5H-Pyrrolo[2,3-d]pyrimidin-6(7H)-one and crystal of salt thereof

Abstract

Provided is a type-I crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one that has, in a powder X-ray diffraction spectrum (CuKα), peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b). (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4°, and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9°, and 26.5°

Description

Crystals of 5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one and its salts

[0001] The present disclosure relates to crystals of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one and salts thereof, which have excellent storage stability and hygroscopicity and are useful as pharmaceuticals or active pharmaceutical ingredients, and to pharmaceutical compositions containing the crystals.

[0002] In general, when a compound is used as an active ingredient of a pharmaceutical product, the compound must be chemically and physically stable in order to maintain stable quality and / or to facilitate storage management.

[0003] Patent Document 1 discloses a compound represented by the following formula (I) as a compound having excellent inhibitory activity against at least one selected from the group consisting of Akt, Rsk, and S6K, and / or having an inhibitory effect on cancer cell proliferation, and / or useful as a medical treatment for various diseases (particularly cancer) in which at least one selected from the group consisting of Akt, Rsk, and S6K is involved.

[0004] However, Patent Document 1 does not describe the crystalline form of this compound, and stable crystals of Compound (I) and their preparation methods are not known at present.

[0005] International Publication No. 2017 / 200087

[0006] The present disclosure aims to provide crystals of the free form of Compound (I) and crystals of its salt form, which are useful as pharmaceuticals or active pharmaceutical ingredients.

[0007] As a result of intensive research aimed at solving the above problems, three crystalline forms (form I crystal, form II crystal, and form III crystal) of the free form of Compound (I) were discovered. Furthermore, crystalline forms of the hydrochloride and maleate of Compound (I) were also discovered. These crystalline forms were found to have excellent solid-state stability and / or low hygroscopicity.

[0008] That is, the present disclosure provides the following [1] to

[32] : [1] Form I crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4°, and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9°, and 26.5° [2] The free form I crystal according to [1], which has peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in its powder X-ray diffraction spectrum (CuKα): (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4°, and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9°, and 26.5° [3] In the powder X-ray diffraction spectrum (CuKα), the following diffraction angles (2θ±0.2°): [4] Form I crystal of the free form according to [1], which has peaks at 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5°. [5] Form I crystal of the free form according to [1], which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 1. [6] Form I crystal of the free form according to [1], which has an endothermic peak at a peak temperature of around 235°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement). [7] A pharmaceutical composition containing form I crystal of the free form according to any one of [1] to [5].[7] A method for producing the free-form Form I crystal according to [1], comprising the steps of dissolving 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one in solvent 1, and adding solvent 2 to the resulting solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. [8] The method according to [7], wherein solvent 1 is dimethyl sulfoxide and solvent 2 is water, or solvent 1 is tetrahydrofuran and solvent 2 is normal heptane, ethyl acetate, or 2-propanol. [9] The method according to [7], wherein solvent 1 is dimethyl sulfoxide and solvent 2 is water.

[10] Form I crystal of the free form according to [1], obtained by crystallization through a step of dissolving 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one in dimethyl sulfoxide, and adding water to the resulting solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one.

[11] Form II crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 10.4°, 22.9°, and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, and 26.5°

[12] The free form II crystal according to

[11] , which has peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in a powder X-ray diffraction spectrum (CuKα): (a) 10.4°, 22.9°, and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, and 26.5°

[13] Form II crystal of the free form according to

[11] , having peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9°.

[14] Form II crystal of the free form according to

[11] , which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 3.

[15] Form II crystal of the free form according to

[11] , which has an endothermic peak at a peak temperature of around 234°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[16] A pharmaceutical composition containing Form II crystal of the free form according to any one of

[11] to

[15] .

[17] Form III crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 11.7°, 23.4°, and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2°, and 26.7°

[18] The free form Form III crystal according to

[17] , having peaks at three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in a powder X-ray diffraction spectrum (CuKα): (a) 11.7°, 23.4°, and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2°, and 26.7°

[19] In the powder X-ray diffraction spectrum (CuKα), the following diffraction angles (2θ±0.2°): 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7°

[20] The form III crystal of free form according to

[17] , which is a crystal having substantially the same powder X-ray diffraction spectrum as the powder X-ray diffraction spectrum shown in Figure 5.

[21] The form III crystal of free form according to

[17] , which has an endothermic peak at a peak temperature of around 234°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[22] A pharmaceutical composition containing the form III crystal of free form according to any one of

[17] to

[21] .

[23] A crystal of the hydrochloride salt of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6°.

[24] A crystalline hydrochloride salt according to

[23] , which has peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6°.

[25] A crystalline hydrochloride salt according to

[23] , which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 7.

[26] A crystalline hydrochloride salt according to

[23] , which has an endothermic peak at a peak temperature of around 241°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[27] A pharmaceutical composition containing the crystalline hydrochloride salt according to any one of

[23] to

[26] .

[28] A powder X-ray diffraction spectrum (CuKα) of the following diffraction angles (2θ±0.2°): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8°. A crystal of maleate of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one having peaks at at least three diffraction angles selected from the group consisting of

[29] A crystalline maleate salt according to

[28] , which has peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8°.

[30] A crystalline maleate salt according to

[28] , which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 9.

[31] A crystalline maleate salt according to

[28] , which has an endothermic peak at a peak temperature of around 245° C. in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[32] A pharmaceutical composition comprising the crystalline maleate salt according to any one of

[28] to

[31] .

[0009] The present disclosure further provides the following

[33] to

[60] .

[33] A method for treating a tumor, comprising the step of administering the pharmaceutical composition according to [6] to a subject.

[34] A method for treating a tumor, comprising the step of administering the pharmaceutical composition according to

[16] to a subject.

[35] A method for treating a tumor, comprising the step of administering the pharmaceutical composition according to

[22] to a subject.

[36] A method for treating a tumor, comprising the step of administering the pharmaceutical composition according to

[27] to a subject.

[37] A method for treating a tumor, comprising the step of administering the pharmaceutical composition according to

[32] to a subject.

[38] Form I crystal of the free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in treating a tumor, wherein the crystal has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4°, and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9°, and 26.5°

[39] The free form I crystal according to

[38] , having peaks at at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b) in a powder X-ray diffraction spectrum (CuKα):(a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4°, and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9°, and 26.5°

[40] In the powder X-ray diffraction spectrum (CuKα), the following diffraction angles (2θ±0.2°):

[41] Form I crystal in the free form according to

[38] , which has peaks at 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5°.

[42] Form I crystal in the free form according to

[38] , which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 1.

[43] Form I crystal in the free form according to

[38] , which has an endothermic peak at a peak temperature of around 235°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[43] Form II crystal of the free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in treating a tumor, wherein the crystal has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 10.4°, 22.9°, and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, and 26.5°

[44] The free form II crystal according to

[43] , having peaks at at least four diffraction angles (2θ±0.2°) selected from the following (b):(a) 10.4°, 22.9°, and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, and 26.5°

[45] Form II crystal of the free form according to

[43] , having peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9°.

[46] Form II crystal in the free form according to

[43] , which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 3.

[47] Form II crystal in the free form according to

[43] , which has an endothermic peak at a peak temperature of around 234°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[48] ​​Form III crystal of the free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in treating a tumor, wherein the crystal has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 11.7°, 23.4°, and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2°, and 26.7°

[49] The free form III crystal according to

[48] , having peaks at at least four diffraction angles (2θ±0.2°) selected from the following (b):(a) 11.7°, 23.4°, and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2°, and 26.7°

[50] In the powder X-ray diffraction spectrum (CuKα), the following diffraction angles (2θ±0.2°): 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7°

[51] The form III crystal in free form according to

[48] , which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum (CuKα) shown in Figure 5.

[52] The form III crystal in free form according to

[48] , which has an endothermic peak at a peak temperature of around 234°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[53] A crystalline hydrochloride salt of the free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in treating a tumor, wherein the following diffraction angles (2θ±0.2°) are observed in the powder X-ray diffraction spectrum (CuKα): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6°.

[54] The crystal of hydrochloride salt according to

[52] , which has peaks at the following diffraction angles (2θ±0.2°): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6° in a powder X-ray diffraction spectrum (CuKα).

[55] A crystalline form of the hydrochloride salt according to

[53] , which has a powder X-ray diffraction spectrum substantially identical to that shown in Figure 7.

[56] A crystalline form of the hydrochloride salt according to

[53] , which has an endothermic peak at a peak temperature of around 241°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

[57] A crystalline form of the maleate salt of the free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one for use in the treatment of tumors, which has the following diffraction angle (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): The crystal has peaks at at least three diffraction angles selected from 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8°.

[58] A crystalline maleate salt according to

[57] , which has peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8°.

[59] A crystalline maleate salt according to

[57] , which is a crystalline maleate salt having substantially the same powder X-ray diffraction spectrum as that shown in Figure 9.

[60] A crystalline maleate salt according to

[57] , which has an endothermic peak at a peak temperature of about 245°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA).

[0010] According to the present disclosure, a stable crystalline form of the compound (I) is provided, which is useful as a compound having an antitumor activity. Furthermore, the stable crystalline forms of the compound (I) of the present disclosure and their preparation methods are currently unknown. In the present disclosure, the crystalline forms of the free form of compound (I) (form I crystal, form II crystal, form III crystal), the hydrochloride salt crystal, and the maleate salt crystal are superior to other crystalline forms in terms of, for example, low hygroscopicity and / or solid-state stability, and are therefore useful forms when the compound is used as an active pharmaceutical ingredient for pharmaceuticals.

[0011] 1 shows a powder X-ray diffraction spectrum (CuKα) of type I crystal of the free form of compound (I) obtained in Example 1 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This shows a thermogravimetric-differential thermal analysis (TG-DTA) curve of type I crystal of the free form of compound (I) obtained in Example 1. This shows a powder X-ray diffraction spectrum (CuKα) of type II crystal of the free form of compound (I) obtained in Example 2 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This shows a thermogravimetric-differential thermal analysis (TG-DTA) curve of type II crystal of the free form of compound (I) obtained in Example 2. This shows a powder X-ray diffraction spectrum (CuKα) of type III crystal of the free form of compound (I) obtained in Example 3 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)).

[0033] Figure 1 shows a thermogravimetry-differential thermal analysis (TG-DTA) curve for Form III crystals of the free form of Compound (I) obtained in Example 3. Figure 2 shows a powder X-ray diffraction spectrum (CuKα) for crystals of the hydrochloride of Compound (I) obtained in Example 4 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). Figure 3 shows a thermogravimetry-differential thermal analysis (TG-DTA) curve for crystals of the hydrochloride of Compound (I) obtained in Example 4. Figure 4 shows a powder X-ray diffraction spectrum (CuKα) for crystals of the maleate of Compound (I) obtained in Example 5 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). Figure 5 shows a thermogravimetry-differential thermal analysis (TG-DTA) curve for crystals of the maleate of Compound (I) obtained in Example 5. 1 shows a powder X-ray diffraction spectrum (CuKα) of the crystals of ½ malate of compound (I) obtained in Comparative Example 1 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This figure shows a thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystals of ½ malate of compound (I) obtained in Comparative Example 1. This figure shows a powder X-ray diffraction spectrum (CuKα) of the crystals of acetate of compound (I) obtained in Comparative Example 2 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This figure shows a thermogravimetric-differential thermal analysis (TG-DTA) curve of the crystals of acetate of compound (I) obtained in Comparative Example 2. This figure shows a moisture adsorption / desorption isotherm of type I crystals of the free form of compound (I) obtained in Example 1. This figure shows a moisture adsorption / desorption isotherm of type II crystals of the free form of compound (I) obtained in Example 2.

[0039] Figure 1 shows the moisture adsorption / desorption isotherm of the Form III crystal of the free form of Compound (I) obtained in Example 3.

[0040] Figure 2 shows the powder X-ray diffraction data at 25°C of the Form I crystal of the free form of Compound (I) obtained in Example 1.

[0041] Figure 3 shows the powder X-ray diffraction data at 210°C of the Form I crystal of the free form of Compound (I) obtained in Example 1.

[0042] Figure 4 shows the powder X-ray diffraction data at 25°C of the Form II crystal of the free form of Compound (I) obtained in Example 2.

[0043] Figure 5 shows the powder X-ray diffraction data at 210°C of the Form II crystal of the free form of Compound (I) obtained in Example 2.

[0044] Figure 6 shows the powder X-ray diffraction data at 25°C of the Form III crystal of the free form of Compound (I) obtained in Example 3.

[0045] Figure 7 shows the moisture adsorption / desorption isotherm of the hydrochloride crystal of Compound (I) obtained in Example 4.

[0046] Figure 8 shows the moisture adsorption / desorption isotherm of the maleate crystal of Compound (I) obtained in Example 5. 1 shows a moisture adsorption / desorption isotherm for crystals of ½ malate of compound (I) obtained in Comparative Example 1. FIG. 2 shows a moisture adsorption / desorption isotherm for crystals of acetate of compound (I) obtained in Comparative Example 2.

[0012] When simply referred to herein as "Compound (I)," it means 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, and is used in the sense of including both "amorphous form" and "crystal."

[0013] In a salt form of compound (I), the molar equivalent of the acid relative to compound (I) can be analyzed, for example, by NMR or liquid chromatography. In the present disclosure, when a crystal of the hydrochloride, maleate, or acetate salt of compound (I) is described, the molar ratio of compound (I) to hydrochloric acid, maleic acid, or acetic acid is 1:1, respectively, and can be determined by analysis such as 1H-NMR. Typically, in a salt of an organic compound, the molar ratio of the acid to the organic compound can be determined by comparing the integral of the methyl proton of the acid with the integral of at least one proton of the organic compound. Since it is known that errors occur in the integral of the proton due to correction of the baseline, etc., of the 1H-NMR chart, a molar ratio of the acid to the organic compound in the range of 0.8 to 1.2:1 can be considered to be 1:1.

[0014] Compound (I) can be synthesized, for example, according to the method described in WO 2017 / 200087 (for example, the method described in Example 32 of the publication), but is not limited to this method.

[0015] As used herein, and unless otherwise specified, the term "crystalline" and related terms used herein, when used to describe a compound, substance, modification, material, component, or product, means that the compound, substance, modification, material, component, or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott, Williams and Wilkins, Baltimore, MD (2005); U.S. Pharmacopeia, 23rd ed., pp. 1843-1844 (1995). "Crystal" also includes hydrates or solvates (pseudopolymorphs), and co-crystals. The terms "crystalline" and "crystalline form" are used interchangeably herein.

[0016] In the technical field, it is known that even in a multi-component system that can form a salt (involving proton transfer due to an acid-base reaction), the major component (drug substance) and the minor component (coformer, counterion, solvent) may form a complex through weak intermolecular interactions such as hydrogen bonding or other interactions (e.g., Cryst. Growth Des. 2012, 12, 2147-2152 dx.doi.org / 10.1021 / cg3002948). In the present disclosure, the "crystal" of a "salt" also encompasses a crystal of such a multi-component complex ("cocrystal").

[0017] As used herein, and unless otherwise specified, the terms "amorphous," "amorphous form," and related terms used herein mean that the substance, component, or product is substantially not crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" describes a disordered solid form, i.e., a solid form lacking long-range crystalline order.

[0018] The term "pharmaceutically acceptable salts" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable salts may be safe for consumption by animals or humans.

[0019] Techniques for characterizing crystalline and amorphous forms may include, but are not limited to, techniques well known in the art, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, solubility measurements, and the like. Characteristic unit cell parameters can be determined using one or more techniques, such as X-ray diffraction and neutron diffraction, including, but not limited to, single crystal diffraction and powder diffraction. Useful techniques for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which can be used, for example, to resolve diffraction peaks associated with a single phase in a sample containing two or more solid phases. Another useful method for analyzing powder diffraction data includes unit cell indexing, which allows one skilled in the art to determine unit cell parameters from a sample containing a crystalline powder.

[0020] In powder X-ray diffraction patterns, due to the nature of the data, the diffraction angle and overall pattern are important when determining the identity of a crystal. The relative intensities of powder X-ray diffraction patterns may vary somewhat depending on the direction of crystal growth, particle size, and measurement conditions, so they should not be interpreted strictly.

[0021] The crystals can be identified by peaks in the powder X-ray diffraction pattern. Here, the "peak" is selected from the intensity peaks obtained by powder X-ray diffraction spectrum (CuKα) having an intensity of 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 15% or more, or 20% or more of the maximum peak intensity. More preferably, the peak has an intensity of 5% or more of the maximum peak intensity of the obtained intensity peaks, more preferably 6% or more of the maximum peak intensity of the obtained intensity peaks, more preferably 7% or more of the maximum peak intensity of the obtained intensity peaks, more preferably 8% or more of the maximum peak intensity of the obtained intensity peaks, more preferably 9% or more of the maximum peak intensity of the obtained intensity peaks, more preferably 10% or more of the maximum peak intensity of the obtained intensity peaks, even more preferably 15% or more of the maximum peak intensity of the obtained intensity peaks, and particularly preferably 20% or more of the maximum peak intensity of the obtained intensity peaks.

[0022] The values ​​obtained from various patterns may have some errors depending on the direction of crystal growth, particle size, measurement conditions, etc. Therefore, in this specification, the values ​​of the diffraction angle (2θ) in the powder X-ray diffraction pattern may have a measurement error in the range of about ±0.2°.

[0023] Furthermore, the measurement temperature of an endothermic peak in a simultaneous thermogravimetry-differential thermal analysis (TG-DTA) curve may vary depending on the rate of temperature rise per minute, the purity of the sample, etc. As used herein, the term "around" a TG-DTA measurement temperature value means a temperature value within ±2, 3, 4, or 5°C of that value. The temperature range is preferably ±5°C, more preferably ±4°C, even more preferably ±3°C, and particularly preferably ±2°C.

[0024] In some embodiments, the crystalline forms of Compound (I) disclosed herein may include multiple crystals (polymorphs) with spatially ordered atomic arrangements and may result in different physicochemical properties. In some embodiments, the crystalline forms disclosed herein may be mixtures containing polymorphs.

[0025] The crystalline form of Compound (I) of the present disclosure may be characterized by a combination of the following embodiments, which are not mutually exclusive: For example, the crystalline form of Compound (I) may be characterized by a combination of the above peaks in an X-ray diffraction pattern and the above endothermic peak measured by TG-DTA.

[0026] Compounds labeled with isotopes (eg, deuterium, 3H, 14C, 35S, 125I, etc.) and the like are also encompassed by the compounds described herein or pharmaceutically acceptable salts thereof.

[0027] Some crystalline forms of Compound (I) disclosed herein are stable upon exposure to conditions of about 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70°C and about 65, 70, 75, 80, or 85% relative humidity for about 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, or 156 weeks or more and about 160, 156, 150, 138, 126, 114, 102, 90, 78, 66, 54, 42, 30, 24, 18, 12, or 6 weeks or less. The conditions may be closed or open conditions. As used herein, "closed" conditions refer to conditions in which the bottles containing the samples during the stability experiment are closed or sealed, and "open" conditions refer to conditions in which the lids are open.

[0028] The crystalline form of Compound (I) disclosed herein is stable upon exposure to conditions of about 70°C and about 75% relative humidity for about two weeks. That is, the crystalline form of Compound (I) disclosed herein exhibits excellent storage stability over an extended period of time. As used herein, "stable" means that the increase in impurities compared to the initial impurity level is about 1.0, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, or 0.01% or less. The increase in impurities is preferably 1.0% or less, more preferably 0.5% or less, more preferably 0.4% or less, more preferably 0.3% or less, more preferably 0.2% or less, more preferably 0.1% or less, even more preferably 0.05% or less, and particularly preferably 0.01% or less.

[0029] In certain embodiments, the crystalline forms of Compound (I) disclosed herein may be highly pure physically and / or chemically. In certain embodiments, the crystals disclosed herein may be at least about 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, or 80% physically and / or chemically pure. In some embodiments, the crystals disclosed herein are substantially pure. As used herein, and unless otherwise specified, "substantially pure" refers to, for example, being substantially free of other solid forms and / or other compounds. In certain embodiments, the crystals disclosed herein contain less than about 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% by weight of one or more other solid forms and / or other compounds.

[0030] Form I crystals of the free form of Compound (I) have, for example, the powder X-ray diffraction spectrum (CuKα) shown in FIG. 1 and the thermogravimetry-differential thermal analysis (TG-DTA) curve shown in FIG. 2.

[0031] Here, characteristic peaks in the powder X-ray diffraction spectrum of type I crystals of the free form of compound (I) include the following diffraction angles (2θ±0.2°): 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5°. More preferably, the characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the type I crystal of the free form of compound (I) have diffraction angles (2θ±0.2°) of 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5° when measured by a reflection method.

[0032] In one embodiment of the present disclosure, type I crystal of the free form of compound (I) has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4°, and 25.1°; and (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9°, and 26.5°.

[0033] In a preferred embodiment of the present disclosure, the type I crystal of the free form of compound (I) has, in its powder X-ray diffraction spectrum, a diffraction angle (2θ±0.2°) having at least two peaks selected from group (a) above and at least two peaks selected from group (b). More preferably, in its powder X-ray diffraction spectrum, a diffraction angle (2θ±0.2°) having at least three peaks selected from group (a) above and at least two peaks selected from group (b). More preferably, in its powder X-ray diffraction spectrum, a diffraction angle (2θ±0.2°) having at least four peaks selected from group (a) above and at least two peaks selected from group (b). Even more preferably, in its powder X-ray diffraction spectrum, a diffraction angle (2θ±0.2°) having at least five peaks selected from group (a) above and at least two peaks selected from group (b). Particularly preferably, in a powder X-ray diffraction spectrum, the diffraction angle (2θ±0.2°) has all peaks from the group (a) above and at least two peaks selected from the group (b) above.

[0034] In another embodiment, the type I crystal of the free form of compound (I) in a preferred embodiment of the present disclosure has, in a powder X-ray diffraction spectrum, at diffraction angles (2θ±0.2°) at least two peaks from group (a) above, and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, even more preferably at least 11, even more preferably at least 12, and particularly preferably all, peaks from group (b) above.

[0035] In another embodiment, in a powder X-ray diffraction spectrum, the type I crystal of the free form of compound (I) has at least three peaks from group (a) above and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, even more preferably at least 11, even more preferably at least 12, and particularly preferably all, peaks from group (b) above at diffraction angles (2θ±0.2°).

[0036] In another embodiment, in a powder X-ray diffraction spectrum, the type I crystal of the free form of compound (I) has at least four peaks from group (a) above and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, even more preferably at least 11, even more preferably at least 12, and particularly preferably all, peaks from group (b) above at diffraction angles (2θ±0.2°).

[0037] In another embodiment, in a powder X-ray diffraction spectrum, the type I crystal of the free form of compound (I) has at least five peaks from group (a) above, and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, even more preferably at least 11, even more preferably at least 12, and particularly preferably all, peaks from group (b) above, at diffraction angles (2θ±0.2°).

[0038] In another embodiment, in a powder X-ray diffraction spectrum, the type I crystal of the free form of compound (I) has, at diffraction angles (2θ±0.2°), all peaks from group (a) above, and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, even more preferably at least 11, even more preferably at least 12, and particularly preferably all peaks from group (b) above.

[0039] The endothermic peak in the thermogravimetry-differential thermal analysis (TG-DTA) curve of the free-form type I crystal of Compound (I) is around 233°C to 237°C, preferably around 235°C.

[0040] The type I crystal of the free form of Compound (I) has a chemical purity of Compound (I) of 90% or more, which can be measured by high performance liquid chromatography (HPLC). Preferably, the type I crystal of the free form of Compound (I) has a chemical purity of 95% or more, more preferably 99% or more.

[0041] The type I crystal of the free form of Compound (I) may be any crystal containing the type I crystal of the free form, and may be a single crystal of the type I crystal of the free form or a polymorphic mixture containing other crystals. Preferably, 90% or more of the type I crystal of the free form is the type I crystal, and more preferably 95% or more of the type I crystal.

[0042] Form I crystals of the free form of Compound (I) can be obtained by dissolving crude Compound (I) in tetrahydrofuran and adding ethyl acetate. However, in this case, the resulting particle size tends to be non-uniform. Of the resulting non-uniform crystals, differences were observed in the amounts of related substances and residual solvent contained in the flake-like portion that could be easily separated, for example, through a sieve with a pore size of 340 μm, and the powder-like portion that passed through the sieve. While both are form I crystals of the free form of Compound (I), it is more preferable to reduce the amount of residual solvent and produce form I crystals of the free form of Compound (I) with uniform quality and high chemical purity.

[0043] In the industrial production of pharmaceuticals, as indicated in ICH guidelines and the like, it is required that the amount of residual solvents be as small as possible. The regulatory limit for ethyl acetate is 5000 ppm or less, that for tetrahydrofuran is 720 ppm or less, and that for dimethyl sulfoxide is 5000 ppm or less. The residual amount of ethyl acetate is preferably 5000 ppm or less, more preferably 4000 ppm or less, more preferably 3000 ppm or less, even more preferably 2000 ppm or less, and particularly preferably 1000 ppm or less. The residual amount of tetrahydrofuran is preferably 720 ppm or less, more preferably 500 ppm or less, and even more preferably 300 ppm or less. The residual amount of dimethyl sulfoxide is preferably 5000 ppm or less, more preferably 3000 ppm or less.

[0044] The type I crystal of the free form of compound (I) according to the present disclosure can be produced, for example, by a method including step (1) of dissolving compound (I) in solvent 1 (good solvent), and step (2) of adding solvent 2 (poor solvent) to the solution obtained in step (1) to obtain solid compound (I).

[0045] Preferred dissolution solvents (solvent 1) in step (1) include dimethyl sulfoxide and tetrahydrofuran. Dimethyl sulfoxide is more preferred. Preferred solvents (solvent 2) added in step (2) include normal heptane, ethyl acetate, or 2-propanol when tetrahydrofuran is used in step (1), and water when dimethyl sulfoxide is used in step (1). Preferably, solvent 1 in step (1) is dimethyl sulfoxide, and solvent 2 in step (2) is water.

[0046] In step (2), an appropriate amount of free-form I crystals of Compound (I) may or may not be added as seed crystals to promote crystallization.

[0047] In step (1), the temperature at which compound (I) is dissolved can be appropriately set. For example, when compound (I) is dissolved in 20 v / w dimethyl sulfoxide, the temperature is preferably from room temperature to 70°C.

[0048] When dimethyl sulfoxide is used in step (1), in step (2), type I crystals of the free form of compound (I) can be precipitated by adding water at an internal temperature of room temperature to 70°C. The temperature at this time is preferably maintained at 40 to 70°C, more preferably 60 to 70°C. The temperature of water when adding water in step (2) is more preferably 40 to 60°C. The amount of water added at this time is preferably 3 v / w or more, more preferably 20 v / w to 25 v / w, relative to compound (I).

[0049] When water is used in step (2), the water is slowly added dropwise over a period of 0.5 to 6 hours to obtain type I crystals of the free form of Compound (I). As is generally known about crystallization, increasing the addition rate produces crystals with a small particle size, while decreasing the addition rate produces crystals with a large particle size.

[0050] The precipitated crystals can be isolated and purified from the suspension containing the crystals by known separation and purification means, such as filtration, washing with water, and drying under reduced pressure.

[0051] Form II crystal of the free form of Compound (I) has, for example, the powder X-ray diffraction spectrum shown in FIG. 3 and the thermogravimetry-differential thermal analysis (TG-DTA) curve shown in FIG. 4.

[0052] Here, characteristic peaks in the crystalline powder X-ray diffraction spectrum (CuKα) of Form II crystal of the free form of Compound (I) include the following diffraction angles (2θ±0.2°): 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9°. More preferably, the characteristic peaks in the powder X-ray diffraction spectrum of Form II crystal of the free form of Compound (I) have diffraction angles (2θ±0.2°) of 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9° when measured by a reflection method.

[0053] In one embodiment of the present disclosure, Form II crystal of the free form of Compound (I) has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 10.4°, 22.9°, and 27.9°; and (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, and 26.5°.

[0054] In a preferred embodiment of the present disclosure, the form II crystal of the free form of Compound (I) has, in its powder X-ray diffraction spectrum, at diffraction angles (2θ±0.2°) at least two peaks from the above group (a) and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, even more preferably at least 11, and particularly preferably all peaks from the above group (b). In another embodiment of the present disclosure, the form II crystal of the free form of Compound (I) has, in its powder X-ray diffraction spectrum, at diffraction angles (2θ±0.2°), In another embodiment, the form II crystal of the free form of Compound (I) may have peaks at all peaks selected from the above group (a).

[0055] In another embodiment, the Form II crystal of the free form of Compound (I) has, in a powder X-ray diffraction spectrum, diffraction angles (2θ±0.2°) of all peaks in the above group (a) and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, even more preferably at least 11, and particularly preferably all peaks in the above group (b).

[0056] The endothermic peak in the thermogravimetry-differential thermal analysis (TG-DTA) curve of Form II crystals of the free form of Compound (I) is around 232°C to 236°C, preferably around 234°C.

[0057] In one embodiment of the present disclosure, Form II crystal of the free form of Compound (I) can be obtained, for example, by a method comprising step (3) of adding Compound (I) to a solvent and dissolving it, followed by step (4) of suspending the compound by heating, and step (5) of cooling the solution of Compound (I) to crystallize Compound (I). In such an embodiment, the solvent used in step (3) can be, for example, methanol. Methanol is preferred.

[0058] When methanol is used in step (4), the heating and suspending temperature can be 50° C. to 100° C., and the reaction heating time can be 0.5 to 48 hours. Preferably, the temperature is 50° C., and the reaction time is 22 hours.

[0059] The crystallization in step (5) may be carried out under stirring. In this case, stirring is carried out using a stirrer, stirring blades, etc., as appropriate depending on the amount of solvent, the size of the reaction vessel, etc. The stirring operation can also be carried out, for example, by shaking the reaction vessel. The stirring speed is usually 1 to 600 rpm, preferably 10 to 100 rpm. In step (5), cooling can be carried out at room temperature, preferably room temperature.

[0060] The free-form type II crystal obtained as described above has a chemical purity of Compound (I) of 90% or more, which can be measured by high-performance liquid chromatography (HPLC). Preferably, the free-form type II crystal has a chemical purity of Compound (I) of 95% or more, more preferably 99% or more.

[0061] The form II crystal of the free form of Compound (I) may be any crystal containing the form II crystal of the free form, and may be a single crystal of the form II crystal of the free form or a polymorphic mixture containing other crystals. Preferably, 90% or more of the form II crystal of the free form is the form II crystal of the free form, and more preferably 95% or more of the form II crystal of the free form.

[0062] Form III crystal of the free form of Compound (I) has, for example, the powder X-ray diffraction spectrum shown in FIG. 5 and the thermogravimetry-differential thermal analysis (TG-DTA) curve shown in FIG. 6.

[0063] Here, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of Form III crystal of the free form of Compound (I) include the following diffraction angles (2θ±0.2°): 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7°. More preferably, the characteristic peaks in the powder X-ray diffraction spectrum of Form III crystal of the free form of Compound (I) have diffraction angles (2θ±0.2°) of 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7° in the X-ray powder diffraction spectrum (CuKα) of Form III crystal of the free form of Compound (I). In one embodiment of the present disclosure, the powder X-ray diffraction spectrum (CuKα) of Form III crystal of the free form of Compound (I) has peaks at at least two diffraction angles (2θ±0.2°) selected from the following (a), and at least two diffraction angles (2θ±0.2°) selected from the following (b):

[0064] (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7°

[0065] In a preferred embodiment of the present disclosure, the Form III crystal of the free form of Compound (I) has, in its powder X-ray diffraction spectrum, at diffraction angles (2θ±0.2°) at least two peaks from group (a) above, and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, more preferably at least 11, more preferably at least 12 or more, even more preferably at least 13, and particularly preferably all peaks from group (b) above. In another embodiment of the present disclosure, the Form III crystal of the free form of Compound (I) has, in its powder X-ray diffraction spectrum, at diffraction angles (2θ±0.2°), In another embodiment, the Form III crystal of the free form of Compound (I) may have peaks at all peaks selected from group (a) above.

[0066] In another embodiment, the Form III crystal of the free form of Compound (I) has, in a powder X-ray diffraction spectrum, diffraction angles (2θ±0.2°) corresponding to all of the peaks in group (a) above, and at least two, preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, more preferably at least nine, more preferably at least 10, more preferably at least 11, more preferably at least 12, even more preferably at least 13, and particularly preferably all of the peaks in group (b) above.

[0067] The endothermic peak in the thermogravimetry-differential thermal analysis (TG-DTA) curve of Form III crystals of the free form of Compound (I) is around 232°C to 236°C, preferably around 234°C.

[0068] In one embodiment of the present disclosure, Form III crystals of Compound (I) can be obtained, for example, by a method comprising step (6) of adding Compound (I) to a solvent and heating under reflux, followed by step (7) of rapidly cooling to crystallize. In such an embodiment, the solvent used in step (6) can be, for example, a solvent such as ethanol or 2-methyltetrahydrofuran, or a mixed solvent of ethanol and 2-methyltetrahydrofuran. Ethanol is preferred.

[0069] The crystallization in step (7) may be carried out under stirring. In this case, stirring is carried out using a stirrer, stirring blades, or the like as appropriate depending on the amount of solvent, the size of the reaction vessel, and the like. The stirring operation can also be carried out, for example, by shaking the reaction vessel. The stirring speed is usually 1 to 600 rpm, and preferably 10 to 100 rpm.

[0070] The free-form Form III crystal obtained as described above has a chemical purity of Compound (I) of 90% or more, which can be measured by high performance liquid chromatography (HPLC). Preferably, the free-form Form III crystal has a chemical purity of Compound (I) of 95% or more, more preferably 99% or more.

[0071] The free-form III crystal of Compound (I) may be any crystal containing the free-form III crystal, and may be a single crystal of the free-form III crystal or a polymorphic mixture containing other crystals. Preferably, 90% or more of the free-form III crystal is the free-form III crystal, and more preferably 95% or more of the free-form III crystal is the free-form III crystal.

[0072] The crystals of the hydrochloride salt of compound (I) have, for example, the powder X-ray diffraction spectrum shown in Figure 7 and the thermogravimetry-differential thermal analysis (TG-DTA) curve shown in Figure 8. Here, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the crystals of the hydrochloride salt of compound (I) include, as diffraction angles (2θ±0.2°), 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6°. More preferably, the characteristic peaks in the powder X-ray diffraction spectrum of the crystals of the hydrochloride salt of Compound (I) have diffraction angles (2θ±0.2°) of 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6° when measured by a reflection method.

[0073] The crystalline form of the hydrochloride salt of compound (I) according to the present disclosure is selected from at least three peaks selected from the above peaks, for example, a crystal having at least three peaks selected from the above peaks, preferably a crystal having at least four peaks selected from the above peaks, more preferably a crystal having at least five peaks selected from the above peaks, more preferably a crystal having at least six peaks selected from the above peaks, more preferably a crystal having at least seven peaks selected from the above peaks, more preferably a crystal having at least eight peaks selected from the above peaks, more preferably a crystal having at least nine peaks selected from the above peaks, more preferably a crystal having at least ten peaks selected from the above peaks, more preferably a crystal having at least 11 peaks selected from the above peaks, more preferably a crystal having at least 12 peaks selected from the above peaks, more preferably a crystal having at least 13 peaks selected from the above peaks, more preferably a crystal having at least 14 peaks selected from the above peaks, more preferably a crystal having at least 15 peaks selected from the above peaks, and particularly preferably a crystal having all of the above peaks.

[0074] The endothermic peak in the thermogravimetry-differential thermal analysis (TG-DTA) curve of the crystals of the hydrochloride of Compound (I) is around 239°C to 243°C, preferably around 241°C.

[0075] In one embodiment of the present disclosure, crystals of the hydrochloride salt of compound (I) can be obtained, for example, by a method including step (8) of adding compound (I) to a solvent, adding hydrochloric acid, and then stirring at room temperature to crystallize. In such an embodiment, the solvent used in step (8) can be, for example, ethyl acetate, methanol, ethanol, or a mixture thereof. A mixture of ethyl acetate and methanol is preferred.

[0076] The crystallization in step (8) may be carried out under stirring. In this case, stirring is carried out using a stirrer, stirring blades, or the like as appropriate depending on the amount of solvent, the size of the reaction vessel, and the like. The stirring operation can also be carried out, for example, by shaking the reaction vessel. The stirring speed is usually 1 to 600 rpm, and preferably 10 to 100 rpm.

[0077] The amount of hydrochloric acid added in step (8) can be 0.9 to 1.1 molar equivalents relative to the amount of compound (I), preferably 1.0 molar equivalent.

[0078] The hydrochloride crystals obtained as described above have a chemical purity of Compound (I) of 90% or more, which can be measured by high performance liquid chromatography (HPLC). Preferably, the hydrochloride crystals have a chemical purity of Compound (I) of 95% or more, more preferably 99% or more.

[0079] The crystalline form of the hydrochloride of Compound (I) may be a single crystalline form of the hydrochloride or a polymorphic mixture containing other crystalline forms, as long as it contains the hydrochloride crystalline form, and preferably contains 90% by weight or more of the hydrochloride crystalline form, more preferably 95% by weight or more of the hydrochloride crystalline form.

[0080] The crystals of the maleate salt of Compound (I) have, for example, the powder X-ray diffraction spectrum shown in FIG. 9 and the thermogravimetry-differential thermal analysis (TG-DTA) curve shown in FIG.

[0081] Here, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of a crystal of the maleate salt of compound (I) can be listed as diffraction angles (2θ±0.2°) of 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8°. More preferably, the characteristic peaks in the powder X-ray diffraction spectrum of the maleate crystal of compound (I) have diffraction angles (2θ±0.2°) of 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8° when measured by a reflection method.

[0082] The crystalline form of maleate salt of compound (I) according to the present disclosure is selected from at least three peaks selected from the above peaks, for example, a crystalline form having at least three peaks selected from the above peaks, preferably a crystalline form having at least four peaks selected from the above peaks, more preferably a crystalline form having at least five peaks selected from the above peaks, more preferably a crystalline form having at least six peaks selected from the above peaks, more preferably a crystalline form having at least seven peaks selected from the above peaks, more preferably a crystalline form having at least eight peaks selected from the above peaks, more preferably a crystalline form having at least nine peaks selected from the above peaks, more preferably a crystalline form having at least ten peaks selected from the above peaks, more preferably a crystalline form having at least the above peaks. A crystal having at least 11 peaks selected from the above, more preferably a crystal having at least 12 peaks selected from the above peaks, more preferably a crystal having at least 13 peaks selected from the above peaks, more preferably a crystal having at least 14 peaks selected from the above peaks, more preferably a crystal having at least 15 peaks selected from the above peaks, more preferably a crystal having at least 16 peaks selected from the above peaks, more preferably a crystal having at least 17 peaks selected from the above peaks, more preferably a crystal having at least 18 peaks selected from the above peaks, more preferably a crystal having at least 19 peaks selected from the above peaks, and particularly preferably a crystal having all of the above peaks.

[0083] The endothermic peak in the thermogravimetry-differential thermal analysis (TG-DTA) curve of the maleate crystals of Compound (I) is around 243°C to 247°C, preferably around 245°C.

[0084] In one embodiment of the present disclosure, crystals of the maleate salt of compound (I) can be obtained, for example, by a method comprising step (10) of adding compound (I) and maleic acid to a solvent, heating and stirring to obtain an amorphous body, step (11) of heating the obtained amorphous body to reflux, and step (12) of stirring at room temperature and then cooling on ice to crystallize. In such an embodiment, the solvent used in step (10) can be, for example, chloroform, methanol, or a mixture thereof. A mixed solvent of chloroform and methanol is preferred. In step (11), for example, acetonitrile can be used as the solvent. In step (11), the reaction can be carried out at a temperature near the boiling point of the solvent, and when the solvent is acetonitrile, the temperature is preferably 85°C.

[0085] The amount of maleic acid added in step (10) must be the same molar equivalent as that of compound (I).

[0086] The crystallization in step (9) may be carried out under stirring. In this case, stirring is carried out using a stirrer, a stirring blade, or the like, as appropriate depending on the amount of solvent, the size of the reaction vessel, etc. Alternatively, the stirring operation may be carried out by, for example, shaking the reaction vessel.

[0087] The maleate crystals obtained as described above have a chemical purity of Compound (I) of 90% or more, which can be measured by high performance liquid chromatography (HPLC). Preferably, the maleate crystals have a chemical purity of Compound (I) of 95% or more, more preferably 99% or more.

[0088] The maleate crystal of Compound (I) may be a single crystal of maleate or a polymorphic mixture containing other crystals, as long as it contains maleate crystals, and preferably contains 90% or more of maleate crystals, more preferably 95% or more of maleate crystals.

[0089] Although one embodiment of obtaining the crystalline forms (form I crystal, form II crystal, form III crystal), hydrochloride crystal, and maleate crystal of the free form of compound (I) of the present disclosure has been described above, this is merely an example. The crystalline forms (form I crystal, form II crystal, form III crystal), hydrochloride crystal, and maleate crystal of compound (I) of the present disclosure are not limited to those obtained by the above-exemplified embodiment of obtaining. A person skilled in the art can produce the crystalline forms (form I crystal, form II crystal, form III crystal), hydrochloride crystal, and maleate crystal of the free form of compound (I) of the present disclosure using known technical means.

[0090] As shown in the Examples below, the Form I crystals, Form II crystals, and Form III crystals of the free form of Compound (I), the hydrochloride crystals of Compound (I), and the maleate crystals of Compound (I) according to the present disclosure have low hygroscopicity and excellent solid-state stability (storage stability, etc.). It is important for drug substances and active ingredients in drugs to have solid-state stability in industrial operations and in maintaining quality.

[0091] In addition, solvents used in the production of pharmaceuticals may be toxic, and from the viewpoint of safety, it is desirable that the amount of solvent remaining in the production process is as small as possible. The type I crystal of the free form of compound (I) does not contain residual solvents in an amount equal to or greater than the limit stipulated in the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines.

[0092] Form I crystals, Form II crystals, Form III crystals of the free form of Compound (I), hydrochloride crystals, and maleate crystals according to the present disclosure have excellent antitumor effects and are useful as pharmaceuticals for treating tumors.

[0093] When using the free-form crystals of Compound (I), Form I crystals, Form II crystals, Form III crystals, hydrochloride crystals, and maleate crystals as pharmaceuticals, various administration forms can be adopted depending on the purpose of prevention or treatment, with or without pulverization of the crystals, and such forms may include, for example, oral preparations such as tablets, capsules, granules, fine granules, powders, dry syrups, etc.; and parenteral preparations such as suppositories, inhalants, nasal drops, ointments, patches, and injections, with oral preparations being preferred. These pharmaceutical compositions can be produced using pharmaceutically acceptable carriers by formulation methods known and commonly used by those skilled in the art.

[0094] As pharmaceutical carriers, various organic or inorganic carrier substances commonly used as formulation materials are used, and are incorporated as excipients, binders, disintegrants, lubricants, coating agents in solid formulations, and as solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as needed.

[0095] Examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, calcium silicate, etc. Examples of binders include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, candy powder, hypromellose, etc. Examples of disintegrants include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, etc.

[0096] Examples of lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, and sodium stearyl fumarate. Examples of coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, and sucrose. Examples of solvents include water, propylene glycol, and physiological saline. Examples of solubilizers include polyethylene glycol, ethanol, α-cyclodextrin, macrogol 400, and polysorbate 80.

[0097] Examples of suspending agents include carrageenan, crystalline cellulose / carmellose sodium, and polyoxyethylene hydrogenated castor oil. Examples of isotonic agents include sodium chloride, glycerin, and potassium chloride. Examples of pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and sodium dihydrogen phosphate. Examples of soothing agents include procaine hydrochloride and lidocaine.

[0098] Examples of preservatives include ethyl parahydroxybenzoate, cresol, and benzalkonium chloride. Examples of antioxidants include sodium sulfite, ascorbic acid, and natural vitamin E. Examples of colorants include titanium oxide, ferric oxide, Food Blue No. 1, and copper chlorophyll. Examples of flavoring and odor correcting agents include aspartame, saccharin, sucralose, 1-menthol, and mint flavor. Examples of stabilizers include sodium metabisulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.

[0099] When preparing a solid oral preparation, an excipient, and if necessary, a binder, a disintegrant, a lubricant, a colorant, a flavoring / flavoring agent, etc., can be added to the free form I crystals, II crystals, III crystals, hydrochloride crystals, or maleate crystals of Compound (I), and then tablets, coated tablets, granules, powders, capsules, etc. can be produced by a conventional method.

[0100] The amounts of Form I crystals, Form II crystals, Form III crystals of the free form of Compound (I), hydrochloride crystals and maleate crystals to be formulated in each dosage unit form vary depending on the symptoms of the patient to which they are to be administered or on the dosage form, but generally, it is desirable that the amount per dosage unit form be about 0.05 to 1000 mg for oral preparations, about 0.1 to 500 mg for injections, and about 1 to 1000 mg for suppositories or external preparations.

[0101] Furthermore, the daily dose of the free-form crystals of Compound (I), Form I crystals, Form II crystals, Form III crystals, hydrochloride crystals, and maleate crystals of the drug having each administration mode varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but typically, treatment with Compound (I) or a pharmaceutically acceptable salt thereof can be performed at a dose level for intermittent administration of, for example, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 200 mg / day, or about 300 mg / day per day for an adult (body weight 50 kg). The dosage may be about 400 mg / day, about 500 mg / day, about 600 mg / day, and about 3000 mg / day, about 2,500 mg / day, about 2,000 mg / day, about 1,500 mg / day, about 1,000 mg / day, about 900 mg / day, about 800 mg / day, about 700 mg / day, or any dosage level within these ranges. This is preferably administered once a day or in divided doses about 2 to 3 times a day.

[0102] Administration of Compound (I) or a pharmaceutically acceptable salt thereof (particularly preferably the hydrochloride or maleate salt) can be, for example, continuous (7 days a week) or intermittent, depending on the pharmacokinetics and clearance / accumulation of the drug in a particular subject. Intermittent administration can be, for example, a 4-day on-3-day off schedule per week (drug holiday), or any other intermittent dosing schedule deemed appropriate using sound medical judgment, although continuous administration is preferred. Administration can be once daily (QD) or two or more times daily (b.i.d., t.i.d., etc.), with a preferred dose being about 20-960 mg / day QD. The daily dose can be a single dose or multiple individual divided doses. For example, two tablets containing 40 mg of Compound (I) or a pharmaceutically acceptable salt thereof (particularly preferably the hydrochloride or maleate salt) can be administered to a subject once daily (QD) for a total dose of 80 mg / day. In one embodiment, two tablets each containing 40 mg of Compound (I) or a pharmaceutically acceptable salt thereof (particularly preferably the hydrochloride or maleate) can be administered twice daily (b.i.d.) for a total dose of 160 mg / day. The amount of Compound (I) or a pharmaceutically acceptable salt thereof administered is calculated as the amount of Compound (I).

[0103] Whether continuous or intermittent, administration continues for a specific treatment cycle, typically at least 28 days, which can be repeated with or without a drug holiday. Longer or shorter cycles, such as 14, 18, 21, 24, 35, 42, or 48 days, or any range in between, can also be used. The cycle can be repeated without or with a drug holiday, depending on the subject. Other schedules are possible, depending on the presence or absence of adverse events, the cancer's response to treatment, patient convenience, etc. An "adverse event" refers to an undesirable or unintended illness or symptom occurring in a patient receiving a drug, regardless of whether it is causally related to the drug. In the case of intermittent administration, it is possible to administer the compound on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, or on days 1, 4, 8, 11, 15, 19, 23, and 27, or on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in a 28-day cycle.

[0104] The powder X-ray diffraction measurement method for the crystals of compound (I) according to the present disclosure can be performed by a reflection method.

[0105] In general, the morphology of many crystalline grains tends to give the sample a preferred orientation in the sample holder. The preferred orientation in the sample affects the intensity of various reflections, resulting in reflections that are sometimes stronger and sometimes weaker than would be expected for a completely unoriented sample.

[0106] The present disclosure will be described in more detail below with reference to examples, but the present disclosure is not limited to these examples. Although the present disclosure has been fully explained with reference to 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 deviate from the scope of the present disclosure, they are included in the present disclosure.

[0107] <Reagents and Measurement Methods> Unless otherwise specified, commercially available reagents were used in the examples. NMR spectra were measured using an AL400 (400 MHz; JEOL) with tetramethylsilane as the internal standard when the deuterated solvent contained tetramethylsilane, or with the non-deuterated proton peak remaining in the NMR solvent as the internal standard otherwise. All δ values ​​are expressed in ppm.

[0108] The meanings of the abbreviations are as follows: s: singlet d: doublet t: triplet dd: double doublet m: multiplet brs: broad singlet DMSO-d6: deuterated dimethyl sulfoxide CDCl3: deuterated chloroform

[0109] Powder X-ray Diffraction Measurement Powder X-ray diffraction was measured according to the following test conditions after lightly crushing an appropriate amount of the test substance in an agate mortar as needed.

[0110] Apparatus: PANalytical Empyrean Target: Cu X-ray output setting: 40 mA, 45 kV Scan range: 2.0 to 40.0° Step size: 0.026° Measurement method: Reflection method

[0111] The operation of the equipment, including data processing, followed the methods and procedures specified for each device. Note that the values ​​obtained from various spectra may vary slightly depending on the crystal growth direction, particle size, measurement conditions, etc. Therefore, these values ​​should not be interpreted strictly.

[0112] Simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement) TG-DTA measurement was performed under the following test conditions: Apparatus: Hitachi High-Tech Science TG / DTA7200 Sample: Approximately 5 mg Sample container: Aluminum Heating rate: Heat up to 300°C at 10°C / min Atmospheric gas: Air Nitrogen gas flow rate: 100 mL / min The apparatus was handled, including data processing, in accordance with the methods and procedures specified for each apparatus.

[0113] Residual Solvent Measurement Residual solvent was measured according to the following test conditions.

[0114] Measurement targets: ethyl acetate, tetrahydrofuran <GC (gas chromatograph) conditions> Apparatus: Shimadzu GC-2010 Plus Detector: FID Column: Inert Cap-5 Science (0.53 mm x 30 m, 5 μm) Column temperature: 40°C for 10 minutes, increased by 2°C per minute to 110°C, then increased by 30°C per minute to 250°C for 15 minutes Injection temperature: 260°C Detection temperature: 260°C Ambient gas: He Linear velocity: 28 cm / min Gas flow rate: 400 mL / min Helium flow rate: 50 mL / min Auxiliary flow rate: 50 mL / min Auxiliary gas: He

[0115] <HS conditions> HS oven temperature: 80°C HS needle temperature: 90°C Transfer temperature: 100°C Measurement time: 30 min Compression time: 3 / min Pulling up time: 0.2 / min Injection time: 0.1 / min GC cycle time: 80 / min

[0116] Measurement target: dimethyl sulfoxide <GC (gas chromatograph) conditions> Detector: FID Column: Inert Cap Pure-WAX, GLScience (30 m x 0.53 mm x 5 μm) Column temperature: 35°C for 5 minutes, heated at 5°C per minute to 80°C, then heated at 3°C ​​per minute to 170°C, then heated at 20°C per minute to 230°C for 10 minutes Injection temperature: 240°C Detection temperature: 240°C Ambient gas: He Flow rate: 28 cm / min Split: 10:1 Injection volume: 1 μL Detection gas flow rates: H2: 50 ml / min, Air: 400 ml / min, N2: 45 ml / min The equipment was handled, including data processing, in accordance with the methods and procedures specified for each equipment.

[0117] Example 1 Preparation of Form I Crystals of the Free Form of Compound (I) Compound (I) (11.7 g) synthesized in accordance with the method described in International Publication No. 2017 / 200087 (Example 32) was suspended in ethyl acetate (110 mL) and stirred at 100 ° C. for 4 hours, followed by stirring at room temperature for 18 hours. The suspension was filtered, and the resulting powder (10.4 g) was resuspended in ethyl acetate (220 mL). The suspension was stirred at 100 ° C. for 5 hours, followed by stirring at room temperature for 9 hours. The suspension was filtered, and Form I crystals of the free form of Compound (I) (9.37 g) were obtained with a yield of 80.1% and a chemical purity of 97.31%.

[0118] The obtained type I crystal of compound (I) １ The H-NMR spectrum was as follows: 1H-NMR (DMSO-D6) δ: 8.23 ​​(1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 6.45 (1H, t, J = 5.2 Hz), 4.49 (2H, d, J = 13.2 Hz), 3.22 (5H, m, 3.29-3.13), 2.71 (2H, t, J = 6.7 Hz), 1.93 (2H, d, J = 12.0 Hz), 1.76 (2H, m, 1.82-1.70), 1.39 (6H, s), 1.03 (9H, s).

[0119] Also, １ From the H-NMR spectrum, it was calculated that the residual solvent contained about 5700 ppm of ethyl acetate. １ The remaining amount of solvent from the H-NMR spectrum was calculated by converting the ratio of the integral values ​​of the peak derived from compound (I) and the solvent peak into a weight ratio using the molecular weight, and then calculating by the formula: weight of solvent ÷ (weight of compound (I) + weight of solvent).

[0120] The powder X-ray diffraction spectrum and thermogravimetry-differential thermal analysis (TG-DTA) curve of the obtained free-form I crystal are as follows: Powder X-ray diffraction spectrum: Shown in Figure 1. Characteristic diffraction angles are as follows:

[0121] Characteristic diffraction angles (2θ±0.2°): 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, 26.5°. The peaks were as shown in the table below (Table 1).

[0122]

[0123] Thermogravimetry-differential thermal analysis (TG-DTA) curve: shown in FIG.

[0124] Preparation Example 1 Preparation of Form I Crystals of the Free Form of Compound (I) Form I crystals of the free form of Compound (I) can also be prepared by the following method. Compound (I) (6.0 g) synthesized according to the method described in International Publication No. 2017 / 200087 (Example 32) was dissolved in a mixed solvent of tetrahydrofuran (42 mL) and ethyl acetate (210 mL) by stirring under reflux in an oil bath at 110 ° C. for 1 hour. The internal temperature at this time was 75 ° C. The oil bath was removed, and the mixture was stirred at room temperature for 3 hours to crystallize Compound (I). The internal temperature of the suspension at this time was 30 ° C. The suspension was filtered and dried under reduced pressure at 65 ° C. for 10 hours to obtain Form I crystals of the free form of Compound (I) (3.83 g, yield 64%).

[0125] The obtained compound (I) (20.00 g) was suspended in dimethyl sulfoxide (400 mL, 20 v / w) and degassed for 5 minutes at room temperature while stirring. After that, nitrogen gas was introduced. The obtained suspension was heated and stirred in an oil bath at 65 °C for 25 minutes to dissolve the crude compound (I), giving a pale yellow solution. The internal temperature at this time was 59 °C.

[0126] This solution was clarified and filtered through a Glass-Fiber Filter (Whatman, GF / B, Φ60 mm), and the container was washed with 20 mL (1 v / w) of dimethyl sulfoxide. At this time, the temperature of the filtrate was 40°C. The filtered filtrate was again heated and stirred in a 65°C oil bath until the internal temperature reached 58°C, and then water (420 mL, 21 v / w) was added to precipitate crystals. Crystals of Compound (I) began to precipitate around the time water (70 mL, 3.5 v / w) was added dropwise over 4 hours, at which time the internal temperature was around 63°C.

[0127] Water (350 mL, 17.5 v / w) was then added dropwise over 70 minutes to further promote crystallization. After the addition of water was completed, the mixture was stirred for another hour at an internal temperature of 67°C, and then the suspension was allowed to cool to room temperature over 3 hours while stirring.

[0128] The resulting suspension was filtered through Kiriyama filter paper (two sheets, No. 3, Φ95 mm (top) and No. 4, Φ95 mm (bottom)), and the collected wet crystals of Compound (I) were washed with water (300 mL, 15 v / w).

[0129] The obtained wet crystals of Compound (I) were dried under reduced pressure at 70°C for 14 hours to obtain pale yellow crystals of Compound (I) in the free form (19.13 g, yield 96%, chemical purity 99.12%). １ From the H-NMR spectrum, it was calculated that the residual solvent contained approximately 2400 ppm of dimethyl sulfoxide, but ethyl acetate and tetrahydrofuran were not detected. The amount of residual solvent was calculated in the same manner as in Example 1. Furthermore, GC analysis of the residual solvents revealed dimethyl sulfoxide (2629 ppm), tetrahydrofuran (ND), and ethyl acetate (ND). Note that ND indicates below the limit of quantitation, and the values ​​below the limit of quantitation for each solvent in GC analysis were 235 ppm for dimethyl sulfoxide, 900 ppm for ethyl acetate, and 145 ppm for tetrahydrofuran.

[0130] Example 2: Preparation of Form II Crystals of the Free Form of Compound (I) 40 mL of methanol was added to 2.00 g of compound (I) synthesized according to the method described in International Publication No. 2017 / 200087, and the mixture was heated, suspended, and stirred at 50°C for 22 hours. The mixture was then allowed to cool and stirred at room temperature for 2 hours, and the solid was collected by filtration. The mixture was dried under reduced pressure at 40°C for 20 hours, yielding 1.883 g of Form II crystals of the free form of compound (I). (Yield: 94%) １ The H-NMR spectrum was as follows:

[0131] 1H-NMR (DMSO-d6) δ: 8.22 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 6.41 (1H, t, J = 5.2 Hz), 4.49 (2H, d, J = 13.6 Hz), 3.30-3.14 (5H, m),2.71 (2H, t, J = 6.7 Hz), 1.92 (2H, d, J = 12.0 Hz), 1.80-1.70 (2H, m), 1.39 (6H, s), 1.03 (9H, s).

[0132] The powder X-ray diffraction spectrum and thermogravimetry-differential thermal analysis (TG-DTA) curve of the obtained free-form crystals of Form II are as follows: Powder X-ray diffraction spectrum: shown in FIG.

[0133] The characteristic diffraction angles are as follows: Characteristic diffraction angles (2θ±0.2°): Diffraction angles (2θ±0.2°) are 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9°. The respective peaks are as shown in the table below (Table 2).

[0134]

[0135] Thermogravimetry-differential thermal analysis (TG-DTA) curve: shown in FIG.

[0136] Example 3: Preparation of Form III Crystals of the Free Form of Compound (I) 28 mL of ethanol was added to 500 mg of compound (I) synthesized in accordance with the method described in WO 2017 / 200087, and the mixture was heated to reflux at an internal temperature of around 78°C. After dissolution was confirmed, the mixture was rapidly cooled in a dry ice-methanol bath (internal temperature reached -2°C in about 1 minute after the start of cooling). After crystal precipitation was confirmed, the mixture was switched to an ice bath, and the mixture was stirred at an internal temperature of around 0°C for 30 minutes, and the solid was collected by filtration. The mixture was dried under reduced pressure at 40°C for 20 hours, and 347 mg of Form III Crystals of the Free Form of Compound (I) was obtained (yield 69%). １ The H-NMR spectrum was as follows:

[0137] 1H-NMR (DMSO-d6) δ: 8.23 ​​(1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.10 (1H, d, J = 8.8 Hz), 6.44 (1H, t, J = 5.2 Hz), 4.50 (2H, d, J = 13.6 Hz), 3.41-3.14 (5H, m), 2.73 (2H, t, J = 6.7 Hz), 1.94 (2H, d, J = 12.0 Hz), 1.85-1.72 (2H, m), 1.40 (6H, s), 1.05 (9H, s).

[0138] The powder X-ray diffraction spectrum and thermogravimetry-differential thermal analysis (TG-DTA) curve of the obtained free-form crystal of Form III are as follows: Powder X-ray diffraction spectrum: shown in FIG.

[0139] The characteristic diffraction angles are as follows. Characteristic diffraction angles (2θ±0.2°): Diffraction angles (2θ±0.2°) are 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7°. The respective peaks are as shown in the table below (Table 3).

[0140]

[0141] Thermogravimetry-differential thermal analysis (TG-DTA) curve: shown in FIG.

[0142] Example 4: Preparation of crystals of hydrochloride of compound (I) Compound (I) (202 mg) synthesized according to the method described in WO 2017 / 200087 was added with 3 ml of ethyl acetate and 3 ml of methanol and stirred, and then 71 μl of 5 M aqueous hydrochloric acid (1 molar equivalent based on compound (I)) was added and stirred at room temperature for 2 hours. The solid was collected by filtration and dried under reduced pressure to obtain crystals of hydrochloride of compound (I) (161 mg). (Yield: 75%) １ The H-NMR spectrum was as follows: 1H-NMR (DMSO-d6) δ: 11.10 (1H, s), 8.96 (1H, br s), 8.22 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 7.18 (1H, d, J = 8.8 Hz), 6.79 (1H, br s), 4.48 (2H, d, J = 13.6 Hz), 3.35-3.19 (5H, m), 2.71 (2H, t, J = 6.7 Hz), 1.95-1.75 (4H, m), 1.39 (6H, s), 1.31 (9H, s).

[0143] The powder X-ray diffraction spectrum and thermogravimetry-differential thermal analysis (TG-DTA) curve of the obtained hydrochloride crystals are as follows: Powder X-ray diffraction spectrum: shown in FIG.

[0144] The characteristic diffraction angles are as follows. Characteristic diffraction angles (2θ±0.2°): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, 31.6°. Simultaneous thermogravimetry and differential thermal analysis were performed according to the test conditions for TG-DTA measurement described in the "<Reagents and Measurement Methods>" section above. However, the heating rate was 10°C / min up to 400°C. The peaks were as shown in the table below (Table 4).

[0145]

[0146] Thermogravimetry-differential thermal analysis (TG-DTA) curve: shown in FIG.

[0147] Example 5: Preparation of Crystals of Maleate of Compound (I) Compound (I) (2.0 g), synthesized according to the method described in International Publication No. WO 2017 / 200087, was dissolved in 20 mL of chloroform / methanol (9 / 1). 405 mg of maleic acid (1 molar equivalent relative to Compound (I)) was added and the mixture was heated and stirred at 45°C. After dissolution was confirmed, the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure at 40°C to obtain 2.43 g of amorphous maleate (101% yield, residual CHCl). 200 mL of acetonitrile was added to 500 mg of amorphous maleate and heated to reflux to dissolve. The mixture was allowed to cool and stir at room temperature. After the internal temperature reached near room temperature, the mixture was cooled on ice and stirred for 1 hour, after which the solid was collected by filtration. The mixture was dried under reduced pressure at 40°C to obtain 332 mg of crystalline maleate (66% yield).

[0148] The obtained crystals of the maleate salt of compound (I) １ The H-NMR spectrum was as follows:

[0149] 1H-NMR (DMSO-d6) δ: 11.12 (1H, s), 8.39(1H, s), 7.99 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.8 Hz), 6.55 (1H, t, J = 5.2 Hz), 6.00 (2H, s), 4.50 (2H, d, J = 13.6 Hz), 3.60-3.07 (7H, m), 1.91 (2H, d, J = 12.0 Hz), 1.80-1.70 (2H, m), 1.39 (6H, s), 1.03 (9H, s).

[0150] The powder X-ray diffraction spectrum and thermogravimetry-differential thermal analysis (TG-DTA) curve of the obtained maleate crystals are as follows: Powder X-ray diffraction spectrum: shown in FIG.

[0151] The characteristic diffraction angles are as follows: Characteristic diffraction angles (2θ±0.2°): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, 30.8°. The peaks are as shown in the table below (Table 5).

[0152]

[0153] The simultaneous thermogravimetry and differential thermal analysis was performed according to the test conditions for TG-DTA measurement described in the section "<Reagents and Measurement Methods>" above. However, the temperature was increased at a rate of 10°C / min up to 400°C. The simultaneous thermogravimetry and differential thermal analysis (TG-DTA measurement) curve is shown in Figure 10.

[0154] Comparative Example 1: Preparation of Crystals of Hemimalate of Compound (I) 75 mL of 1-propanol was added to 1.00 g of compound (I) synthesized according to the method described in International Publication No. WO 2017 / 200087. The mixture was heated and stirred until the internal temperature reached approximately 75°C, at which point the mixture dissolved. 129 mg (0.55 eq.) of L-malic acid was added, and the mixture was washed in with 5 mL of 1-propanol. The internal temperature was raised to 90°C, and the mixture was stirred at the same temperature for 30 minutes, after which it was allowed to cool and stirred at room temperature. Crystals precipitated at approximately 70°C, and the mixture was stirred for 30 minutes while maintaining the same temperature. After cooling and stirring overnight at 10°C or below, the solid was collected by filtration. The mixture was dried under reduced pressure at 40°C for 2 days, yielding 1.00 g of hemimalate (90% yield). １ The H-NMR spectrum was as follows:

[0155] 1H-NMR (DMSO-d6) δ: 8.22 (1H, s), 7.94 (1H, d, J = 8.8 Hz), 7.11 (1H, d, J = 8.8 Hz), 6.54 (1H, t, J = 5.2 Hz), 4.49 (2H, d, J = 12.8 Hz), 3.85-3.80 (0.5H, m), 3.37-3.16 (5H, m), 2.88 (2H, br s), 2.51-2.26 (1H, m ), 1.93-1.72 (4H, m ), 1.41 (6H, s), 1.15 (9H, s).

[0156] The powder X-ray diffraction spectrum and thermogravimetry-differential thermal analysis (TG-DTA) curve of the obtained 1 / 2 malate of Compound (I) are as follows: Powder X-ray diffraction spectrum: shown in FIG.

[0157] The characteristic diffraction angles are as follows: Characteristic diffraction angles (2θ±0.2°): 6.1°, 7.1°, 10.0°, 11.2°, 17.2°, 19.6°, 16.6°, 25.2° Simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement) curve: Shown in FIG. 12.

[0158] Comparative Example 2: Preparation of crystals of acetate salt of compound (I) 1 mL of butyl acetate and 998 uL of acetic acid (1 molar equivalent relative to compound (I)) were added to 1.00 g of compound (I) synthesized in accordance with the method described in WO 2017 / 200087, and the mixture was stirred at room temperature to dissolve.

[0159] The mixture was heated to 50°C, 9 mL of butyl acetate was added, and after stirring for 1 hour, a solid precipitated. The mixture was allowed to cool to room temperature and stirred, and then stirred under ice cooling for 1 hour, after which the solid was filtered out. The mixture was dried under reduced pressure at 40°C for 20 hours to obtain 693 mg of acetate. (Yield: 63%) １ The H-NMR spectrum was as follows: 1H-NMR (DMSO-d6) δ: 8.22 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 6.53 (1H, t, J = 5.2 Hz), 4.48 (2H, d, J = 12.8 Hz), 3.30-3.13 (5H, m), 2.74 (2H, t, J = 6.7 Hz), 1.88-1.7 (7H, m), 1.38 (6H, s), 1.05 (9H, s).

[0160] The powder X-ray diffraction spectrum and thermogravimetry-differential thermal analysis (TG-DTA) curve of the acetate salt of the compound (I) obtained are as follows: Powder X-ray diffraction spectrum: shown in FIG.

[0161] Characteristic diffraction angles are as follows: Characteristic diffraction angles (2θ±0.2°): 11.2°, 11.5°, 12.6°, 13.3°, 15.4°, 15.8°, 17.1°, 17.7°, 18.2°, 18.8°, 19.9°, 21.1°, 21.7°, 22.0°, 23.2°, 23.4°, 23.8°, 26.2°, 26.9°, 27.8° Simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement) curve: shown in FIG. 14.

[0162] Test Example 1 Solid Stability Test The storage stability of each of Form I crystals, Form II crystals, and Form III crystals of the free form of Compound (I) obtained by the methods described in Examples 1, 2, and 3 above was tested under the following conditions: Storage condition: 70°C / 75% RH (open system and closed system) Measurement point: 2 weeks Storage amount: Approximately 50 mg Storage container: Brown glass bottle

[0163] The powder X-ray diffraction measurement of the sample after storage was performed by the method described above. The change in the amount of related substances (the amount of substances detected other than Compound (I)) was measured by weighing approximately 1 mg of the sample and dissolving it in approximately 5 mL of a water / acetonitrile mixture (1:1). 5 μL of this solution was accurately measured and analyzed by HPLC using the following method.

[0164] Column: InertSustain C18, 4.6 x 150 mm, 3 μm Column temperature: 40°C Column flow rate: 1.0 mL / min Mobile phase: A; 10 mM phosphate buffer (pH 5.5) / acetonitrile (9:1), B; acetonitrile Detection UV: 220 nm Gradient: Time (min) A B 0-20 100% → 40% 0% → 60% 20-27 40% 60% 27-28 40% → 100% 60% → 0% 28-35 95% 5%

[0165] As a result, no change in the powder X-ray diffraction patterns was observed for the free-form crystals of Form I, II, and III, and they were found to be extremely stable crystals. Furthermore, as shown in Table 6 below, the amount of related substances in each crystal was small after storage, and no change in appearance was observed.

[0166]

[0167] Test Example 2: Dynamic Moisture Adsorption / Desorption Test A VTI-SA+ (TA Instruments) was used for the test. Approximately 10 mg of free-form type I crystals, free-form type II crystals, and free-form type III crystals were each weighed and placed in a pan. The temperature was raised to 60°C at a rate of 1 degree per minute while confirming that the weight fluctuation was within 0.0100% over 5 minutes. If the weight fluctuated, the temperature was maintained for a maximum of 5 hours before proceeding to the next step. The temperature was then lowered to 25°C, and the humidity was increased from 5% RH to 95% RH, and then reduced to 5% RH. During this time, humidity was increased by 5% RH increments while confirming that the weight fluctuation was within 0.00100% over 5 minutes. If the weight fluctuated, the humidity was maintained for a maximum of 2 hours before proceeding to the next step.

[0168] 15, 16, and 17, it was confirmed that the free-form type I crystal, the free-form type II crystal, and the free-form type III crystal have low hygroscopicity. In particular, it was revealed that the free-form type I crystal and the free-form type III crystal exhibit excellent low hygroscopicity.

[0169] Test Example 3 Thermal Stability Test A thermal stability test was performed using the free-form crystals I, II, and III obtained by the methods described in Examples 1, 2, and 3 above. Powder X-ray diffraction measurement was performed at 25°C, and the temperature was raised to 50°C over 30 minutes, followed by powder X-ray diffraction measurement. The temperature was further raised to 210°C at a rate of 10°C / 10 minutes, followed by powder X-ray diffraction measurement. The temperature was lowered to 25°C over 30 minutes, followed by powder X-ray diffraction measurement. The obtained spectra were examined for the appearance or decrease of new peaks in the target spectrum before and after the start of the test.

[0170] The results of the thermal stability tests at 25°C and 210°C for the free-form crystals I, II and III are shown in Figures 18, 19, 20, 21, 22 and 23, respectively.

[0171] As a result, no change in the crystalline form of the free-form I crystal was observed when heated up to 210°C, confirming its stability. On the other hand, new peaks appeared in the free-form II crystal and the free-form III crystal upon heating, indicating that the crystalline form was not maintained.

[0172] Test Example 4 Solid Stability Test The storage stability of the hydrochloride crystals, maleate crystals, 1 / 2 malate crystals and acetate crystals of Compound (I) obtained by the methods described in Examples 4, 5, Comparative Examples 1 and 2 above was tested under the conditions of Test Example 1.

[0173] As a result, no change in the powder X-ray diffraction patterns was observed for both the hydrochloride crystals and the maleate crystals of Compound (I), and they were found to be extremely stable crystals. Furthermore, as shown in Tables 7 and 8 below, the hydrochloride crystals and the maleate crystals of Compound (I) contained only small amounts of related substances after storage and showed no change in appearance.

[0174] As shown in Tables 9 and 10 below, the crystals of the 1 / 2 malate and acetate salt of Compound (I) showed no change in appearance after storage, but contained a large amount of related substances.

[0175]

[0176] Test Example 5 Dynamic Moisture Adsorption / Desorption Test The storage stability of the hydrochloride crystals, maleate crystals, 1 / 2 malate crystals and acetate crystals of Compound (I) obtained by the methods described in Examples 4, 5, Comparative Examples 1 and 2 above was tested under the conditions of Test Example 2.

[0177] The results are shown in Figures 24, 25, 26, and 27. It was confirmed that the maleate crystals exhibited low hygroscopicity, and that the hydrochloride crystals exhibited lower hygroscopicity than the 1 / 2 malate crystals.

Claims

1. Form I crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1° (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5° 2. The free-form crystal of claim 1, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b): (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4°, and 25.1°; and (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9°, and 26.5°.

3. The free-form I crystal according to claim 1, which has peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.2°, 6.7°, 8.3°, 8.7°, 9.3°, 9.7°, 11.1°, 13.0°, 13.7°, 15.4°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.1°, 25.9°, and 26.5°.

4. The free-form crystal of Form I according to claim 1, which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in FIG.

5. The free-form I crystal according to claim 1, which has an endothermic peak at a peak temperature of about 235°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

6. A pharmaceutical composition containing the free-form crystal of Form I described in any one of claims 1 to 5.

7. A method for producing the free-form Form I crystal of claim 1, comprising the steps of dissolving 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one in solvent 1, and adding solvent 2 to the resulting solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one.

8. The method of claim 7, wherein solvent 1 is dimethyl sulfoxide and solvent 2 is water, or solvent 1 is tetrahydrofuran and solvent 2 is normal heptane, ethyl acetate, or 2-propanol.

9. The method of claim 7, wherein solvent 1 is dimethyl sulfoxide and solvent 2 is water.

10. Form I crystal of the free form according to claim 1, obtained by crystallization through the steps of dissolving 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one in dimethyl sulfoxide and adding water to the resulting solution to obtain 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one.

11. Form II crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 10.4°, 22.9° and 27.9° (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8° and 26.5° 12. The free form Form II crystal according to claim 11, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b): (a) 10.4°, 22.9°, and 27.9°; and (b) 6.7°, 7.5°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, and 26.5°.

13. The free form II crystal according to claim 11, which has peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.7°, 7.5°, 10.4°, 12.7°, 13.4°, 14.6°, 16.5°, 17.9°, 18.3°, 19.8°, 20.6°, 21.8°, 22.9°, 26.5°, and 27.9°.

14. The free-form crystal of Form II according to claim 11, which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 3.

15. The free-form crystal of Form II according to claim 11, which has an endothermic peak at a peak temperature of about 234°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

16. A pharmaceutical composition containing the free-form crystal of Form II according to any one of claims 11 to 15.

17. Form III crystal of a free form of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, having peaks in a powder X-ray diffraction spectrum (CuKα) at ​​at least two diffraction angles (2θ±0.2°) selected from the following (a) and at least two diffraction angles (2θ±0.2°) selected from the following (b): (a) 11.7°, 23.4° and 24.2° (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2° and 26.7° 18. The free form crystal of Form III according to claim 17, which has peaks in a powder X-ray diffraction spectrum (CuKα) at ​​three diffraction angles (2θ±0.2°) selected from the following (a) and at least four diffraction angles (2θ±0.2°) selected from the following (b): (a) 11.7°, 23.4°, and 24.2°; and (b) 6.8°, 7.5°, 8.8°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 26.2°, and 26.7°.

19. The free form Form III crystal according to claim 17, which has peaks at the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.8°, 7.5°, 8.8°, 11.7°, 12.9°, 13.9°, 14.9°, 16.7°, 17.8°, 18.8°, 19.7°, 20.7°, 22.0°, 23.4°, 24.2°, 26.2°, and 26.7°.

20. The free-form crystal of Form III according to claim 17, which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 5.

21. The free-form crystal of Form III according to claim 17, which has an endothermic peak at a peak temperature of about 234°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA measurement).

22. A pharmaceutical composition containing the free-form crystal of Form III according to any one of claims 17 to 21.

23. A crystal of hydrochloride salt of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, having peaks at at least three diffraction angles selected from the following diffraction angles (2θ±0.2°) in a powder X-ray diffraction spectrum (CuKα): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6°.

24. A crystalline form of the hydrochloride salt according to claim 23, which has peaks in its powder X-ray diffraction spectrum (CuKα) at ​​the following diffraction angles (2θ±0.2°): 6.7°, 7.4°, 11.2°, 12.6°, 14.1°, 16.6°, 20.0°, 21.1°, 22.0°, 22.6°, 23.2°, 24.5°, 26.4°, 28.0°, 30.0°, and 31.6°.

25. A crystalline form of the hydrochloride salt according to claim 23, which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 7.

26. The hydrochloride crystals according to claim 23, which have an endothermic peak at a peak temperature of about 241°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA).

27. A pharmaceutical composition containing the hydrochloride crystals according to any one of claims 23 to 26.

28. In the powder X-ray diffraction spectrum (CuKα), the following diffraction angles (2θ±0.2°): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8° A crystal of maleate of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one having peaks at at least three diffraction angles selected from the group consisting of 29. A crystalline maleate salt according to claim 28, which has peaks in its powder X-ray diffraction spectrum (CuKα) at ​​the following diffraction angles (2θ±0.2°): 6.5°, 9.8°, 12.1°, 13.0°, 13.9°, 14.7°, 15.2°, 15.9°, 17.7°, 18.4°, 19.0°, 20.1°, 20.9°, 21.5°, 22.9°, 23.4°, 25.3°, 28.0°, 29.7°, and 30.8°.

30. A crystalline maleate salt according to claim 28, which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 9.

31. The crystalline maleate salt according to claim 28, which has an endothermic peak at a peak temperature of about 245°C in simultaneous thermogravimetry-differential thermal analysis (TG-DTA).

32. A pharmaceutical composition containing the crystalline maleate salt according to any one of claims 28 to 31.