment of the present invention provides an antitumor agent for oral administration comprising the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)). An embodiment of the present invention also provides a method for treating a tumor, the method comprising a step of orally administering an effective amount of the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) to a subject in need thereof. Moreover, an embodiment of the present invention provides use of the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) for producing an antitumor agent for oral administration. Furthermore, an embodiment of the present invention provides the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) for use in the treatment of a tumor by oral administration.

[0098] An embodiment of the present invention provides a pharmaceutical composition comprising the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)). A pharmaceutical composition according to an embodiment of the present invention comprises the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) and a pharmacologically acceptable carrier. Moreover, an embodiment of the present invention provides use of the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) for producing a pharmaceutical composition. Another embodiment of the present invention provides the above-described crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) for use as a medicine.

[0099] Various organic and inorganic carrier substances customarily used as formulation ingredients can be used as the pharmacologically acceptable carrier, and examples of them that can be blended include an excipient, a binder, a disintegrant, a lubricant, and a coating agent in solid formulations, and a solvent, a solubilizer, a suspending agent, an isotonic agent, a buffering agent, and a soothing agent in liquid formulations. In addition, an antiseptic, an antioxidant, a colorant, a sweetener, a stabilizer, and other formulation additive may also be used if necessary.

[0100] Examples of the excipient include starches, saccharides, polysaccharides, and inorganic compounds. Examples of starches include potato starch, corn starch, rice starch, and partially pregelatinized starch. Examples of saccharides include monosaccharides, disaccharides, trisaccharides, and sugar alcohols, such as lactose, white sugar, trehalose, D-mannitol, raffinose, xylitol, and erythritol. Examples of polysaccharides include cellulose and dextran, such as crystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Examples of inorganic compounds include silicates, such as light anhydrous silicic acid and calcium silicate. Examples of the binder include hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, syrup powder, and hypromellose. Examples of the disintegrant include sodium starch glycolate, calcium carmellose, sodium croscarmellose, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch. Examples of the lubricant include talc, magnesium stearate, sucrose fatty acid ester, stearic acid, and sodium stearyl fumarate. Examples of the coating agent include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, and white sugar. Examples of the solvent include water, propylene glycol, and physiological saline solution. Examples of the solubilizer include polyethylene glycol, alcohols such as ethanol, cyclodextrins, cyclodextrin derivatives, ionic surfactants, and nonionic surfactants, for example, sorbitan fatty acid esters such as polysorbate 80, sucrose fatty acid ester, and sodium lauryl sulfate. Examples of the suspending agent include carrageenan, crystalline cellulose^sodium carmellose, polyoxyethylene hydrogenated castor oil, gum arabic, and sodium alginate. Examples of the isotonic agent include sodium chloride, glycerol, and potassium chloride. Examples of the pH adjuster and the buffering agent include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and sodium dihydrogen phosphate. Examples of the soothing agent include procaine hydrochloride and lidocaine. Examples of the antiseptic include ethyl p-hydroxybenzoate, cresol, and benzalkonium chloride. Examples of the antioxidant include sodium sulfite, ascorbic acid, and natural vitamin E. Examples of the colorant include titanium oxide, iron sesquioxide, edible blue No. 1, and copper chlorophyll. Examples of the flavoring agent include aspartame, saccharin, sucralose, l-menthol, and mint flavor. Examples of the stabilizing agent include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutyl hydroxytoluene.

[0101] In the case of preparing an oral solid formulation, the crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) may be mixed with an excipient and optionally with a binder, a disintegrant, a lubricant, a colorant, a flavoring agent, etc., and then formulated into tablets, coated tablets, granules, powder, capsules, etc. by a conventional method. In the case of preparing an injection, the crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) may be mixed with a pH adjuster, a buffering agent, a stabilizer, an isotonic agent, a local anesthetic, etc., and then formulated into injections for subcutaneous, intramuscular, and intravenous use by a conventional method.

[0102] The amount of the crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) to be incorporated into each dosage unit form will vary depending on the symptom of the patient to whom it is applied, or on its formulation, etc. In general, the amount per dosage unit form in terms of Compound (1) in free form is desirably about 0.05 to 1,000 mg for oral formulations, about 0.1 to 500 mg for injections, and about 1 to 1,000 mg for suppositories or topical formulations.

[0103] Moreover, the daily dose of the crystal of Compound (1) (i.e., crystal of Compound (1) in free form or crystal of Compound (1) with an acid (crystal of salt or co-crystal)) in the above dosage form will vary depending on the symptom, body weight, age, sex, etc. of the patient. In general, the daily dose for adults (body weight: 50 kg) may usually be about 0.05 to 5,000 mg, and preferably 0.1 to 1,000 mg in terms of Compound (1) in free form. EXAMPLES

[0104] Hereinafter, the present invention will be further described in detail by means of examples, but the invention is not limited in any way by these examples. Although the invention is sufficiently described by the examples, it is understood that various changes and / or modifications may be made by those skilled in the art. Therefore, as long as such changes and / or modifications do not depart from the scope of the invention, they are encompassed by in the present invention.

[0105] In the following examples explaining compounds, % denotes weight percent unless otherwise noted.

[0106] Powder X-ray diffraction measurement Powder X-ray diffraction was measured under one of the following test conditions, after lightly pulverizing a suitable amount of test substance in an agate mortar as required.

[0107] Instrument: EMPYREAN manufactured by PANalytical (Method A) Reflection method (focusing method) Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scanned range: 20 = 5.0 to 40.0°. Step: 20 = 0.0131° Average time / step: 8.670 s Scan speed: 0.0015° / s Divergence slit: 1° Scattering slit: 2.0 mm Receiving slit: 8.0 mm Instrument: EMPYREAN manufactured by PANalytical (Method B) Transmission method Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scanned range: 20 = 2.0 to 40.0° Step: 20 = 0.0066° Average time / step: 8.670 s Scan speed: 0.0008° / s Divergence slit: 1 / 2° Scattering slit: 2.0 mm Receiving slit: None

[0108] The instrument, including data processing, was handled in accordance with the method and procedure indicated for each instrument. The values obtained from various spectra may somewhat vary depending on the direction of crystal growth, particle size, measurement conditions, and so on. Therefore, these values should not be strictly interpreted.

[0109] Simultaneous thermogravimetric-differential thermal analysis (TG-DTA) was performed on 1 to 5 mg of the test substance under the following test conditions. Instrument: TG / DTA7200 manufactured by Hitachi High-Tech Science Corporation Sample vessel: Made of aluminum Heating rate: Temperature was increased from 25OC to 400°C at 10°C / min. Atmosphere gas: Atmospheric air (200 mL / min) Control substance: Empty pan The instrument, including data processing, was handled in accordance with the method and procedure indicated for each instrument.

[0110] Example 1: Production of type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin=3-yl)=7H=pyrrolo[2i32d]pyrimidin=72yl)bicyclo[2.2.1]heptan212yl)=52 methylpyrazine-2-carboxamide (Compound (1)) (Step 1) Synthesis of tert-butyl(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate Tert-butyl(4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (65.9 g) synthesized according to the method described in Patent Literature 1 was dissolved in N-methylpyrrolidone (1,500 mL) by stirring at 90°C for 30 minutes in a nitrogen atmosphere. After cooling to 35°C, diisopropylethylamine (46.5 g), triethylsilylacetylene (33.7 g), copper(I) iodide (4.57 g), dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) (8.50 g), and N-methylpyrrolidone (80 mL) were added, and the mixture was stirred at 90°C for 2 hours in a nitrogen atmosphere. After cooling to 40°C, 10% aqueous sodium dihydrogen phosphate solution and ethyl acetate were added. The organic layer was washed with diluted ammonia and water, to which activated carbon (33.0 g) and SH silica gel (65.9 g) were added and the mixture was stirred at 40°C for 1 hour and at room temperature for 2 hours. The insoluble substance was filtered over Celite, and then solvent was removed under reduced pressure. Acetonitrile was added to the residue and the mixture was stirred at room temperature for 15 hours. The precipitated solid was filtered, washed with acetonitrile, and dried under reduced pressure to give the title compound (37.4 g).

[0111] (Step 2) Synthesis of 7-(4-aminobicyclo[2.2.1]heptan-1 -yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolor2,3-d]pyrimidin-4-amine To tert-butyl(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (65.0 g), 5-10% hydrochloric acid methanol solution (520 mL) was added and the mixture was stirred at 50°C for 3 hours in a nitrogen atmosphere. Under ice-cold conditions, 2 mol / L sodium hydroxide solution was added dropwise to bring the pH to around 12. The precipitated solid was filtered, washed with 50% methanol, and dried under reduced pressure to give the title compound (50.3 g).

[0112] (Step 3) Synthesis of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2 -carboxamide To a mixture of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d1pyrimidin-4-amine (48.3 g) obtained in Step 2, 5-methylpyrazine-2-carboxylic acid (13.4 g), 1-hydroxybenzotriazole monohydrate (16.0 g), diisopropylethylamine (24.6 g), and methylene chloride (1,450 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.9 g) was added in a nitrogen atmosphere and the mixture was stirred for 17 hours. The reaction solution was washed with 10% aqueous sodium dihydrogen phosphate solution, saturated aqueous sodium carbonate solution, and saturated saline solution, and dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was removed under reduced pressure. To the obtained residue, methanol was added and the mixture was stirred at room temperature for 2 hours. The precipitated solid was filtered, washed with methanol, and dried under reduced pressure to give the title compound (54.8 g).

[0113] (Step 4) Synthesis of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1 -yl)-5-methylpyrazine-2-carboxamide (Compound (1)) To a mixture of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (80.0 g), methylene chloride (1,000 mL), and methanol (1,000 mL), potassium carbonate (7.03 g) was added in a nitrogen atmosphere and the mixture was stirred for 18 hours. The insoluble substance was filtered over Celite, and the solvent was removed under reduced pressure. To the obtained residue, methanol and water were added and the mixture was stirred for 1 hour. The precipitated solid was filtered, washed with 50% methanol, and dried under reduced pressure to give the title compound (64.5 g) as a pale yellow solid (type III crystal). The structure of the obtained pale yellow solid was analyzed by 1H-NMR (instrument: AVNEO 400 manufactured by Bruker, 400 MHz, Scans: 4, DMSO-d6) and confirmed to be N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)).

[0114] The powder X-ray diffraction spectrum (method A) of the type III crystal obtained in Step 4 was acquired by the procedure described above and is shown in Figure 1. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (20 ± 0.2°): 6.6°, 8.8°, 11.6°, 12.3°, 13.8°, 17.9°, 18.6°, 21.3°, and 22.3 Other peaks are shown in Table 1 below. Table 1 Position of peak (°20) Intensity (cts) 6.6 377 7.9 75 8.8 191 11.6 220 12.3 140 13.2 1,026 13.8 3,936 15.0 350 15.7 926 15.9 510 17.2 53 17.9 325 Position of peak (°20) Intensity (cts) 18.6 1,578 19.7 61 20.2 68 21.3 413 22.3 659 23.0 125 23.6 179 24.1 156 25.6 778 26.0 820 26.6 328 27.0 625 Position of peak (°20) Intensity (cts) 28.3 63 29.1 105 30.7 235 31.6 114 32.2 101 32.9 53 33.5 67 33.8 77 34.6 47 35.2 94 36.6 46 The simultaneous thermogravimetric-differential thermal analysis curve of the crystal obtained in Step 4 was acquired by the procedure described above and is shown in Figure 2. An exothermic peak (onset value) was observed at around 228°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0115] Example 2: Production of type II crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)bicyclo[2.2.1]heptan- 1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) A type III crystal of Compound (1) in free form was synthesized in the same manner as in Example 1. The same procedure was employed for other examples, reference example, and comparative examples described below. Tetrahydrofuran (6 mL) was added to the type III crystal of Compound (1) in free form (300 mg), and the suspension was stirred at 25°C for about 24 hours. The resultant was filtered to collect the solid, which was dried under reduced pressure at room temperature for about 30.5 hours to give 199.3 mg of the title crystal.

[0116] The powder X-ray diffraction spectrum (method A) of the resulting crystal was acquired by the procedure described above and is shown in Figure 3. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (20 ± 0.2°): 7.8°, 10.6°, 14.0°, 14.8°, 15.6°, 17.2°, 20.1°, 21.6°, 22.2°, 24.7°, 25.8°, and 28.9° Other peaks are shown in Table 2 below. Table 2 Position of peak (°20) Intensity (cts) 7.8 413 8.6 71 10.6 454 12.4 102 13.1 78 14.0 1,012 14.4 675 14.8 2,212 15.1 330 15.6 601 17.2 289 18.4 223 19.0 256 20.1 390 20.6 375 Position of peak (°20) Intensity (cts) 21.2 317 21.6 3,076 22.2 1,525 22.7 79 23.3 107 24.1 240 24.7 648 25.8 578 26.2 273 26.8 101 27.4 452 27.6 273 28.2 160 28.9 1,042 29.4 251 Position of peak (°20) Intensity (cts) 29.8 126 30.4 121 30.9 272 31.9 199 32.7 130 33.4 69 34.1 98 34.7 118 35.7 64 37.4 58 38.3 78 38.9 60 39.4 51 The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 4. An exothermic peak (onset value) was observed at around 236°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0117] Reference example 1: Production of type VII crystal of N-(4-(4-amino-6-ethynyl-5-(qumolm-3-yl)-7H-pviTolo[2,3-d]pvrimidm-7-vl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) A mixture of water and ethanol (1:1 v / v) (6 mL) was added to the type III crystal of Compound (1) in free form (300 mg). The suspension was stirred at 50°C for about 2 hours, and then filtered to collect the solid, thereby obtaining type VII crystal in free form. The resultant was dried under reduced pressure at room temperature for about 65 hours to give 286.9 mg of the title crystal.

[0118] The powder X-ray diffraction spectrum (method B) of the resulting crystal was acquired by the procedure described above and is shown in Figure 5. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (20 ± 0.2°): 7.1°, 7.7°, 13.0°, 17.2°, 18.5°, 21.3°, 22.6°, 23.5°, 24.2°, and 26.1° The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 6. An exothermic peak (onset value) was observed at around 225°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0119] Comparative example 1: Production of type VIII crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) The type III crystal of Compound (1) in free form (10.0 g) was dissolved in dimethyl sulfoxide (140 mL) at 45°C, and cooled to 30-35°C. Then, dimethyl sulfoxide (10 mL) and water (37.5 mL) were added, and the mixture was stirred at room temperature for 5.5 hours and filtered to collect the solid, which was dried under reduced pressure at 50°C to give 9.6 g of the title crystal.

[0120] The powder X-ray diffraction spectrum (method B) of the resulting crystal was acquired by the procedure described above and is shown in Figure 7. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum were as follows. Characteristic diffraction angles (20 ± 0.2°): 7.1°, 7.8°, 12.8°, 13.6°, 14.2°, 14.8°, 17.0°, 18.3°, 21.2°, 22.5°, 24.0°, and 25.9° The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 8. An exothermic peak (onset value) was observed at around 207°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0121] Test Example 1: Solid stability test The solid stability of the type II crystal of Compound (1) in free form, the type III crystal of Compound (1) in free form, the type VII crystal of Compound (1) in free form, and the type VIII crystal of Compound (1) in free form obtained in the examples, reference example, and comparative example were evaluated after 4 weeks of storage by the following procedure. Storage conditions: 80°C (closed system) (HIFLEX (high-temperature storage chamber manufactured by ETAC)) Storage period: 4 weeks Storage volume: Approximately 30 mg Storage container: Glass bottle The results are shown in Table 3 below. Table 3 Chemical purity before storage Chemical purity after 4 weeks of storage at 80°C Change Type II crystal in free form 99.80% 99.78% -0.02% Type III crystal in free form 99.58% 99.60% +0.02% Type VII crystal in free form 99.63% 99.63% - Type VIII crystal in free form 99.62% 99.43% -0.19%

[0122] Changes in the mass of the related substances (the amounts of detected substances other than Compound (1)) were analyzed by HPLC according to the following method. Approximately 8 mg of each sample was weighed and dissolved in 1 mL of a chloroform-methanol mixture (1:1 v / v). Fifty pL of this solution was measured and diluted with 950 pL of an acetonitrile-water mixture (7:3), and 5 pL of the resulting solution was accurately measured and used as the sample for the analysis. HPLC assay (stability test) The mass of the related substances in the sample solution was determined by HPLC analysis. The instrument, including data processing, was handled in accordance with the method and procedure indicated for each instrument. Column: InertSustainSwift C18 (2.1 x 50 mm, 1.9 pm) manufactured by GL Sciences UV detection: 220 nm Column temperature: 40°C Flow rate: 0.3 mL / min Sample cooler: 10°C Sample concentration: 0.1 mg / mL Mobile phase A: 10 mmol / L phosphate buffer (pH 6.8) / acetonitrile (95:5) mixture Mobile phase B: Acetonitrile The gradients are shown in Table 4. Table 4 Time (min.) Mobile phase A (vol%) Mobile phase B (vol%) 0 80 20 18 21 79 20 21 79 20.5 80 20 25 80 20

[0123] As a result, the type II crystal of Compound (1) in free form, the type III crystal of Compound (1) in free form, and the type VII crystal of Compound (1) in free form were found to be extremely stable crystals with almost no increase in the related substances.

[0124] Test Example 2: Dynamic vapor sorption (DVS) test Vapor sorption tests were performed using the type II crystal of Compound (1) in free form, the type III crystal of Compound (1) in free form, the type VII crystal of Compound (1) in free form, and the type VIII crystal of Compound (1) in free form obtained in the examples, reference example, and comparative example. Vapor sorption tests were conducted under the following conditions. Approximately 10 mg of the sample was filled into a specialized quartz holder to continuously measure and record the weight of the sample at each humidity was under the following conditions. The instrument, including data processing, was handled in accordance with the method and procedure indicated for each instrument. Instrument: VTI-SA+ (manufactured by TA Instruments) Drying temperature: 60°C Heating rate: 1°C / min Equilibration of drying: Confirmation of no more than 0.01 wt% decrease in 5 minutes within a period not exceeding 300 minutes Measurement temperature: 25°C Equilibration of humidification: Confirmation of no more than 0.01 wt% increase in 5 minutes within a period not exceeding 120 minutes Relative humidity program: Increase from 5 to 95% RH in increments of 5% RH, and decrease from 95% to 5% RH in increments of 5% RH. Changes in the weight over the range of the measurement conditions obtained in these tests are shown in Figures 9 through 12.

[0125] As shown in the figures, the type II crystal of Compound (1) in free form showed a weight increase of 0.16% under 95% relative humidity in the vapor sorption test, and this weight increase of less than 1% indicates that it was hardly hygroscopic. The type III crystal of Compound (1) in free form showed hygroscopicity that sharply increased at above 65% RH, but this adsorption was found to be reversible since desorption of water occurred when the humidity was decreased. On the other hand, as shown in the figures, the type VII crystal in free form and the type VIII crystal in free form showed mass increases of 1% or more under 95% relative humidity in the vapor sorption test, indicating that they were highly hygroscopic. Furthermore, these crystals did not cause desorption of water even when the humidity was decreased, indicating that the reaction was irreversible.

[0126] The above results showed that the type II crystal of Compound (1) in free form had lower hygroscopicity than the type III crystal of Compound (1) in free form, the type VII crystal of Compound (1) in free form, and the type VIII crystal of Compound (1) in free form, and was superior in terms of industrial manufacturing of a pharmaceutical product of stable quality among the candidate compounds for the development of the pharmaceutical product. The type III crystal in free form was considered to be useful, like the type II crystal in free form, as a candidate compound for a pharmaceutical product in controlled humidity environment, because it has low hygroscopicity as long as RH is less than 65%. The type II crystal of Compound (1) in free form and the type III crystal of Compound (1) in free form were confirmed to have excellent properties as pharmaceutical products or active pharmaceutical ingredients.

[0127] Example 3: Production of type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)bicyclo[2.2.1]heptan-1 -yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with succinic acid Succinic acid (6.88 g) and acetonitrile (90 mL) were added to the type III crystal of Compound (1) in free form (10 g), and the suspension was stirred at 50°C for about 1 hour, and then filtered to collect the solid. The solid was suspended / washed twice with ethanol and dried under reduced pressure at 40°C for about 19.5 hours to give 11.71 g of the title crystal.

[0128] The powder X-ray diffraction spectrum (method A) of the resulting crystal was acquired by the procedure described above and is shown in Figure 13. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (29 ± 0.2°): 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° Other peaks are shown in Table 5 below. Table 5 Position of peak (°29) Intensity (cts) 7.5 54 8.2 93 10.4 350 11.6 84 12.3 545 13.3 879 13.7 54 14.6 825 14.9 467 15.7 484 16.7 123 17.2 788 18.3 1,114 18.6 123 19.7 2,557 20.4 248 Position of peak (°29) Intensity (cts) 20.8 372 21.2 53 21.7 106 22.3 491 22.8 78 23.2 368 23.5 334 24.4 491 24.7 784 25.4 110 26.0 358 27.5 469 28.2 59 28.6 79 29.2 168 29.4 202 Position of peak (°29) Intensity (cts) 29.7 215 30.4 174 31.1 269 31.6 130 32.1 28 32.6 51 33.3 176 33.7 56 34.2 123 34.8 81 35.2 125 36.7 65 37.6 56 38.1 54 The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 14. An endothermic peak (onset value) was observed at around 202°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0129] Example 4: Production of type I crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)bicyclo[2.2.1]heptan-1 -yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with sorbic acid Sorbic acid (109 mg) and acetonitrile (5 mL) were added to the type III crystal of Compound (1) in free form (500 mg). The suspension was stirred at 50°C for about 7.5 hours, and then filtrated to collect the solid, which was dried under reduced pressure at 40°C for about 13.5 hours to give 568.4 mg of the title crystal.

[0130] The powder X-ray diffraction spectrum (method A) of the resulting crystal was acquired by the procedure described above and is shown in Figure 15. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (20 ± 0.2°): 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° Other peaks are shown in Table 6 below. Table 6 Position of peak (°20) Intensity (cts) 5.2 267 7.5 48 9.1 105 10.3 84 12.3 629 12.6 1,011 13.7 88 14.3 109 14.7 525 15.4 860 15.9 807 16.2 163 17.1 858 17.6 257 18.9 1,892 19.6 167 Position of peak (°20) Intensity (cts) 20.6 118 21.6 605 22.2 1,384 22.5 144 22.9 87 24.1 329 24.7 98 25.2 157 25.8 1,157 26.3 82 26.7 144 27.4 707 28.0 162 28.3 152 28.9 493 29.4 208 Position of peak (°20) Intensity (cts) 29.9 154 30.5 71 30.8 85 31.5 78 32.2 32 32.8 116 34.1 85 34.9 63 36.0 77 36.7 62 37.1 50 37.4 52 38.5 105 38.9 126 39.5 28 The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 16. An endothermic peak (onset value) was observed at around 173°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0131] Comparative example 2: Production of type I crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin232yl)27H2pyrrolo[2J32d]pyrimidin-2-yl)bicyclo[2j2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with citric acid Citric acid (560 mg) and 10 mL of ethanol were added to the type III crystal of Compound (1) in free form (500 mg). The suspension was stirred at 25°C for about 5.5 hours, and then filtrated to collect the solid, which was dried under reduced pressure at 40°C for about 13.5 hours to give 664.3 mg of the title crystal.

[0132] The powder X-ray diffraction spectrum (method A) of the resulting crystal was acquired by the procedure described above and is shown in Figure 17. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (20 ± 0.2°): 5.6°, 8.7°, 9.6°, 11.2°, 13.0°, 13.9°, 15.2°, 16.8°, 20.9°, and 24.2° The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 18. An endothermic peak (onset value) was observed at around 191°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0133] Comparative example 3: Production of type IV crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolor2,3-d]pyrimidin-7-yl)bicyclor2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with citric acid Citric acid (37.3 mg) and tetrahydrofuran (3 mL) were added to the type III crystal of Compound (1) in free form (100 mg). The suspension was stirred at 50°C for about 47.5 hours, and then filtrated to collect the solid, which was dried under reduced pressure at 40°C for about 18.5 hours to give 85.6 mg of the title crystal.

[0134] The powder X-ray diffraction spectrum (method B) of the resulting crystal was acquired by the procedure described above and is shown in Figure 19. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (20 ± 0.2°): 5.4°, 11.0°, and 19.1° The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 20. An endothermic peak (onset value) was observed at around 149°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0135] Comparative example 4: Production of type I crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolor2,3-d]pyrimidin-7-yl)bicyclor2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with phosphoric acid Phosphoric acid (39.7 pL) and tetrahydrofuran (6 mL) were added to the type III crystal of Compound (1) in free form (300 mg). The suspension was stirred at 50°C for about 3 hours, and then filtrated to collect the solid, which was dried under reduced pressure at room temperature for about 40 minutes to give 111.6 mg of the title crystal.

[0136] The powder X-ray diffraction spectrum (method B) of the resulting crystal was acquired by the procedure described above and is shown in Figure 21. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included the following peaks. Characteristic diffraction angles (20 ± 0.2°): 5.3°, 8.6°, 10.6°, 11.1°, 12.5°, 13.5°, 17.3°, 19.7°, 22.3°, and 23.1° The simultaneous thermogravimetric-differential thermal analysis curve of the resulting crystal was acquired by the procedure described above and is shown in Figure 22. An exothermic peak (onset value) was observed at around 205°C in the simultaneous thermogravimetric-differential thermal analysis curve.

[0137] Test Example 3: Solid stability test The solid stability of the type III crystal of Compound (1) with succinic acid, the type I crystal of Compound (1) with citric acid, the type IV crystal of Compound (1) with citric acid, the type I crystal of Compound (1) with sorbic acid, and the type I crystal of Compound (1) with phosphoric acid obtained in the examples, reference example, and comparative examples were evaluated after 4 weeks of storage. The evaluation method, storage, and measurement conditions were as described in Test Example 1. The results are shown in Table 7 below. Table 7 Chemical purity before storage Chemical purity after 4 weeks of storage at 80°C Change Type III crystal of Compound (1) with succinic acid 99.62% 99.63% +0.01% Type I crystal of Compound (1) with citric acid 99.75% 99.03% -0.72% Type IV crystal of Compound (1) with citric acid 99.91% 93.49% -6.42% Type I crystal of Compound (1) with sorbic acid 99.74% 99.72% -0.02% Type I crystal of Compound (1) with phosphoric acid 99.90% 99.50% -0.40%

[0138] As a result, the type III crystal of Compound (1) with succinic acid and the type I crystal of Compound (1) with sorbic acid were found to be extremely stable crystals with almost no increase in the related substances. On the other hand, the type I crystal of Compound (1) with citric acid, the type IV crystal of Compound (1) with citric acid, and the type I crystal of Compound (1) with phosphoric acid were found to be unstable crystals with decreases in purity.

[0139] Test Example 4: Dynamic vapor sorption (DVS) test Vapor sorption tests were performed using the type III crystal of Compound (1) with succinic acid, the type I crystal of Compound (1) with citric acid, the type IV crystal of Compound (1) with citric acid, the type I crystal of Compound (1) with sorbic acid, and the type I crystal of Compound (1) with phosphoric acid obtained in the examples, reference example, and comparative examples. Vapor sorption tests were conducted under the same conditions as in Test Example 2. Changes in the weight over the range of the measurement conditions obtained in these tests are shown in Figures 23 through 27.

[0140] As shown in the figures, the type III crystal of Compound (1) with succinic acid and the type I crystal of Compound (1) with sorbic acid showed weight increases of 0.28% and 0.26%, respectively, under 95% relative humidity in the vapor sorption test, and these weight increases of less than 1% indicate that they were hardly hygroscopic. On the other hand, as shown in the figures, the type I crystal of Compound (1) with citric acid, the type IV crystal of Compound (1) with citric acid, and the type I crystal of Compound (1) with phosphoric acid each showed a mass increase of 1% or more under 95% relative humidity in the vapor sorption test, indicating that they were highly hygroscopic.

[0141] The above results showed that the type III crystal of Compound (1) with succinic acid and the type I crystal of Compound (1) with sorbic acid had lower hygroscopicity than the type I crystal of Compound (1) with citric acid, the type IV crystal of Compound (1) with citric acid, and the type I crystal of Compound (1) with phosphoric acid, and were superior in terms of industrial manufacturing of a pharmaceutical product of stable quality among the candidate compounds for the development of the pharmaceutical product. The type III crystal of Compound (1) with succinic acid and the type I crystal of Compound (1) with sorbic acid were confirmed to have excellent properties as pharmaceutical products or active pharmaceutical ingredients.

[0142] Test Example 5: Plasma concentration determination test The Compound (1) in free form (type II crystal), the type III crystal of Compound (1) with one equivalent of succinic acid, and the type I crystal of Compound (1) with one equivalent of sorbic acid obtained in the examples were tested for plasma concentrations in male beagle dogs after oral administration under hypochlorhydria conditions.

[0143] (Selection of beagle dogs) In order to select three male beagle dogs for the test, plasma concentrations were determined in five male beagle dogs under hypochlorhydria conditions after administration in a solution form and administration in a capsule-filled form. Three dogs with larger differences in AUClast (area under the plasma concentration-time curve from 0 hours after administration to the point at which the final concentration can be calculated by the linear trapezoidal method before Tmax and by the log-trapezoidal method after Tmax) and Cmax (maximum plasma concentration) between the administration in the solution form and the administration in the capsule-filled form were selected. Subsequently, tests were conducted to determine plasma concentrations in them after oral administration of the Compound (1) in free form (type II crystal), the type III crystal of Compound (1) with one equivalent of succinic acid, and the type I crystal of Compound (1) with one equivalent of sorbic acid in capsule-filled forms. The following procedures were employed for the preparation of a liquid dosage, capsule filling, and animal experiments.

[0144] (Methods for preparation of liquid dosage, capsule filling, and animal experiments) Compound (1) in free form was dissolved in a 20% HP-P-CD solution containing 0.1N hydrochloric acid to prepare a solution of 20 mg / 5 mL. Compound (1) in free form (type II crystal), the type III crystal of Compound (1) with one equivalent of succinic acid, and the type I crystal of Compound (1) with one equivalent of sorbic acid were each filled into a gelatin capsule at 20 mg / kg in terms of the molecular weight of Compound (1) (free form). The male beagle dogs selected for the study were fasted starting between 11:00 a.m. to 12:00 p.m. on the day before Compound (1) was administered and fed after blood was collected 8 hours after the administration of the compound. The dogs were not allowed to drink water from 30 minutes before to 2 hours after the administration of the compound, but were allowed to drink freely at other time. Intravenous administration of atropine (atropine sulfate injection 0.5 mg “Fuso”) at a dose of 0.02 mg / kg was followed by intramuscular administration of pentagastrin at a dose of 0.01 mg / kg 30 minutes prior to the administration of the compound. Thirty minutes after the administration of atropine, the dogs were orally force-fed a capsule filled with the compound, encouraged to self-swallow the capsule with 5 mL of distilled water, and further orally force-fed 50 mL of distilled water using a catheter. Alternatively, the compound dissolved in liquid dosage was administered orally via a catheter at a dose of 20 mg / 5 mL / kg, and the catheter was immediately rinsed with 10 mL of distilled water. Pentagastrin was again intramuscularly administered at 0.01 mg / kg 15 minutes and 1 hour after the administration of the compound. Before and after (0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after) the administration, the person in charge of collecting blood held the dog’s forelimb to distend the blood vessel using a clothespin or the like. Then, the blood collection site was disinfected with alcohol cotton, and about 0.2 mL of blood was collected using a heparinized syringe and needle. After the blood was drawn, the puncture site was pressed with a cotton pad to adequately stop bleeding. The collected blood samples were ice-cooled, and plasma was isolated by centrifugation as soon as possible. The isolated plasma was immediately frozen on dry ice and then stored frozen in a freezer set at -80°C. AUClast, Cmax, and Tmax (time to reach maximum blood concentration) were calculated using Phoenix WinNonlin (v7.0.0, Certara USA, Inc.) from the concentration of Compound (1) in each plasma sample measured by MRM method and quantified from the calibration curve using LC / MS / MS.

[0145] The results are shown in Table 8. The type II crystal of Compound (1) in free form, the type III crystal of Compound (1) with succinic acid, and the type I crystal of Compound (1) with sorbic acid were assumed to be crystalline forms that can exert medicinal effects in vivo as well. These results confirmed that all of the crystalline forms were orally administrable. Table 8 Type II crystal of Compound (1) in free form Type III crystal of Compound (1) with succinic acid Type I crystal of Compound (1) with sorbic acid AUCiast (gM-hr) 13.0 ± 4.0 25.1 ± 8.4 18.1 ± 13.1 Cmax (gM) 1.26 ± 0.09 2.24 ± 0.75 1.68 ± 0.88 tmax (hr) 4.0 ± 0.0 5.3 ± 1.2 6.0 ± 2.0

[0146] All references and publications cited herein are incorporated herein by reference in their entirety regardless of their purposes. This specification also includes the disclosure of the claims, description, and drawings of Japanese patent application No. 2022-071154 (filed on April 22, 2022), which is the basis for the priority claim of this application. Some embodiments of the present invention have been described but these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments can be implemented in various other forms, and various omissions, replacements, and modifications can be made without departing from the gist of the invention. These embodiments and variations thereof are encompassed by the scope and gist of the invention as well as by the scope of the invention stated in the claims and equivalents thereof.

Claims

1. A type II crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (20 ± 0.2°) of:(i) one or more selected from the group consisting of 15.6°, 20.1°, 24.7°, and 28.9°; and(ii) two or more selected from the group consisting of 7.8°, 10.6°, 14.0°, 14.8°, 17.2°, 21.6°, 22.2°, and 25.8°.

2. The crystal according to claim 1, wherein the crystal has peaks in a powderX-ray diffraction spectrum at a total of five or more diffraction angles (20 ± 0.2°) selected from groups (i) and (ii) above; orwherein the crystal has peaks in a powder X-ray diffraction spectrum at a total of seven or more diffraction angles (20 ± 0.2°) selected from groups (i) and (ii) above; orwherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 3.

3. The crystal according to claim 1 or claim 2, wherein an exothermic peakdetermined by simultaneous thermogravimetric-differential thermal analysis is around 236°C.

4. A method for producing the type II crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide according to any one of claims 1 to 3, the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide in tetrahydrofuran.

5. A type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (20 ± 0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5°.2023256032   25 Jun 2026

6. The crystal according to claim 5, wherein the crystal has peaks in a powderX-ray diffraction spectrum at five or more diffraction angles (20 ± 0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5°; or wherein the crystal has peaks in a powder X-ray diffraction spectrum at seven or more diffraction angles (20 ± 0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5°; orwherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 13.

7. The crystal according to claim 5 or claim 6, wherein an endothermic peakdetermined by simultaneous thermogravimetric-differential thermal analysis is around 202°C.

8. A method for producing the type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid according to any one of claims 5 to 7, the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and succinic acid at an equivalent ratio of 1:1-10 in acetonitrile.

9. A type I crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with sorbic acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (20 ± 0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4°.

10. The crystal according to claim 9, wherein the crystal has peaks in a powderX-ray diffraction spectrum at five or more diffraction angles (20 ± 0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4°; or wherein the crystal has peaks in a powder X-ray diffraction spectrum at seven ormore diffraction angles (20 ± 0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4°; orwherein the crystal has a powder X-ray diffraction spectrum substantially identical to2023256032   25 Jun 2026the powder X-ray diffraction spectrum shown in Figure 15.

11. The crystal according to claim 9 or claim 10, wherein an endothermic peakdetermined by simultaneous thermogravimetric-differential thermal analysis is around 173°C.

12. A method for producing the type I crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with sorbic acid according to any one of claims 9 to 11, the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and sorbic acid at an equivalent ratio of 1:1-10 in acetonitrile.

13. A type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (20 ± 0.2°) of:(i) one or more selected from the group consisting of 8.8°, 11.6°, and 17.9°; and(ii) two or more selected from the group consisting of 6.6°, 12.3°, 13.8°, 18.6°, 21.3°, and 22.3°.

14. The crystal according to claim 13, wherein the crystal has peaks in a powderX-ray diffraction spectrum at a total of five or more diffraction angles (20 ± 0.2°) selected from groups (i) and (ii) above; orwherein the crystal has peaks in a powder X-ray diffraction spectrum at a total of seven or more diffraction angles (20 ± 0.2°) selected from groups (i) and (ii) above; orwherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 1.

15. The crystal according to claim 13 or claim 14, wherein an exothermic peakdetermined by simultaneous thermogravimetric-differential thermal analysis is around 228°C.

16. A method for producing the type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2023256032   25 Jun 20262-carboxamide according to any one of claims 13 to 15, the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide in methanol and water.

17. The crystal according to any one of claims 1 to 3, 5 to 7, 9 to 11 and 13 to15, wherein the crystal has a crystal purity of 95% by weight or more.

18. The crystal according to any one of claims 1 to 3, 5 to 7, 9 to 11 and 13 to15, wherein the crystal has a chemical purity of 95% or more.

19. A pharmaceutical composition comprising the crystal according to any oneof claims 1 to 3, 5 to 7, 9 to 11 and 13 to 15, 17 and 18.

20. A method for treating a tumor mediated by EGFR, comprising orallyadministering an effective amount of crystal according to any one of claims 1 to 3, 5 to 7, 9 to 11 and 13 to 15, 17 and 18, or the pharmaceutical composition according to claim 19 to a subject in need thereof.

21. Use of the crystal according to any one of claims 1 to 3, 5 to 7, 9 to 11 and13 to 15, 17 and 18 in the manufacture of a medicament for treating a tumor mediated by EGFR, wherein the medicament is adapted for oral administration.

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