Crystalline form of salts of quaternary condensed ring compounds, method of preparation thereof, and use thereof

Abstract

The present invention relates to the crystalline form of a salt of a quaternary condensed ring compound, a method for preparing the same, and the use thereof. Specifically, the present invention relates to the crystalline form of a salt of a quaternary condensed ring compound represented by formula (I), a method for preparing the same, a therapeutically effective amount of the compound or its crystalline form, and a pharmaceutical composition comprising the use thereof as a tyrosine kinase inhibitor. JPEG2026517098000068.jpg37170

Description

[Technical Field]

[0001] This invention belongs to the field of pharmaceuticals, and more particularly to the crystalline form of salts of quaternary condensed ring compounds, methods for preparing them, and their uses. [Background technology]

[0002] The tyrosine kinase activity of the ABL1 protein is normally tightly regulated, with the N-terminal cap region of the SH3 domain playing a crucial role. One regulatory mechanism involves myristoylation of the two glycine residues in the N-terminal cap, followed by interaction with the myristic acid binding site of the SH1 catalytic domain. A marker for chronic myeloid leukemia (CML) is the Philadelphia chromosome (Ph), formed by a reciprocal translocation of the t(9,22) chromosome in hematopoietic stem cells. This chromosome harbors the oncogene BCR-ABL1, which encodes a chimeric BCR-ABL1 protein lacking an N-terminal cap and possessing a constitutively active tyrosine kinase domain.

[0003] Drugs such as imatinib, nilotinib, and dasatinib, which inhibit the tyrosine kinase activity of BCR-ABL1 via ATP competition, may be effective in treating CML, but some patients experience relapses due to the emergence of drug-resistant clones. For example, small molecules or combinations thereof can be used to inhibit the activity of BCR-ABL1 and BCR-ABL1 variants via the ATP binding site, the myristoyl binding site, or a combination of both sites.

[0004] Patent PCT / CN2022 / 122536 protects a class of quaternary condensed ring compounds. Considering the importance of studying the salt and crystalline forms of pharmaceutical compounds in clinical research, and in order to improve the solubility and solid stability of the product, reduce storage costs, extend the product lifecycle, and enhance the bioavailability of the product, this invention comprehensively studies the crystalline forms of salts of the above compounds. [Overview of the project]

[0005] All the content involved in Patent PCT / CN2022 / 122536 is incorporated herein by reference.

[0006] The object of the present invention is to provide a crystalline form of an acidic salt of a compound represented by formula (I):

Chemical formula

[0007] In the formula, Ring A is C , , 1-3 , , , , 1-3 ,

[0008] , , aryl or 5- to 6-membered heteroaryl; R1 is C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 13 alkylthio, or C 1-3 haloalkoxy; M1 is selected from N or CH; M2 is selected from NH or CH2; M3 is selected from N or CH; R2 or R3 is each independently C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio, or C 1-3 haloalkoxy; The acidic salt is selected from ethyl sulfonate, mesylate, sulfate, hydrochloride, p-toluenesulfonate, besylate, isethionate, or 1,5-naphthalenedisulfonate.

[0008] In a more preferred embodiment of the present invention, the compound represented by formula (I) is further as described by the general formula (I-a):

Chemical formula

[0009] In a more preferred embodiment of the present invention, ring A is phenyl or pyridyl; R1 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy selected from; M1 is N; M2 is NH; M3 is N; R2 or R3 is each independently hydrogen, C 1-3 alkyl, or C 1-3 haloalkyl selected from.

[0010] In a more preferred embodiment of the present invention, R1 is selected from -CF2, -CF3, -CF2Cl, -OCF2, -OCF3, or -OCF2Cl; R2 or R3 is each independently selected from -CH3, -CH2CH3, -CF2, -CF3, or -CF2Cl.

[0011] In a more preferred embodiment of the present invention, the specific structure of the compound represented by formula (I) is as follows:

Chemical formula

[0012] In a more preferred embodiment of the present invention, the crystalline form is a crystalline form of hydrobromide, hydrochloride, sulfate, p-tosylate, mesylate, besylate, oxalate, acetate, ethylsulfonate, maleate, phosphate, fumarate, succinate, malonate, adipine, malate, tartrate, 1,5-napadisylate, isethionate, citrate, hippurate, lactate, benzoate, palmitate, or salicylate. Preferably, the crystalline form of hydrobromide, ethylsulfonate, mesylate, sulfate, hydrochloride, p-tosylate, besylate, isethionate, 1,5-napadisylate, maleate, fumarate, succinate, malate, or tartrate; and More preferably, the crystalline form is ethyl sulfonate, mesylate, sulfate, hydrochloride, p-tosylate, besylate, isethionate, or 1,5-napadisylate.

[0013] In a more preferred embodiment of the present invention, the crystalline form of the acidic salt is: crystalline form A of ethyl sulfonate, crystalline form B of ethyl sulfonate, crystalline form A of mesylate, crystalline form B of mesylate, crystalline form A of sulfate, crystalline form B of sulfate, crystalline form C of sulfate, crystalline form D of sulfate, crystalline form E of sulfate, crystalline form F of sulfate, form G of sulfate, crystalline form A of hydrochloride, crystalline form B of hydrochloride, crystalline form C of hydrochloride, crystalline form A of p-tosylate, crystalline form B of the p-tosylate, crystalline form C of p-tosylate, and the crystal Crystal form D, crystal form E of p-tosylate, crystal form A of besylate, crystal form B of besylate, crystal form C of besylate, crystal form A of isethionate, crystal form B of isethionate, or crystal form A of 1,5-napadisylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where, The X-ray powder diffraction pattern of crystalline form A of the ethyl sulfonate has diffraction peaks at 5.9±0.2°; or at 17.7±0.2°; or at 22.3±0.2°; or at 16.7±0.2°; or at 21.0±0.2°; or at 18.0±0.2°; or at 5.6±0.2°; or at 29.7±0.2°; or at 23.8±0.2°; or at 12.2±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks B selected from them; The X-ray powder diffraction pattern of crystalline form B of the ethyl sulfonate has diffraction peaks at 5.6±0.2°; or at 16.5±0.2°; or at 8.4±0.2°; or at 10.0±0.2°; or at 17.6±0.2°; or at 23.7±0.2°; or at 27.7±0.2°; or at 15.2±0.2°; or at 28.9±0.2°; or at 12.8±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form A of the mesylate has diffraction peaks at 6.0±0.2°; or at 17.8±0.2°; or at 21.4±0.2°; or at 16.5±0.2°; or at 22.4±0.2°; or at 12.2±0.2°; or at 24.3±0.2°; or at 23.5±0.2°; or at 29.8±0.2°; or at 19.8±0.2°; preferably, it includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, it includes any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form B of the mesylate has diffraction peaks at 6.0±0.2°; or at 18.0±0.2°; or at 22.6±0.2°; or at 30.1±0.2°; or at 6.6±0.2°; or at 12.2±0.2°; or at 13.2±0.2°; or at 15.5±0.2°; or at 21.4±0.2°; or at 24.0±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form A of the sulfate has diffraction peaks at 5.8±0.2°; or at 21.6±0.2°; or at 17.6±0.2°; or at 19.7±0.2°; or at 16.5±0.2°; or at 12.0±0.2°; or at 12.3±0.2°; or at 17.2±0.2°; or at 13.6±0.2°; or at 25.9±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form B of the sulfate has diffraction peaks at 5.7±0.2°; or at 16.9±0.2°; or at 17.4±0.2°; or at 22.5±0.2°; or at 19.3±0.2°; or at 9.9±0.2°; or at 20.1±0.2°; or at 13.8±0.2°; or at 11.1±0.2°; or at 18.6±0.2°; preferably, it includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, it includes any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of the sulfate in crystalline form C has diffraction peaks at 5.6±0.2°; or at 16.7±0.2°; or at 8.3±0.2°; or at 12.7±0.2°; or at 15.3±0.2°; or at 17.6±0.2°; or at 10.0±0.2°; or at 15.5±0.2°; or at 13.1±0.2°; or at 21.0±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form D of the sulfate has diffraction peaks at 17.3±0.2°; or at 24.3±0.2°; or at 20.6±0.2°; or at 26.2±0.2°; or at 22.1±0.2°; or at 18.6±0.2°; or at 15.1±0.2°; or at 12.9±0.2°; or at 25.9±0.2°; or at 18.0±0.2°; preferably, it includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, it includes any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form E of the sulfate has diffraction peaks at 5.8±0.2°; or at 17.2±0.2°; or at 9.8±0.2°; or at 13.8±0.2°; or at 20.0±0.2°; or at 22.6±0.2°; or at 19.2±0.2°; or at 22.2±0.2°; or at 11.1±0.2°; or at 26.2±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of the crystalline form F of the sulfate has diffraction peaks at 6.0±0.2°; or at 16.0±0.2°; or at 22.4±0.2°; or at 17.3±0.2°; or at 20.0±0.2°; or at 18.5±0.2°; or at 20.5±0.2°; or at 14.4±0.2°; or at 24.9±0.2°; or at 24.4±0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of the sulfate in crystalline form G has diffraction peaks at 5.9±0.2°; or at 16.7±0.2°; or at 17.6±0.2°; or at 5.6±0.2°; or at 16.9±0.2°; or at 22.2±0.2°; or at 29.5±0.2°; or at 27.7±0.2°; or at 25.1±0.2°; or at 10.2±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt has diffraction peaks at 22.4±0.2°; or at 14.0±0.2°; or at 17.1±0.2°; or at 6.2±0.2°; or at 19.4±0.2°; or at 25.2±0.2°; or at 17.5±0.2°; or at 21.6±0.2°; or at 19.8±0.2°; or at 23.4±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt has diffraction peaks at 6.7±0.2°; or at 27.0±0.2°; or at 23.4±0.2°; or at 13.4±0.2°; or at 11.0±0.2°; or at 24.1±0.2°; or at 15.6±0.2°; or at 4.5±0.2°; or at 20.0±0.2°; or at 10.2±0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 diffraction peaks from the above; more preferably including any 6, 7, or 8 diffraction peaks selected from there. The X-ray powder diffraction pattern of the hydrochloride salt in crystalline form C has diffraction peaks at 16.5±0.2°; or 20.4±0.2°; or 22.2±0.2°; or 9.7±0.2°; or 17.8±0.2°; or 5.3±0.2°; or 17.5±0.2°; or 6.0±0.2°; or 14.3±0.2°; or 21.7±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of crystalline form A of the p-tosylate has diffraction peaks at 16.8±0.2°; or 19.9±0.2°; or 5.7±0.2°; or 22.5±0.2°; or 21.8±0.2°; or 24.9±0.2°; or 22.3±0.2°; or 20.8±0.2°; or 26.6±0.2°; or 12.4±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form B of the p-tosylate has diffraction peaks at 5.5±0.2°; or at 19.9±0.2°; or at 13.2±0.2°; or at 21.9±0.2°; or at 28.1±0.2°; or at 14.1±0.2°; or at 10.9±0.2°; or at 17.6±0.2°; or at 9.5±0.2°; or at 20.4±0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of the crystalline form C of the p-tosylate has diffraction peaks at 5.8±0.2°; or at 17.3±0.2°; or at 16.7±0.2°; or at 22.0±0.2°; or at 19.6±0.2°; or at 23.1±0.2°; or at 22.4±0.2°; or at 20.1±0.2°; or at 29.0±0.2°; or at 12.8±0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of the crystalline form D of the p-tosylate has diffraction peaks at 4.9±0.2°; or 5.7±0.2°; or 17.2±0.2°; or 22.0±0.2°; or 19.5±0.2°; or 28.9±0.2°; or 25.5±0.2°; or 12.7±0.2°; or 14.8±0.2°; or 23.0±0.2°; preferably, it includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, it includes any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form E of the p-tosylate has diffraction peaks at 5.4±0.2°; or at 16.1±0.2°; or at 9.9±0.2°; or at 16.7±0.2°; or at 8.4±0.2°; or at 23.1±0.2°; or at 26.9±0.2°; or at 25.7±0.2°; or at 25.2±0.2°; or at 28.2±0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form A of the besylate has diffraction peaks at 5.7±0.2°; or at 17.2±0.2°; or at 21.8±0.2°; or at 5.5±0.2°; or at 16.6±0.2°; or at 23.0±0.2°; or at 17.6±0.2°; or at 20.3±0.2°; or at 27.3±0.2°; or at 28.8±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of the besylate in crystalline form B has diffraction peaks at 19.7±0.2°; or 17.4±0.2°; or 13.6±0.2°; or 22.6±0.2°; or 9.7±0.2°; or 5.7±0.2°; or 14.2±0.2°; or 29.1±0.2°; or 12.8±0.2°; or 23.7±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the besylate in crystalline form C has diffraction peaks at 5.4±0.2°; or at 16.6±0.2°; or at 16.9±0.2°; or at 15.0±0.2°; or at 12.7±0.2°; or at 19.4±0.2°; or at 8.3±0.2°; or at 20.9±0.2°; or at 13.8±0.2°; or at 9.9±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form A of isethionate has diffraction peaks at 5.4±0.2°; or at 16.1±0.2°; or at 20.9±0.2°; or at 20.0±0.2°; or at 25.2±0.2°; or at 15.1±0.2°; or at 16.7±0.2°; or at 25.7±0.2°; or at 12.7±0.2°; or at 19.5±0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form B of isethionate has diffraction peaks at 5.9±0.2°; or at 16.7±0.2°; or at 21.2±0.2°; or at 19.5±0.2°; or at 22.5±0.2°; or at 10.0±0.2°; or at 13.0±0.2°; or at 24.3±0.2°; or at 15.5±0.2°; or at 17.5±0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from them; The X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate has diffraction peaks at 21.3±0.2°; or 10.2±0.2°; or 9.5±0.2°; or 17.1±0.2°; or 9.9±0.2°; or 16.7±0.2°; or 25.8±0.2°; or 5.7±0.2°; or 8.0±0.2°; or 23.7±0.2°; preferably includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably includes any 6, 7, or 8 diffraction peaks selected from them.

[0014] A more preferred embodiment of the present invention provides crystalline form A of the ethyl sulfonate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is 2θ = 5.9±0.2°, 17.7±0.2°, and The diffraction pattern includes at least one diffraction peak at 22.3±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 2θ = 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, and 29.7±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0015] For example, the X-ray powder diffraction pattern of crystalline form A of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2° and 16.7±0.2°; Alternatively, 5.9±0.2°, 16.7±0.2°, and 21.0±0.2°; Alternatively, 17.7±0.2°, 16.7±0.2°, and 18.0±0.2°; Alternatively, 22.3±0.2°, 5.6±0.2°, and 29.7±0.2°; Alternatively, 5.9±0.2°, 16.7±0.2°, 5.6±0.2°, and 29.7±0.2°; Alternatively, 5.9±0.2°, 17.7±0.2°, 16.7±0.2°, 21.0±0.2°, 5.6±0.2°, and 29.7±0.2°; Alternatively, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, and 29.7±0.2°.

[0016] The X-ray powder diffraction pattern of crystalline form A of the ethyl sulfonate optionally includes one or more diffraction peaks at 2θ values ​​of 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, 28.0±0.2°, 24.9±0.2°, 10.0±0.2°, and 11.8±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from those; more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from those.

[0017] For example, the X-ray powder diffraction pattern of crystalline form A of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 23.8±0.2°, and 12.2±0.2°; Alternatively, 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, and 28.0±0.2°.

[0018] The X-ray powder diffraction pattern of crystalline form A of ethyl sulfonate includes one or more diffraction peaks at 2θ of 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, 28.0±0.2°, 24.9±0.2°, 10.0±0.2°, and 11.8±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0019] For example, the X-ray powder diffraction pattern of crystalline form A of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, and 29.7±0.2°; Alternatively, 5.9±0.2°, 22.3±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, and 12.2±0.2°; or 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, and 12.2±0.2°; Alternatively, 17.7±0.2°, 16.7±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, 28.0±0.2°, 24.9±0.2°, and 10.0±0.2°.

[0020] The X-ray powder diffraction patterns of crystalline form A of ethyl sulfonate are as follows: 2θ values ​​of 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, 28.0±0.2°, 24.9±0.2°, 10.0±0.2°, 11.8±0.2°, 13.8±0.2°, and 27. The diffraction peaks include one or more at 8±0.2°, 12.7±0.2°, 22.6±0.2°, and 14.5±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0021] For example, the X-ray powder diffraction pattern of crystalline form A of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 22.3±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, and 18.4±0.2°; or 5.9±0.2°, 17.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, and 12.2±0.2°; Alternatively, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, and 28.0±0.2°; Alternatively, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, 28.0±0.2°, and 24.9±0.2°.

[0022] Most preferably, for crystalline form A of the ethyl sulfonate, the number of acid molecules is 1, and its X-ray powder diffraction pattern is measured using Cu-Kα radiation. The characteristic X-ray diffraction peaks, expressed by the 2θ angle and interplanar spacing d, are as shown in Table 1. [Table 1]

[0023] More preferably, the X-ray powder diffraction pattern of crystalline form A of the ethyl sulfonate is as shown in Figure 1; its DSC pattern is substantially as shown in Figure 2; and its TGA pattern is substantially as shown in Figure 3.

[0024] A more preferred embodiment of the present invention provides crystalline form B of the ethyl sulfonate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.6±0.2°, 16.5±0.2°, and The diffraction pattern includes at least one diffraction peak at 8.4±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 2θ = 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, and 15.2±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0025] For example, the X-ray powder diffraction pattern of crystalline form B of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 10.0±0.2°, and 17.6±0.2°; Alternatively, 16.5±0.2°, 17.6±0.2°, and 23.7±0.2°; Alternatively, 8.4±0.2°, 27.7±0.2°, and 15.2±0.2°; Alternatively, 8.4±0.2°, 23.7±0.2°, 27.7±0.2°, and 15.2±0.2°; Alternatively, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, and 15.2±0.2°.

[0026] The X-ray powder diffraction pattern of crystalline form B of the ethyl sulfonate optionally includes one or more diffraction peaks at 2θ values ​​of 28.9±0.2°, 12.8±0.2°, 13.8±0.2°, 21.1±0.2°, 11.8±0.2°, 18.6±0.2°, and 13.1±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from those; more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from those.

[0027] For example, the X-ray powder diffraction pattern of crystalline form B of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 28.9±0.2°, and 12.8±0.2°; Alternatively, 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 28.9±0.2°, 12.8±0.2°, and 13.8±0.2°; Alternatively, 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 28.9±0.2°, 12.8±0.2°, 13.8±0.2°, and 21.1±0.2°.

[0028] The X-ray powder diffraction pattern of crystalline form B of ethyl sulfonate includes one or more diffraction peaks at 2θ of 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 12.8±0.2°, 13.8±0.2°, 21.1±0.2°, 11.8±0.2°, 18.6±0.2°, and 13.1±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0029] For example, the X-ray powder diffraction pattern of crystalline form B of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, and 15.2±0.2°; Alternatively, 5.6±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, and 12.8±0.2°; Alternatively, 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, and 12.8±0.2°; Alternatively, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 12.8±0.2°, and 13.8±0.2°.

[0030] The X-ray powder diffraction patterns of crystalline form B of ethyl sulfonate are as follows, with 2θ values ​​of 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 12.8±0.2°, 13.8±0.2°, 21.1±0.2°, 11.8±0.2°, 18.6±0.2°, 13.1±0.2°, 20.1±0.2°, and 25. The diffraction peaks include one or more at 3±0.2°, 19.5±0.2°, 25.6±0.2°, and 26.3±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0031] For example, the X-ray powder diffraction pattern of crystalline form B of ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, and 28.9±0.2°; Alternatively, 16.5±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, and 12.8±0.2°; Alternatively, 5.6±0.2°, 16.5±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 21.1±0.2°, and 11.8±0.2°; Alternatively, 16.5±0.2°, 8.4±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 21.1±0.2°, and 11.8±0.2°; Alternatively, 5.6±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 12.8±0.2°, and 13.8±0.2°; Alternatively, 16.5±0.2°, 8.4±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 13.8±0.2°, 21.1±0.2°, and 11.8±0.2°; Alternatively, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 12.8±0.2°, 13.8±0.2°, 21.1±0.2°, and 11.8±0.2°.

[0032] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 2. [Table 2]

[0033] More preferably, the X-ray powder diffraction pattern of crystalline form B of the ethyl sulfonate is substantially as shown in Figure 4; its DSC pattern is substantially as shown in Figure 5; and its TGA pattern is substantially as shown in Figure 6.

[0034] A more preferred embodiment of the present invention provides a crystalline form A of the mesylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 6.0±0.2°, 17.8±0.2°, and 21 The diffraction peaks include at least one diffraction peak at 0.4±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0035] For example, the X-ray powder diffraction pattern of mesylate crystal form A has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 17.8±0.2°, and 16.5±0.2°; Alternatively, 17.8±0.2°, 16.5±0.2°, and 22.4±0.2°; Alternatively, 21.4±0.2°, 16.5±0.2°, and 12.2±0.2°; Alternatively, 6.0±0.2°, 17.8±0.2°, 16.5±0.2°, and 22.4±0.2°; Alternatively, 17.8±0.2°, 16.5±0.2°, 22.4±0.2°, and 12.2±0.2°; Alternatively, 17.8±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°; Alternatively, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°.

[0036] The X-ray powder diffraction pattern of crystalline form A of the mesylate further optionally includes one or more diffraction peaks at 2θ = 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, 25.8±0.2°, 14.8±0.2°, 28.0±0.2°, and 33.9±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0037] For example, the X-ray powder diffraction pattern of mesylate crystal form A has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 29.8±0.2°, and 19.8±0.2°; or 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 29.8±0.2°, 19.8±0.2°, and 16.7±0.2°; Alternatively, 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, and 25.8±0.2°.

[0038] The X-ray powder diffraction pattern of crystalline form A of the mesylate contains one or more diffraction peaks at 2θ of 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, 25.8±0.2°, 14.8±0.2°, 28.0±0.2°, and 33.9±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions and are optionally chosen.

[0039] For example, the X-ray powder diffraction pattern of mesylate crystal form A has diffraction peaks where 2θ is less than or equal to: 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, and 29.8±0.2°; or 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, and 19.8±0.2°; Alternatively, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, and 16.7±0.2°.

[0040] The X-ray powder diffraction patterns of mesylate crystal morphology A are as follows: 2θ = 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, 25.8±0.2°, 14.8±0.2°, 28.0±0.2°, 33.9±0.2°, 22.0±0.2°, 10.7± The diffraction peaks include one or more at 0.2°, 23.7±0.2°, 20.7±0.2°, and 27.2±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0041] For example, the X-ray powder diffraction pattern of mesylate crystal form A has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°; Alternatively, 6.0±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, and 29.8±0.2°; Alternatively, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, and 29.8±0.2°; or 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, and 25.8±0.2°; Alternatively, 6.0±0.2°, 21.4±0.2°, 16.5±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, and 25.8±0.2°; or 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, and 25.8±0.2°; or 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, and 25.8±0.2°; Also, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 16.7±0.2°, 25.8±0.2°, 14.8±0.2°, 28.0±0.2°, and 33.9±0.2°.

[0042] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 3. [Table 3]

[0043] More preferably, the X-ray powder diffraction pattern of crystalline form A of the mesylate is substantially as shown in Figure 7; its DSC pattern is substantially as shown in Figure 8; and its TGA pattern is substantially as shown in Figure 9.

[0044] A more preferred embodiment of the present invention provides crystalline form B of the mesylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 6.0±0.2°, 18.0±0.2°, and 22 The diffraction peaks include at least one at 0.6±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one at 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0045] For example, the X-ray powder diffraction pattern of mesylate crystal form B has diffraction peaks where 2θ is less than or equal to: 18.0±0.2°, 12.2±0.2°, and 13.2±0.2°; Alternatively, 22.6±0.2°, 13.2±0.2°, and 15.5±0.2°; Alternatively, 6.0±0.2°, 30.1±0.2°, 12.2±0.2°, and 13.2±0.2°; Alternatively, 18.0±0.2°, 30.1±0.2°, 6.6±0.2°, and 12.2±0.2°; Alternatively, 6.0±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°; Alternatively, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°.

[0046] The X-ray powder diffraction pattern of crystalline form B of the mesylate further optionally includes one or more diffraction peaks at 2θ = 21.4±0.2°, 24.0±0.2°, 12.0±0.2°, 10.1±0.2°, 24.6±0.2°, 16.6±0.2°, and 19.8±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0047] For example, the X-ray powder diffraction pattern of mesylate crystal form B has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 21.4±0.2°, and 24.0±0.2°; or 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 21.4±0.2°, 24.0±0.2°, and 12.0±0.2°; Alternatively, 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 21.4±0.2°, 24.0±0.2°, 12.0±0.2°, and 10.1±0.2°.

[0048] The X-ray powder diffraction pattern of crystalline form B of the mesylate contains one or more diffraction peaks at 2θ = 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, 24.0±0.2°, 12.0±0.2°, 10.1±0.2°, 24.6±0.2°, 16.6±0.2°, and 19.8±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0049] For example, the X-ray powder diffraction pattern of mesylate crystal form B has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°; Alternatively, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, and 21.4±0.2°; Alternatively, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, 24.0±0.2°, and 12.0±0.2°.

[0050] The X-ray powder diffraction patterns of mesylate crystal morphology B are as follows: 2θ = 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, 24.0±0.2°, 12.0±0.2°, 10.1±0.2°, 24.6±0.2°, 16.6±0.2°, 19.8±0.2°, 25.5±0.2°, 20.3± The diffraction peaks include one or more at 0.2°, 26.0±0.2°, 31.3±0.2°, and 28.4±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0051] For example, the X-ray powder diffraction pattern of mesylate crystal form B has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°; Alternatively, 6.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, and 21.4±0.2°; or 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, 24.0±0.2°, and 12.0±0.2°; or 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, 24.0±0.2°, 12.0±0.2°, and 10.1±0.2°; Alternatively, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, 24.6±0.2°, 16.6±0.2°, 19.8±0.2°, and 25.5±0.2°.

[0052] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 4. [Table 4]

[0053] More preferably, the X-ray powder diffraction pattern of crystalline form B of the mesylate is substantially as shown in Figure 10; its DSC pattern is substantially as shown in Figure 11.

[0054] A more preferred embodiment of the present invention provides crystalline form A of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.8±0.2°, 21.6±0.2°, and 17. The diffraction peaks include at least one diffraction peak at 6±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0055] For example, the X-ray powder diffraction pattern of crystalline form A of sulfate has diffraction peaks where 2θ is less than or equal to: 17.6±0.2°, 12.3±0.2°, and 17.2±0.2°; Alternatively, 5.8±0.2°, 19.7±0.2°, 16.5±0.2°, and 12.0±0.2°; Alternatively, 21.6±0.2°, 16.5±0.2°, 12.0±0.2°, and 12.3±0.2°; Alternatively, 17.6±0.2°, 16.5±0.2°, 12.0±0.2°, and 12.3±0.2°; Alternatively, 5.8±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°; Alternatively, 21.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°; Alternatively, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°.

[0056] The X-ray powder diffraction pattern of crystalline form A of the sulfate optionally includes one or more diffraction peaks at 2θ of 13.6±0.2°, 25.9±0.2°, 23.5±0.2°, 21.8±0.2°, 14.4±0.2°, 10.4±0.2°, and 24.7±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0057] For example, the X-ray powder diffraction pattern of crystalline form A of sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 13.6±0.2°, and 25.9±0.2°; Alternatively, 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 13.6±0.2°, 25.9±0.2°, and 23.5±0.2°; Alternatively, 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 13.6±0.2°, 25.9±0.2°, 23.5±0.2°, and 21.8±0.2°.

[0058] The X-ray powder diffraction pattern of crystalline form A of sulfate includes one or more diffraction peaks at 2θ of 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, 25.9±0.2°, 23.5±0.2°, 21.8±0.2°, 14.4±0.2°, 10.4±0.2°, and 24.7±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0059] For example, the X-ray powder diffraction pattern of crystalline form A of sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°; Alternatively, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, and 13.6±0.2°; Alternatively, 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, and 25.9±0.2°; Alternatively, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, 25.9±0.2°, and 23.5±0.2°.

[0060] The X-ray powder diffraction patterns of crystalline form A of sulfates are as follows: 2θ = 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, 25.9±0.2°, 23.5±0.2°, 21.8±0.2°, 14.4±0.2°, 10.4±0.2°, 24.7±0.2°, 27.3±0.2°, 24.5± The diffraction peaks include one or more at 0.2°, 20.7±0.2°, 9.8±0.2°, and 26.7±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0061] For example, the X-ray powder diffraction pattern of crystalline form A of sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°; Alternatively, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, and 13.6±0.2°; Alternatively, 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 23.5±0.2°, and 21.8±0.2°; Alternatively, 5.8±0.2°, 17.6±0.2°, 16.5±0.2°, 12.3±0.2°, 13.6±0.2°, 23.5±0.2°, 21.8±0.2°, 10.4±0.2°, 24.7±0.2°, and 27.3±0.2°; Alternatively, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, 25.9±0.2°, 23.5±0.2°, 21.8±0.2°, and 14.4±0.2°.

[0062] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 5. [Table 5]

[0063] More preferably, the X-ray powder diffraction pattern of crystalline form A of the sulfate is substantially as shown in Figure 17; its DSC pattern is substantially as shown in Figure 18; and its TGA pattern is substantially as shown in Figure 19.

[0064] A more preferred embodiment of the present invention provides crystalline form B of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is 2θ = 5.7±0.2°, 16.9±0.2°, and 17. The diffraction peaks include at least one at 4±0.2°, preferably two diffraction peaks selected from there, and more preferably three diffraction peaks selected from there; optionally, the diffraction peaks may further include at least one at 2θ = 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°, preferably two, three, four, or five diffraction peaks selected from there.

[0065] For example, the X-ray powder diffraction pattern of crystalline form B of sulfate has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 22.5±0.2°, and 19.3±0.2°, Alternatively, 16.9±0.2°, 22.5±0.2°, and 19.3±0.2°; Alternatively, 16.9±0.2°, 19.3±0.2°, 9.9±0.2°, and 20.1±0.2°; Alternatively, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, and 20.1±0.2°; Alternatively, 5.7±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°; Alternatively, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, and 20.1±0.2°; Alternatively, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°.

[0066] The X-ray powder diffraction pattern of crystalline form B of the sulfate optionally includes one or more diffraction peaks at 2θ of 11.1±0.2°, 18.6±0.2°, 27.2±0.2°, 26.8±0.2°, 24.2±0.2°, 25.4±0.2°, and 23.7±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0067] For example, the X-ray powder diffraction pattern of crystalline form B of sulfate has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 11.1±0.2°, and 18.6±0.2°; Alternatively, 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 11.1±0.2°, 18.6±0.2°, and 27.2±0.2°; Alternatively, 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 11.1±0.2°, 18.6±0.2°, 27.2±0.2°, and 26.8±0.2°.

[0068] The X-ray powder diffraction pattern of crystalline form B of the sulfate includes one or more diffraction peaks at 2θ of 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, 11.1±0.2°, 18.6±0.2°, 27.2±0.2°, 26.8±0.2°, 24.2±0.2°, 25.4±0.2°, and 23.7±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions and are of any choice.

[0069] For example, the X-ray powder diffraction pattern of crystalline form B of sulfate has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°; Alternatively, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, and 11.1±0.2°; Alternatively, 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, 11.1±0.2°, and 18.6±0.2°; Alternatively, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, 11.1±0.2°, 18.6±0.2°, and 27.2±0.2°.

[0070] The X-ray powder diffraction patterns of crystalline form B of sulfates were as follows: 2θ = 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, 11.1±0.2°, 18.6±0.2°, 27.2±0.2°, 26.8±0.2°, 24.2±0.2°, 25.4±0.2°, 23.7±0.2°, 28.5±0.2°, 29.1±0. The diffraction peaks include one or more at 0.2°, 15.4±0.2°, 20.8±0.2°, and 11.6±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0071] For example, the X-ray powder diffraction pattern of crystalline form B of sulfate has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°; Alternatively, 5.7±0.2°, 16.9±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, and 11.1±0.2°; Alternatively, 16.9±0.2°, 17.4±0.2°, 19.3±0.2°, 20.1±0.2°, 11.1±0.2°, 27.2±0.2°, 24.2±0.2°, 25.4±0.2°, 23.7±0.2°, and 28.5±0.2°; or 5.7±0.2°, 16.9±0.2°, 19.3±0.2°, 9.9±0.2°, 11.1±0.2°, 18.6±0.2°, 27.2±0.2°, 25.4±0.2°, 23.7±0.2°, and 28.5±0.2°; Alternatively, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, 11.1±0.2°, 18.6±0.2°, 24.2±0.2°, 25.4±0.2°, and 23.7±0.2°.

[0072] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 6. [Table 6]

[0073] More preferably, the X-ray powder diffraction pattern of crystalline form B of the sulfate is substantially as shown in Figure 20; its DSC pattern is substantially as shown in Figure 21; and its TGA pattern is substantially as shown in Figure 22.

[0074] A more preferred embodiment of the present invention provides a crystalline form C of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.6±0.2°, 16.7±0.2°, and 8.3 The diffraction peaks include at least one diffraction peak at ±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0075] For example, the X-ray powder diffraction pattern of crystalline form C of sulfate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2° and 12.7±0.2°; 16.7±0.2°, 17.6±0.2°, and 15.5±0.2°; Alternatively, 8.3±0.2°, 17.6±0.2°, and 15.5±0.2°; Alternatively, 5.6±0.2°, 15.3±0.2°, 17.6±0.2°, and 15.5±0.2°; Alternatively, 5.6±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°; Alternatively, 16.7±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°; Alternatively, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°.

[0076] The X-ray powder diffraction pattern of the crystalline form C of the sulfate optionally includes one or more diffraction peaks at 2θ of 13.1±0.2°, 21.0±0.2°, 25.7±0.2°, 25.3±0.2°, 19.5±0.2°, 20.1±0.2°, and 18.6±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0077] For example, the X-ray powder diffraction pattern of crystalline form C of sulfate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 13.1±0.2°, and 21.0±0.2°; Alternatively, 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 13.1±0.2°, 21.0±0.2°, and 25.7±0.2°; Alternatively, 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 13.1±0.2°, 21.0±0.2°, 25.7±0.2°, and 25.3±0.2°.

[0078] The X-ray powder diffraction pattern of the crystalline form C of sulfate includes one or more diffraction peaks at 2θ of 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, 21.0±0.2°, 25.7±0.2°, 25.3±0.2°, 19.5±0.2°, 20.1±0.2°, and 18.6±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0079] For example, the X-ray powder diffraction pattern of crystalline form C of sulfate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°; Alternatively, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, and 13.1±0.2°; Alternatively, 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, and 21.0±0.2°; Alternatively, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, 21.0±0.2°, and 25.7±0.2°.

[0080] The X-ray powder diffraction patterns of the sulfate crystal morphology C are as follows: 2θ = 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, 21.0±0.2°, 25.7±0.2°, 25.3±0.2°, 19.5±0.2°, 20.1±0.2°, 18.6±0.2°, 13.9±0.2°, 23.8±0. The diffraction peaks include one or more at 0.2°, 22.3±0.2°, 33.7±0.2°, and 24.4±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0081] For example, the X-ray powder diffraction pattern of crystalline form C of sulfate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°; Alternatively, 5.6±0.2°, 16.7±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, and 13.1±0.2°; Alternatively, 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, and 21.0±0.2°; or 5.6±0.2°, 16.7±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, 21.0±0.2°, and 25.7±0.2°; Alternatively, 16.7±0.2°, 8.3±0.2°, 15.3±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, 21.0±0.2°, 25.7±0.2°, 25.3±0.2°, and 19.5±0.2°.

[0082] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 7. [Table 7]

[0083] More preferably, the X-ray powder diffraction pattern of the crystalline form C of the sulfate is substantially as shown in Figure 23; its DSC pattern is substantially as shown in Figure 24; and its TGA pattern is substantially as shown in Figure 25.

[0084] A more preferred embodiment of the present invention provides a crystalline form D of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is 2θ = 17.3±0.2°, 24.3±0.2°, and 20. The diffraction peaks include at least one diffraction peak at 6±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0085] For example, the X-ray powder diffraction pattern of crystalline form D of sulfate has diffraction peaks where 2θ is less than or equal to: 17.3±0.2°, 26.2±0.2°, and 12.9±0.2°; Alternatively, 24.3±0.2°, 22.1±0.2°, and 18.6±0.2°; Alternatively, 17.3±0.2°, 26.2±0.2°, and 22.1±0.2°; Alternatively, 24.3±0.2°, 26.2±0.2°, 22.1±0.2°, and 18.6±0.2°; Alternatively, 17.3±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°; Alternatively, 24.3±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°; Alternatively, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°.

[0086] The X-ray powder diffraction pattern of crystalline form D of the sulfate optionally includes one or more diffraction peaks at 2θ values ​​of 25.9±0.2°, 18.0±0.2°, 25.8±0.2°, 22.9±0.2°, 29.1±0.2°, 6.8±0.2°, and 11.4±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from those; more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from those.

[0087] For example, the X-ray powder diffraction pattern of crystalline form D of sulfate has diffraction peaks where 2θ is less than or equal to: 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 25.9±0.2°, and 18.0±0.2°; Alternatively, 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 25.9±0.2°, 18.0±0.2°, and 25.8±0.2°; Alternatively, 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 25.9±0.2°, 18.0±0.2°, 25.8±0.2°, and 22.9±0.2°.

[0088] The X-ray powder diffraction pattern of crystalline form D of sulfate includes one or more diffraction peaks at 2θ of 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, 25.9±0.2°, 18.0±0.2°, 25.8±0.2°, 22.9±0.2°, 29.1±0.2°, 6.8±0.2°, and 11.4±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0089] For example, the X-ray powder diffraction pattern of crystalline form D of sulfate has diffraction peaks where 2θ is less than or equal to: 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°; Alternatively, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, and 25.9±0.2°; Alternatively, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, 25.9±0.2°, 18.0±0.2°, and 25.8±0.2°.

[0090] The X-ray powder diffraction patterns of crystalline form D of sulfates are as follows: 2θ = 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, 25.9±0.2°, 18.0±0.2°, 25.8±0.2°, 22.9±0.2°, 29.1±0.2°, 6.8±0.2°, 11.4±0.2°, 19.5±0.2°, 34.8±0. The diffraction peaks include one or more at 0.2°, 24.9±0.2°, 19.2±0.2°, and 26.6±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0091] For example, the X-ray powder diffraction pattern of crystalline form D of sulfate has diffraction peaks where 2θ is less than or equal to: 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°; Alternatively, 17.3±0.2°, 24.3±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, and 25.9±0.2°; Alternatively, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, and 25.9±0.2°; or 24.3±0.2°, 20.6±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, 25.9±0.2°, 18.0±0.2°, 25.8±0.2°, and 22.9±0.2°; Alternatively, 24.3±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 25.8±0.2°, 22.9±0.2°, 29.1±0.2°, 6.8±0.2°, 11.4±0.2°, and 19.5±0.2°; or 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, 25.9±0.2°, 18.0±0.2°, 25.8±0.2°, and 22.9±0.2°; Alternatively, 20.6±0.2°, 18.6±0.2°, 25.9±0.2°, 18.0±0.2°, 6.8±0.2°, 11.4±0.2°, 19.5±0.2°, 34.8±0.2°, 24.9±0.2°, and 19.2±0.2°.

[0092] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 8. [Table 8]

[0093] More preferably, the X-ray powder diffraction pattern of crystalline form D of the sulfate is substantially as shown in Figure 26; its DSC pattern is substantially as shown in Figure 27; and its TGA pattern is substantially as shown in Figure 28.

[0094] A more preferred embodiment of the present invention provides an X-ray powder diffraction pattern of crystalline form E of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, with 2θ values ​​of 5.8±0.2°, 17.2±0.2°, and 9.8±0.2°. The diffraction peaks include at least one, preferably two, and more preferably three, selected diffraction peaks, selected from among them; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°, preferably two, three, four, or five, selected from among them.

[0095] For example, the X-ray powder diffraction pattern of crystalline form E of sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 13.8±0.2°, and 22.6±0.2°; Alternatively, 17.2±0.2°, 20.0±0.2°, and 19.2±0.2°; Alternatively, 9.8±0.2°, 22.6±0.2°, and 22.2±0.2°; Alternatively, 5.8±0.2°, 13.8±0.2°, 20.0±0.2°, and 22.6±0.2°; Alternatively, 17.2±0.2°, 20.0±0.2°, 22.6±0.2°, and 19.2±0.2°; Alternatively, 5.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°; or 17.2±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°; Alternatively, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°.

[0096] The X-ray powder diffraction pattern of crystalline form E of the sulfate optionally includes one or more diffraction peaks at 2θ of 11.1±0.2°, 26.2±0.2°, 24.3±0.2°, 20.6±0.2°, 18.6±0.2°, 19.7±0.2°, and 15.1±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0097] For example, the X-ray powder diffraction pattern of crystalline form E of sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 11.1±0.2°, and 26.2±0.2°; Alternatively, 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 11.1±0.2°, 26.2±0.2°, and 24.3±0.2°; Alternatively, 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 11.1±0.2°, 26.2±0.2°, 24.3±0.2°, and 20.6±0.2°.

[0098] The X-ray powder diffraction pattern of crystalline form E of the sulfate includes one or more diffraction peaks at 2θ of 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, 26.2±0.2°, 24.3±0.2°, 20.6±0.2°, 18.6±0.2°, 19.7±0.2°, and 15.1±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0099] For example, the X-ray powder diffraction pattern of crystalline form E of sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°; Alternatively, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, and 11.1±0.2°; or 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, and 26.2±0.2°; Alternatively, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, 26.2±0.2°, and 24.3±0.2°.

[0100] The X-ray powder diffraction patterns of crystalline form E of sulfates were as follows: 2θ = 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, 26.2±0.2°, 24.3±0.2°, 20.6±0.2°, 18.6±0.2°, 19.7±0.2°, 15.1±0.2°, 29.1±0.2°, 12.1±0. The diffraction peaks include one or more at 0.2°, 21.3±0.2°, 12.9±0.2°, and 8.8±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0101] For example, the X-ray powder diffraction pattern of crystalline form E of sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°; Alternatively, 5.8±0.2°, 17.2±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, and 11.1±0.2°; Alternatively, 5.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.2±0.2°, 11.1±0.2°, 26.2±0.2°, 24.3±0.2°, 20.6±0.2°, 18.6±0.2°, and 19.7±0.2°; Alternatively, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, 26.2±0.2°, and 24.3±0.2°; Alternatively, 17.2±0.2°, 9.8±0.2°, 20.0±0.2°, 19.2±0.2°, 22.2±0.2°, 26.2±0.2°, 24.3±0.2°, 20.6±0.2°, 18.6±0.2°, and 19.7±0.2°; or 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, 26.2±0.2°, 24.3±0.2°, and 20.6±0.2°; Alternatively, 9.8±0.2°, 13.8±0.2°, 19.2±0.2°, 22.2±0.2°, 26.2±0.2°, 24.3±0.2°, 20.6±0.2°, 12.1±0.2°, 21.3±0.2°, and 12.9±0.2°.

[0102] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 9. [Table 9]

[0103] More preferably, the X-ray powder diffraction pattern of the crystalline form E of the sulfate is substantially as shown in Figure 29; its DSC pattern is substantially as shown in Figure 30; and its TGA pattern is substantially as shown in Figure 31.

[0104] A more preferred embodiment of the present invention provides a crystalline form F of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 6.0±0.2°, 16.0±0.2°, and 22. The diffraction peaks include at least one at 4±0.2°, preferably two diffraction peaks selected from there, and more preferably three diffraction peaks selected from there; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°, preferably two, three, four, or five diffraction peaks selected from there.

[0105] For example, the X-ray powder diffraction pattern of crystalline form F of sulfate has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 17.3±0.2°, and 14.4±0.2°; Alternatively, 16.0±0.2°, 20.0±0.2°, and 18.5±0.2°; Alternatively, 6.0±0.2°, 17.3±0.2°, 20.0±0.2°, and 18.5±0.2°; Alternatively, 16.0±0.2°, 20.0±0.2°, 18.5±0.2°, and 14.4±0.2°; Alternatively, 22.4±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°; Alternatively, 16.0±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°; Alternatively, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°.

[0106] The X-ray powder diffraction pattern of the crystalline form F of the sulfate optionally includes one or more diffraction peaks at 2θ of 24.9±0.2°, 24.4±0.2°, 17.5±0.2°, 26.2±0.2°, 18.0±0.2°, 27.5±0.2°, and 21.5±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0107] For example, the X-ray powder diffraction pattern of crystalline form F of sulfate has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 24.9±0.2°, and 24.4±0.2°; or 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 24.9±0.2°, 24.4±0.2°, and 17.5±0.2°; Alternatively, 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 24.9±0.2°, 24.4±0.2°, 17.5±0.2°, and 26.2±0.2°.

[0108] The X-ray powder diffraction pattern of crystalline form F of sulfate includes one or more diffraction peaks at 2θ of 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 24.9±0.2°, 24.4±0.2°, 17.5±0.2°, 26.2±0.2°, 18.0±0.2°, 27.5±0.2°, and 21.5±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0109] For example, the X-ray powder diffraction pattern of crystalline form F of sulfate has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°; Alternatively, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, and 24.9±0.2°; or 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 24.9±0.2°, and 24.4±0.2°; Alternatively, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 24.9±0.2°, 24.4±0.2°, and 17.5±0.2°.

[0110] The X-ray powder diffraction patterns of crystalline form F of sulfates were as follows: 2θ = 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 24.9±0.2°, 24.4±0.2°, 17.5±0.2°, 26.2±0.2°, 18.0±0.2°, 27.5±0.2°, 21.5±0.2°, 12.8±0.2°, 23.2±0. The diffraction peaks include one or more at 0.2°, 20.9±0.2°, 30.2±0.2°, and 28.8±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0111] For example, the X-ray powder diffraction pattern of crystalline form F of sulfate has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°; or 6.0±0.2°, 16.0±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, and 24.9±0.2°; Alternatively, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, and 24.9±0.2°; or 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 24.9±0.2°, and 24.4±0.2°; or 6.0±0.2°, 16.0±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 17.5±0.2°, 26.2±0.2°, and 18.0±0.2°; Alternatively, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 26.2±0.2°, 18.0±0.2°, 27.5±0.2°, and 21.5±0.2°; Alternatively, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 18.5±0.2°, 20.5±0.2°, 24.9±0.2°, 24.4±0.2°, 27.5±0.2°, 21.5±0.2°, and 12.8±0.2°.

[0112] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 10. [Table 10]

[0113] More preferably, the X-ray powder diffraction pattern of the crystalline form F of the sulfate is substantially as shown in Figure 32; its DSC pattern is substantially as shown in Figure 33; and its TGA pattern is substantially as shown in Figure 34.

[0114] A more preferred embodiment of the present invention provides a crystalline form G of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.9±0.2°, 16.7±0.2°, and 17. The diffraction peaks include at least one diffraction peak at 6±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0115] For example, the X-ray powder diffraction pattern of crystalline form G of sulfate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 5.6±0.2°, and 16.9±0.2°; Alternatively, 5.9±0.2°, 5.6±0.2°, 16.9±0.2°, and 27.7±0.2°; Alternatively, 16.7±0.2°, 16.9±0.2°, 22.2±0.2°, and 29.5±0.2°; Alternatively, 5.9±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°.

[0116] The X-ray powder diffraction pattern of the crystalline form G of the sulfate optionally includes one or more diffraction peaks at 2θ values ​​of 25.1±0.2°, 10.2±0.2°, 24.4±0.2°, 8.4±0.2°, 12.1±0.2°, 24.2±0.2°, and 15.4±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from those; more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from those.

[0117] For example, the X-ray powder diffraction pattern of crystalline form G of sulfate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 25.1±0.2°, and 10.2±0.2°; or 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 25.1±0.2°, 10.2±0.2°, and 24.4±0.2°; Alternatively, 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 25.1±0.2°, 10.2±0.2°, 24.4±0.2°, and 8.4±0.2°.

[0118] The X-ray powder diffraction pattern of the sulfate in crystalline form G includes one or more diffraction peaks at 2θ of 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 25.1±0.2°, 10.2±0.2°, 24.4±0.2°, 8.4±0.2°, 12.1±0.2°, 24.2±0.2°, and 15.4±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions and are of any choice.

[0119] For example, the X-ray powder diffraction pattern of crystalline form G of sulfate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°; Alternatively, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, and 25.1±0.2°; or 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 25.1±0.2°, and 10.2±0.2°; Alternatively, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 25.1±0.2°, 10.2±0.2°, and 24.4±0.2°.

[0120] The X-ray powder diffraction patterns of crystalline form G of sulfates were as follows, with 2θ values ​​of 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 25.1±0.2°, 10.2±0.2°, 24.4±0.2°, 8.4±0.2°, 12.1±0.2°, 24.2±0.2°, 15.4±0.2°, 19.6±0.2°, and 18.8±0. The diffraction peaks include one or more at 2°, 23.5±0.2°, 13.1±0.2°, and 20.3±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0121] For example, the X-ray powder diffraction pattern of crystalline form G of sulfate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°; or 5.9±0.2°, 16.7±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, and 25.1±0.2°; Alternatively, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, and 25.1±0.2°; Alternatively, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 25.1±0.2°, 10.2±0.2°, 24.4±0.2°, and 8.4±0.2°; Alternatively, 17.6±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 24.4±0.2°, 8.4±0.2°, 19.6±0.2°, 18.8±0.2°, 23.5±0.2°, and 13.1±0.2°.

[0122] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 11. [Table 11]

[0123] More preferably, the X-ray powder diffraction pattern of the crystalline form G of the sulfate is substantially as shown in Figure 35; its DSC pattern is substantially as shown in Figure 36; and its TGA pattern is substantially as shown in Figure 37.

[0124] A more preferred embodiment of the present invention provides crystalline form A of the hydrochloride salt of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 22.4±0.2°, 14.0±0.2°, and 17 The diffraction pattern includes at least one diffraction peak at 0.1±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 2θ = 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0125] For example, the X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 22.4±0.2° and 6.2±0.2°; Alternatively, 22.4±0.2°, 6.2±0.2°, and 19.4±0.2°; Alternatively, 22.4±0.2°, 6.2±0.2°, 19.4±0.2°, and 25.2±0.2°; Alternatively, 14.0±0.2°, 19.4±0.2°, 25.2±0.2°, and 17.5±0.2°; Alternatively, 22.4±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°; Alternatively, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°.

[0126] The X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt optionally includes one or more diffraction peaks at 2θ values ​​of 19.8±0.2°, 23.4±0.2°, 10.6±0.2°, 30.5±0.2°, 12.4±0.2°, 9.8±0.2°, and 11.1±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from those; more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from those; For example, the X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 19.8±0.2°, and 23.4±0.2°; Alternatively, 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 19.8±0.2°, 23.4±0.2°, 10.6±0.2°, and 30.5±0.2°.

[0127] The X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt includes one or more diffraction peaks at 2θ = 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, 21.6±0.2°, 19.8±0.2°, 23.4±0.2°, 10.6±0.2°, 30.5±0.2°, 12.4±0.2°, 9.8±0.2°, and 11.1±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which are selected from these positions.

[0128] For example, the X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°; Alternatively, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, 21.6±0.2°, and 19.8±0.2°; Alternatively, 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, 21.6±0.2°, 19.8±0.2°, and 23.4±0.2°.

[0129] The X-ray powder diffraction patterns of crystalline form A of the hydrochloride salt are as follows: 2θ = 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, 21.6±0.2°, 19.8±0.2°, 23.4±0.2°, 10.6±0.2°, 30.5±0.2°, 12.4±0.2°, 9.8±0.2°, 11.1±0.2°, 24.5±0.2°, 26.6±0. The diffraction peaks include one or more at 0.2°, 26.9±0.2°, 31.4±0.2°, and 35.2±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0130] For example, the X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°; Alternatively, 22.4±0.2°, 14.0±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, 21.6±0.2°, and 19.8±0.2°; Alternatively, 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 26.6±0.2°, 26.9±0.2°, 31.4±0.2°, and 35.2±0.2°.

[0131] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 12. [Table 12]

[0132] More preferably, the X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt is substantially as shown in Figure 12; its DSC pattern is substantially as shown in Figure 13; and its TGA pattern is substantially as shown in Figure 14.

[0133] A more preferred embodiment of the present invention provides crystalline form B of the hydrochloride salt of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acid atoms is 1, and its X-ray powder diffraction pattern is such that 2θ is 6.7±0.2°, 27.0±0.2°, and 23. The diffraction peaks include at least one diffraction peak at 4±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0134] For example, the X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 6.7±0.2° and 13.4±0.2°; Alternatively, 6.7±0.2°, 13.4±0.2°, and 1.0±0.2°; Alternatively, 6.7±0.2°, 13.4±0.2°, 11.0±0.2°, and 24.1±0.2°; Alternatively, 6.7±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°; Alternatively, 27.0±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°.

[0135] The X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt optionally includes one or more diffraction peaks at 2θ of 20.0±0.2°, 10.2±0.2°, 14.3±0.2°, 10.0±0.2°, 20.5±0.2°, 23.0±0.2°, and 31.0±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0136] For example, the X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 20.0±0.2°, and 10.2±0.2°; Alternatively, 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 20.0±0.2°, 10.2±0.2°, 14.3±0.2°, and 10.0±0.2°.

[0137] The X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt includes one or more diffraction peaks at 2θ of 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, 20.0±0.2°, 10.2±0.2°, 14.3±0.2°, 10.0±0.2°, 20.5±0.2°, 23.0±0.2°, and 31.0±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0138] For example, the X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2; Alternatively, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, 20.0±0.2°; Alternatively, 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, 20.0±0.2°, and 10.2±0.2°.

[0139] The X-ray powder diffraction patterns of crystalline form B of sulfates were as follows: 2θ = 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, 20.0±0.2°, 10.2±0.2°, 14.3±0.2°, 10.0±0.2°, 20.5±0.2°, 23.0±0.2°, 31.0±0.2°, 25.4±0.2°, 30.2±0. The diffraction peaks include one or more at 0.2°, 22.3±0.2°, 18.6±0.2°, and 17.4±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0140] For example, the X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°; Alternatively, 6.7±0.2°, 27.0±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, and 20.0±0.2°; Alternatively, 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, 20.0±0.2°, and 10.2±0.2°.

[0141] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 13. [Table 13]

[0142] More preferably, the X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt is substantially as shown in Figure 15.

[0143] A more preferred embodiment of the present invention provides a crystalline form C of the hydrochloride salt of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 16.5±0.2°, 20.4±0.2°, and 2 The diffraction pattern includes at least one diffraction peak at 2.2±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 2θ = 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0144] For example, the X-ray powder diffraction pattern of crystalline form C of hydrochloride has diffraction peaks where 2θ is less than or equal to: 16.5±0.2° and 9.7±0.2°; Alternatively, 16.5±0.2°, 9.7±0.2°, and 17.8±0.2°; Alternatively, 16.5±0.2°, 17.8±0.2°, 5.3±0.2°, and 6.0±0.2°; Alternatively, 16.5±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°; Alternatively, 20.4±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°; Alternatively, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°.

[0145] The X-ray powder diffraction pattern of the crystalline form C of the hydrochloride salt optionally includes one or more diffraction peaks at 2θ of 14.3±0.2°, 21.7±0.2°, 24.6±0.2°, 10.9±0.2°, 27.2±0.2°, 20.8±0.2°, and 19.7±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0146] For example, the X-ray powder diffraction pattern of crystalline form C of hydrochloride has diffraction peaks where 2θ is less than or equal to: 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 14.3±0.2°, and 21.7±0.2°; Alternatively, 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 14.3±0.2°, 21.7±0.2°, 24.6±0.2°, and 10.9±0.2°.

[0147] The X-ray powder diffraction pattern of the crystalline form C of the hydrochloride salt includes one or more diffraction peaks at 2θ of 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, 14.3±0.2°, 21.7±0.2°, 24.6±0.2°, 10.9±0.2°, 27.2±0.2°, 20.8±0.2°, and 19.7±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which are selected from these positions.

[0148] For example, the X-ray powder diffraction pattern of crystalline form C of hydrochloride has diffraction peaks where 2θ is less than or equal to: 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°; Alternatively, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, and 14.3±0.2°; Alternatively, 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, 14.3±0.2°, and 21.7±0.2°.

[0149] The X-ray powder diffraction patterns of the hydrochloride salt in crystalline form C show the following 2θ values: 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, 14.3±0.2°, 21.7±0.2°, 24.6±0.2°, 10.9±0.2°, 27.2±0.2°, 20.8±0.2°, 19.7±0.2°, 15.6±0.2°, and 26.0±0. The diffraction peaks include one or more at 2°, 18.8±0.2°, 30.7±0.2°, and 10.5±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0150] For example, the X-ray powder diffraction pattern of crystalline form C of hydrochloride has diffraction peaks where 2θ is less than or equal to: 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°; Alternatively, 16.5±0.2°, 20.4±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, and 14.3±0.2°; Alternatively, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, and 14.3±0.2°; Alternatively, 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, 14.3±0.2°, and 21.7±0.2°.

[0151] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 14. [Table 14]

[0152] More preferably, the X-ray powder diffraction pattern of the hydrochloride salt in crystalline form C is substantially as shown in Figure 16.

[0153] A more preferred embodiment of the present invention provides a crystalline form A of the p-tosylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 16.8±0.2°, 19.9±0.2°, and The diffraction pattern includes at least one diffraction peak at 5.7±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, and 20.8±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0154] For example, the X-ray powder diffraction pattern of crystalline form A of p-tosylate has diffraction peaks where 2θ is less than or equal to: 16.8±0.2° and 22.5±0.2°; Alternatively, 16.8±0.2°, 22.5±0.2°, and 21.8±0.2°; Alternatively, 16.8±0.2°, 22.5±0.2°, 21.8±0.2°, and 24.9±0.2°; Alternatively, 19.9±0.2°, 24.9±0.2°, 22.3±0.2°, and 20.8±0.2°; Alternatively, 16.8±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, and 20.8±0.2°; or 19.9 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, and 20.8 ± 0.2°; or 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, and 20.8 ± 0.2°.

[0155] The X-ray powder diffraction pattern of crystalline form A of p-toluenesulfonate may further optionally include one or more diffraction peaks at 2θ of 26.6 ± 0.2°, 12.4 ± 0.2°, 15.1 ± 0.2°, 13.8 ± 0.2°, 21.3 ± 0.2°, 27.7 ± 0.2°, and 20.5 ± 0.2°; preferably, it includes at least any 2 to 3, or 4 to 5, or 6 to 7 diffraction peaks selected therefrom, and more preferably, it includes any 2, 3, 4, 6, or 7 diffraction peaks selected therefrom.

[0156] For example, the X-ray powder diffraction pattern of crystalline form A of p-toluenesulfonate has diffraction peaks where 2θ is as follows: 16.8 ± 0.2°, 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 26.6 ± 0.2°, and 12.4 ± 0.2°;[[ID=…]] or 16.8 ± 0.2°, 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 26.6 ± 0.2°, 12.4 ± 0.2°, 15.1 ± 0.2°, and 13.8 ± 0.2°.

[0157] The X-ray powder diffraction pattern of crystalline form A of p-toluenesulfonate includes one or more diffraction peaks at 2θ of 16.8 ± 0.2°, 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, 20.8 ± 0.2°, 26.6 ± 0.2°, 12.4 ± 0.2°, 15.1 ± 0.2°, 13.8 ± 0.2°, 21.3 ± 0.2°, 27.7 ± 0.2°, and 20.5 ± 0.2°; preferably, it includes diffraction peaks at optionally selected positions of 4, 6, 8, or 10 selected therefrom.

[0158] For example, the X-ray powder diffraction pattern of crystalline form A of p-toluenesulfonate has diffraction peaks at 2θ as follows: 16.8 ± 0.2°, 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, and 20.8 ± 0.2°; or 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, 20.8 ± 0.2°, and 26.6 ± 0.2°; or 16.8 ± 0.2°, 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, 20.8 ± 0.2°, 26.6 ± 0.2°, and 12.4 ± 0.2°; or 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, 20.8 ± 0.2°, 26.6 ± 0.2°, 12.4 ± 0.2°, and 15.1 ± 0.2°.

[0159] The X-ray powder diffraction pattern of crystalline form A of p-toluenesulfonate includes one or more diffraction peaks at 2θ of 16.8 ± 0.2°, 19.9 ± 0.2°, 5.7 ± 0.2°, 22.5 ± 0.2°, 21.8 ± 0.2°, 24.9 ± 0.2°, 22.3 ± 0.2°, 20.8 ± 0.2°, 26.6 ± 0.2°, 12.4 ± 0.2°, 15.1 ± 0.2°, 13.8 ± 0.2°, 21.3 ± 0.2°, 27.7 ± 0.2°, 20.5 ± 0.2°, 24.7 ± 0.2°, 31.2 ± 0.2°, 17.3 ± 0.2°, 32.1 ± 0.2°, and 25.8 ± 0.2°; preferably, it includes diffraction peaks at at least any 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18 positions selected therefrom; more preferably, it includes diffraction peaks at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected therefrom.

[0160] For example, the X-ray powder diffraction pattern of crystalline form A of p-tosylate has diffraction peaks where 2θ is less than or equal to: 16.8±0.2°, 19.9±0.2°, 5.7±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, and 20.8±0.2°; 16.8±0.2°, 19.9±0.2°, 5.7±0.2°, 12.4±0.2°, 13.8±0.2°, 22.5±0.2°, 21.8±0.2°, and 20.8±0.2°; Alternatively, 16.8±0.2°, 19.9±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, and 26.6±0.2°; Alternatively, 19.9±0.2°, 5.7±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, and 26.6±0.2°; Alternatively, 19.9±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, 26.6±0.2°, 32.1±0.2°, and 25.8±0.2°; Alternatively, 16.8±0.2°, 19.9±0.2°, 5.7±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, 26.6±0.2°, and 12.4±0.2°; Alternatively, 16.8±0.2°, 19.9±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, 26.6±0.2°, 12.4±0.2°, and 15.1±0.2°; Alternatively, 16.8±0.2°, 19.9±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, 26.6±0.2°, 31.2±0.2°, 17.3±0.2°, 32.1±0.2°, and 25.8±0.2°.

[0161] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 15. [Table 15]

[0162] More preferably, the X-ray powder diffraction pattern of crystalline form A of the p-tosylate of the compound is substantially as shown in Figure 38; its DSC pattern is substantially as shown in Figure 39; and its TGA pattern is substantially as shown in Figure 40.

[0163] A more preferred embodiment of the present invention provides crystalline form B of the p-tosylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.5±0.2°, 19.9±0.2°, and 1 The diffraction pattern includes at least one diffraction peak at 3.2±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, and 17.6±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0164] For example, the X-ray powder diffraction pattern of crystalline form B of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.5±0.2° and 21.9±0.2°; Alternatively, 5.5±0.2°, 21.9±0.2°, and 28.1±0.2°; Alternatively, 5.5±0.2°, 21.9±0.2°, 28.1±0.2°, and 14.1±0.2°; Alternatively, 5.5±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, and 17.6±0.2°.

[0165] The X-ray powder diffraction pattern of crystalline form B of the p-tosylate optionally includes one or more diffraction peaks at 2θ of 9.5±0.2°, 20.4±0.2°, 17.8±0.2°, 22.1±0.2°, 21.5±0.2°, 16.3±0.2°, and 26.5±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0166] For example, the X-ray powder diffraction pattern of crystalline form B of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1B±0.2°, 9.5±0.2°, and 20.4±0.2°; Alternatively, 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 9.5±0.2°, 20.4±0.2°, 17.8±0.2°, and 22.1±0.2°.

[0167] The X-ray powder diffraction pattern of crystalline form B of the p-tosylate includes one or more diffraction peaks at 2θ of 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, 17.6±0.2°, 9.5±0.2°, 20.4±0.2°, 17.8±0.2°, 22.1±0.2°, 21.5±0.2°, 16.3±0.2°, and 26.5±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0168] For example, the X-ray powder diffraction pattern of crystalline form B of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, and 17.6±0.2°; or 5.5 ± 0.2°, 19.9 ± 0.2°, 13.2 ± 0.2°, 21.9 ± 0.2°, 28.1 ± 0.2°, 14.1 ± 0.2°, 10.9 ± 0.2°, 17.6 ± 0.2°, 9.5 ± 0.2°, and 20.4 ± 0.2°.

[0169] The X-ray powder diffraction pattern of crystalline form B of p-toluenesulfonate contains one or more diffraction peaks at 2θ of 5.5 ± 0.2°, 19.9 ± 0.2°, 13.2 ± 0.2°, 21.9 ± 0.2°, 28.1 ± 0.2°, 14.1 ± 0.2°, 10.9 ± 0.2°, 17.6 ± 0.2°, 9.5 ± 0.2°, 20.4 ± 0.2°, 17.8 ± 0.2°, 22.1 ± 0.2°, 21.5 ± 0.2°, 16.3 ± 0.2°, 26.5 ± 0.2°, 27.4 ± 0.2°, 10.1 ± 0.2°, 12.9 ± 0.2°, 29.2 ± 0.2°, and 22.9 ± 0.2°; preferably, it contains diffraction peaks at at least any 2-3, or 4-5, or 7-8, or 10-12, or 15-18 positions selected therefrom; more preferably, it contains diffraction peaks at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected therefrom.

[0170] For example, the X-ray powder diffraction pattern of crystalline form B of p-toluenesulfonate has diffraction peaks where 2θ is as follows: 5.5 ± 0.2°, 19.9 ± 0.2°, 13.2 ± 0.2°, 21.9 ± 0.2°, 28.1 ± 0.2°, and 14.1 ± 0.2°; or 5.5 ± 0.2°, 19.9 ± 0.2°, 21.9 ± 0.2°, 28.1 ± 0.2°, 14.1 ± 0.2°, and 10.9 ± 0.2°; or 5.5 ± 0.2°, 19.9 ± 0.2°, 13.2 ± 0.2°, 21.9 ± 0.2°, 28.1 ± 0.2°, 14.1 ± 0.2°, 10.9 ± 0.2°, and 17.6 ± 0.2°; or 5.5 ± 0.2°, 19.9 ± 0.2°, 21.9 ± 0.2°, 28.1 ± 0.2°, 14.1 ± 0.2°, 10.9 ± 0.2°, 17.6 ± 0.2°, and 9.5 ± 0.2°.

[0171] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 16. [Table 16]

[0172] More preferably, the X-ray powder diffraction pattern of crystalline form B of the p-tosylate is substantially as shown in Figure 41; its DSC pattern is substantially as shown in Figure 42; and its TGA pattern is substantially as shown in Figure 43.

[0173] A more preferred embodiment of the present invention provides a crystalline form C of the p-tosylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.8±0.2°, 17.3±0.2°, and 1 The diffraction peaks include at least one at 6.7±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0174] For example, the X-ray powder diffraction pattern of crystalline form C of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2° and 22.0±0.2°; Alternatively, 5.8±0.2°, 22.0±0.2°, and 19.6±0.2°; Alternatively, 5.8±0.2°, 22.0±0.2°, 19.6±0.2°, and 23.1±0.2°; Alternatively, 5.8±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°.

[0175] The X-ray powder diffraction pattern of crystalline form C of the p-tosylate optionally includes one or more diffraction peaks at 2θ of 29.0±0.2°, 12.8±0.2°, 21.6±0.2°, 11.5±0.2°, 13.8±0.2°, 27.4±0.2°, and 20.9±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0176] For example, the X-ray powder diffraction pattern of crystalline form C of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 29.0±0.2°, and 12.8±0.2°; Alternatively, 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 29.0±0.2°, 12.8±0.2°, 21.6±0.2°, and 11.5±0.2°.

[0177] The X-ray powder diffraction pattern of crystalline form C of the p-tosylate includes one or more diffraction peaks at 2θ of 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, 20.1±0.2°, 29.0±0.2°, 12.8±0.2°, 21.6±0.2°, 11.5±0.2°, 13.8±0.2°, 27.4±0.2°, and 20.9±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which are selected from these, is included.

[0178] For example, the X-ray powder diffraction pattern of crystalline form C of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°; Alternatively, 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, 20.1±0.2°, 29.0±0.2°, and 12.8±0.2°.

[0179] The X-ray powder diffraction patterns of the crystalline form C of p-tosylates were as follows, with 2θ values ​​of 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, 20.1±0.2°, 29.0±0.2°, 12.8±0.2°, 21.6±0.2°, 11.5±0.2°, 13.8±0.2°, 27.4±0.2°, 20.9±0.2°, 33.2±0.2°, and 25. The diffraction peaks include one or more at 7±0.2°, 9.8±0.2°, 25.2±0.2°, and 32.8±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0180] For example, the X-ray powder diffraction pattern of crystalline form C of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°; Alternatively, 5.8±0.2°, 17.3±0.2°, 23.1±0.2°, 22.4±0.2°, 20.1±0.2°, 29.0±0.2°, 12.8±0.2°, and 21.6±0.2°; Alternatively, 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, 20.1±0.2°, 29.0±0.2°, and 12.8±0.2°.

[0181] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 17. [Table 17]

[0182] More preferably, the X-ray powder diffraction pattern of crystalline form C of the p-tosylate is substantially as shown in Figure 44; its DSC pattern is substantially as shown in Figure 45; and its TGA pattern is substantially as shown in Figure 46.

[0183] A more preferred embodiment of the present invention provides a crystalline form D of the p-tosylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 4.9±0.2°, 5.7±0.2°, and 17 The diffraction pattern includes at least one diffraction peak at 0.2±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0184] For example, the X-ray powder diffraction pattern of crystalline form D of p-tosylate has diffraction peaks where 2θ is less than or equal to: 4.9±0.2° and 22.0±0.2°; Alternatively, 4.9±0.2°, 22.0±0.2°, and 19.5±0.2°; Alternatively, 4.9±0.2°, 22.0±0.2°, 19.5±0.2°, and 28.9±0.2°; Alternatively, 4.9±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°.

[0185] The X-ray powder diffraction pattern of crystalline form D of the p-tosylate optionally includes one or more diffraction peaks at 2θ of 14.8±0.2°, 23.0±0.2°, 20.6±0.2°, 27.3±0.2°, 30.4±0.2°, 24.8±0.2°, and 27.7±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0186] For example, the X-ray powder diffraction pattern of crystalline form D of p-tosylate has diffraction peaks where 2θ is less than or equal to: 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 14.8±0.2°, and 23.0±0.2°; Alternatively, 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 14.8±0.2°, 23.0±0.2°, 20.6±0.2°, and 27.3±0.2°.

[0187] The X-ray powder diffraction pattern of crystalline form D of the p-tosylate includes one or more diffraction peaks at 2θ = 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, 12.7±0.2°, 14.8±0.2°, 23.0±0.2°, 20.6±0.2°, 27.3±0.2°, 30.4±0.2°, 24.8±0.2°, and 27.7±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which are selected from these.

[0188] For example, the X-ray powder diffraction pattern of crystalline form D of p-tosylate has diffraction peaks where 2θ is less than or equal to: 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°; Alternatively, 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, 12.7±0.2°, 14.8±0.2°, and 23.0±0.2°.

[0189] The X-ray powder diffraction patterns of crystalline form D of p-tosylates are as follows: 2θ = 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, 12.7±0.2°, 14.8±0.2°, 23.0±0.2°, 20.6±0.2°, 27.3±0.2°, 30.4±0.2°, 24.8±0.2°, 27.7±0.2°, 11.5±0.2° The diffraction peaks include one or more at 34.9±0.2°, 9.9±0.2°, and 35.0±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0190] For example, the X-ray powder diffraction pattern of crystalline form D of p-tosylate has diffraction peaks where 2θ is less than or equal to: 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°; Alternatively, 4.9±0.2°, 5.7±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, 12.7±0.2°, 14.8±0.2°, and 23.0±0.2°; Alternatively, 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, 12.7±0.2°, 14.8±0.2°, and 23.0±0.2°.

[0191] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 18. [Table 18]

[0192] More preferably, the X-ray powder diffraction pattern of crystalline form D of the p-tosylate is substantially as shown in Figure 47; its DSC pattern is substantially as shown in Figure 48; and its TGA pattern is substantially as shown in Figure 49.

[0193] A more preferred embodiment of the present invention provides a crystalline form E of the p-tosylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.4±0.2°, 16.1±0.2°, and The diffraction pattern includes at least one diffraction peak at 9.9±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 2θ = 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0194] For example, the X-ray powder diffraction pattern of crystalline form E of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2° and 16.7±0.2°; Alternatively, 5.4±0.2°, 16.7±0.2°, and 8.4±0.2°; Alternatively, 5.4±0.2°, 16.7±0.2°, 8.4±0.2°, and 23.1±0.2°; Alternatively, 16.1±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°; Alternatively, 9.9±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°; Alternatively, 5.4±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°.

[0195] The X-ray powder diffraction pattern of crystalline form E of the p-tosylate optionally includes one or more diffraction peaks at 2θ values ​​of 25.2±0.2°, 28.2±0.2°, 18.5±0.2°, 16.9±0.2°, 32.4±0.2°, 11.6±0.2°, and 15.1±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from those; more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from those.

[0196] For example, the X-ray powder diffraction pattern of crystalline form E of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 25.2±0.2°, and 28.2±0.2°; Alternatively, 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 25.2±0.2°, 28.2±0.2°, 18.5±0.2°, and 16.9±0.2°.

[0197] The X-ray powder diffraction pattern of crystalline form E of the p-tosylate includes one or more diffraction peaks at 2θ of 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, 25.2±0.2°, 28.2±0.2°, 18.5±0.2°, 16.9±0.2°, 32.4±0.2°, 11.6±0.2°, and 15.1±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0198] For example, the X-ray powder diffraction pattern of crystalline form E of p-tosylate has diffraction peaks where 2θ is less than or equal to: 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, and 25.2±0.2°; Alternatively, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, 25.2±0.2°, 28.2±0.2°, and 18.5±0.2°.

[0199] The X-ray powder diffraction patterns of crystalline form E of p-tosylates are as follows: 2θ = 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, 25.2±0.2°, 28.2±0.2°, 18.5±0.2°, 16.9±0.2°, 32.4±0.2°, 11.6±0.2°, 15.1±0.2°, 21.5±0.2°, 23.5± The diffraction peaks include one or more at 0.2°, 20.0±0.2°, 13.8±0.2°, and 17.5±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0200] For example, the X-ray powder diffraction pattern of crystalline form E of p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°; or 5.4±0.2°, 16.1±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, 25.2±0.2°, and 28.2±0.2°; Alternatively, 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, 25.2±0.2°, and 28.2±0.2°.

[0201] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 19. [Table 19]

[0202] More preferably, the X-ray powder diffraction pattern of crystalline form E of the p-tosylate is substantially as shown in Figure 50; its DSC pattern is substantially as shown in Figure 51; and its TGA pattern is substantially as shown in Figure 52.

[0203] A more preferred embodiment of the present invention provides a crystalline form A of the besylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.7±0.2°, 17.2±0.2°, and 21 The diffraction peaks include at least one at 0.8±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one at 2θ = 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0204] For example, the X-ray powder diffraction pattern of besylate crystalline form A has diffraction peaks where 2θ is less than or equal to: 5.7±0.2° and 5.5±0.2°; Alternatively, 5.7±0.2°, 5.5±0.2°, and 16.6±0.2°; Alternatively, 5.7±0.2°, 5.5±0.2°, 16.6±0.2°, and 23.0±0.2°; Alternatively, 5.7±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°.

[0205] The X-ray powder diffraction pattern of crystalline form A of the besylate further optionally includes one or more diffraction peaks at 2θ of 27.3±0.2°, 28.8±0.2°, 11.5±0.2°, 13.8±0.2°, 25.5±0.2°, 19.9±0.2°, and 21.3±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0206] For example, the X-ray powder diffraction pattern of besylate crystalline form A has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 27.3±0.2°, and 28.8±0.2°; Alternatively, 5.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 27.3±0.2°, 28.8±0.2°, 11.5±0.2°, and 13.8±0.2°.

[0207] The X-ray powder diffraction pattern of crystalline form A of the besylate contains one or more diffraction peaks at 2θ of 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, 20.3±0.2°, 27.3±0.2°, 28.8±0.2°, 11.5±0.2°, 13.8±0.2°, 25.5±0.2°, 19.9±0.2°, and 21.3±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions and are optionally chosen.

[0208] For example, the X-ray powder diffraction pattern of besylate crystalline form A has diffraction peaks where 2θ is less than or equal to: 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°; Alternatively, 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, 20.3±0.2°, 27.3±0.2°, and 28.8±0.2°.

[0209] The X-ray powder diffraction patterns of besylate crystal morphology A are as follows: 2θ = 5.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, 20.3±0.2°, 27.3±0.2°, 28.8±0.2°, 11.5±0.2°, 13.8±0.2°, 25.5±0.2°, 19.9±0.2°, 21.3±0.2°, 24.3±0.2°, 11.9± The diffraction peaks include one or more at 0.2°, 23.8±0.2°, 26.5±0.2°, and 25.3±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0210] For example, the X-ray powder diffraction pattern of besylate crystalline form A has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°; Alternatively, 5.7±0.2°, 17.2±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, 20.3±0.2°, 27.3±0.2°, and 13.8±0.2°; Alternatively, 5.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, 20.3±0.2°, 27.3±0.2°, and 28.8±0.2°.

[0211] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 20. [Table 20]

[0212] More preferably, the X-ray powder diffraction pattern of crystalline form A of the besylate is substantially as shown in Figure 53.

[0213] A more preferred embodiment of the present invention provides crystalline form B of the besylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 19.7±0.2°, 17.4±0.2°, and 1 The diffraction peaks include at least one diffraction peak at 3.6±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0214] For example, the X-ray powder diffraction pattern of besylate crystalline form B has diffraction peaks where 2θ is less than or equal to: 19.7±0.2° and 22.6±0.2°; Alternatively, 19.7±0.2°, 22.6±0.2°, and 9.7±0.2°; Alternatively, 19.7±0.2°, 22.6±0.2°, 9.7±0.2°, and 5.7±0.2°; Alternatively, 19.7±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°.

[0215] The X-ray powder diffraction pattern of crystalline form B of the besylate further optionally includes one or more diffraction peaks at 2θ of 12.8±0.2°, 23.7±0.2°, 26.4±0.2°, 27.3±0.2°, 24.0±0.2°, 20.7±0.2°, and 21.6±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0216] For example, the X-ray powder diffraction pattern of besylate crystalline form B has diffraction peaks where 2θ is less than or equal to: 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 12.8±0.2°, and 23.7±0.2°; Alternatively, 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 12.8±0.2°, 23.7±0.2°, 26.4±0.2°, and 27.3±0.2°.

[0217] The X-ray powder diffraction pattern of crystalline form B of the besylate contains one or more diffraction peaks at 2θ of 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, 29.1±0.2°, 12.8±0.2°, 23.7±0.2°, 26.4±0.2°, 27.3±0.2°, 24.0±0.2°, 20.7±0.2°, and 21.6±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which can be selected from these.

[0218] For example, the X-ray powder diffraction pattern of besylate crystalline form B has diffraction peaks where 2θ is less than or equal to: 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°; Alternatively, 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, 29.1±0.2°, 12.8±0.2°, and 23.7±0.2°.

[0219] The X-ray powder diffraction patterns of besylate crystal morphology B are as follows: 2θ = 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, 29.1±0.2°, 12.8±0.2°, 23.7±0.2°, 26.4±0.2°, 27.3±0.2°, 24.0±0.2°, 20.7±0.2°, 21.6±0.2°, 16.2±0.2°, 22.0± The diffraction peaks include one or more at 0.2°, 22.9±0.2°, 18.7±0.2°, and 19.3±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0220] For example, the X-ray powder diffraction pattern of besylate crystalline form B has diffraction peaks where 2θ is less than or equal to: 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°; Alternatively, 19.7±0.2°, 17.4±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, 29.1±0.2°, 12.8±0.2°, and 23.7±0.2°; Alternatively, 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, 29.1±0.2°, 12.8±0.2°, and 23.7±0.2°.

[0221] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 21. [Table 21]

[0222] More preferably, the X-ray powder diffraction pattern of crystalline form B of the besylate is substantially as shown in Figure 54; its DSC pattern is substantially as shown in Figure 55; and its TGA pattern is substantially as shown in Figure 56.

[0223] A more preferred embodiment of the present invention provides a crystalline form C of the besylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.4±0.2°, 16.6±0.2°, and 16 The diffraction peaks include at least one at 0.9±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one diffraction peak at 2θ = 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0224] For example, the X-ray powder diffraction pattern of besylate crystalline form C has diffraction peaks where 2θ is less than or equal to: 5.4±0.2° and 15.0±0.2°; Alternatively, 5.4±0.2°, 15.0±0.2°, and 12.7±0.2°; Alternatively, 5.4±0.2°, 15.0±0.2°, 12.7±0.2°, and 19.4±0.2°; Alternatively, 5.4±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°.

[0225] The X-ray powder diffraction pattern of the besylate in crystalline form C optionally includes one or more diffraction peaks at 2θ of 13.8±0.2°, 9.9±0.2°, 25.6±0.2°, 25.2±0.2°, 16.2±0.2°, 18.5±0.2°, and 19.9±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0226] For example, the X-ray powder diffraction pattern of besylate crystalline form C has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 13.8±0.2°, and 9.9±0.2°; Alternatively, 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 13.8±0.2°, 9.9±0.2°, 25.6±0.2°, and 25.2±0.2°.

[0227] The X-ray powder diffraction pattern of the besylate in crystalline form C includes one or more diffraction peaks at 2θ of 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, 20.9±0.2°, 13.8±0.2°, 9.9±0.2°, 25.6±0.2°, 25.2±0.2°, 16.2±0.2°, 18.5±0.2°, and 19.9±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which are selected from these, is included.

[0228] For example, the X-ray powder diffraction pattern of besylate crystalline form C has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°; Alternatively, 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, 20.9±0.2°, 13.8±0.2°, and 9.9±0.2°.

[0229] The X-ray powder diffraction patterns of the besylate crystalline form C are as follows: 2θ = 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, 20.9±0.2°, 13.8±0.2°, 9.9±0.2°, 25.6±0.2°, 25.2±0.2°, 16.2±0.2°, 18.5±0.2°, 19.9±0.2°, 22.1±0.2°, 30.2±0. The diffraction peaks include one or more at 0.2°, 26.1±0.2°, 27.0±0.2°, and 12.9±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0230] For example, the X-ray powder diffraction pattern of besylate crystalline form C has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°; Alternatively, 5.4±0.2°, 16.6±0.2°, 19.4±0.2°, 8.3±0.2°, 20.9±0.2°, 13.8±0.2°, 9.9±0.2°, and 25.6±0.2°; Alternatively, 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, 20.9±0.2°, 13.8±0.2°, and 9.9±0.2°.

[0231] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 22. [Table 22]

[0232] More preferably, the X-ray powder diffraction pattern of the crystalline form C of the besylate is substantially as shown in Figure 57; its DSC pattern is substantially as shown in Figure 58; and its TGA pattern is substantially as shown in Figure 59.

[0233] A more preferred embodiment of the present invention provides crystalline form A of the isethionate salt of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.4±0.2°, 16.1±0.2°, and 2 The diffraction peaks include at least one at 0.9±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, the diffraction peaks may further include at least one at 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0234] For example, the X-ray powder diffraction pattern of crystalline form A of isethionate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2° and 20.0±0.2°; Alternatively, 5.4±0.2°, 20.0±0.2°, and 25.2±0.2°; Alternatively, 5.4±0.2°, 20.0±0.2°, 25.2±0.2°, and 15.1±0.2°; Alternatively, 5.4±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°.

[0235] The X-ray powder diffraction pattern of crystalline form A of isethionate salt optionally includes one or more diffraction peaks at 2θ of 12.7±0.2°, 19.5±0.2°, 22.1±0.2°, 8.4±0.2°, 23.7±0.2°, 28.3±0.2°, and 9.9±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0236] For example, the X-ray powder diffraction pattern of crystalline form A of isethionate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 12.7±0.2°, and 19.5±0.2°; Alternatively, 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 12.7±0.2°, 19.5±0.2°, 22.1±0.2°, and 8.4±0.2°.

[0237] The X-ray powder diffraction pattern of crystalline form A of isethionate contains one or more diffraction peaks at 2θ of 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, 25.7±0.2°, 12.7±0.2°, 19.5±0.2°, 22.1±0.2°, 8.4±0.2°, 23.7±0.2°, 28.3±0.2°, and 9.9±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which can be selected from these.

[0238] For example, the X-ray powder diffraction pattern of crystalline form A of isethionate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°; Alternatively, 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, 25.7±0.2°, 12.7±0.2°, and 19.5±0.2°.

[0239] The X-ray powder diffraction patterns of isethionate in crystalline form A show the following 2θ values: 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, 25.7±0.2°, 12.7±0.2°, 19.5±0.2°, 22.1±0.2°, 8.4±0.2°, 23.7±0.2°, 28.3±0.2°, 9.9±0.2°, 20.7±0.2°, 16.9± The diffraction peaks include one or more at 0.2°, 27.0±0.2°, 26.1±0.2°, and 13.6±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0240] For example, the X-ray powder diffraction pattern of crystalline form A of isethionate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°; Alternatively, 5.4±0.2°, 20.9±0.2°, 20.0±0.2°, 16.7±0.2°, 25.7±0.2°, 12.7±0.2°, 19.5±0.2°, and 22.1±0.2°; Alternatively, 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, 25.7±0.2°, 12.7±0.2°, and 19.5±0.2°.

[0241] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 23. [Table 23]

[0242] More preferably, the X-ray powder diffraction pattern of crystalline form A of the isethionate is substantially as shown in Figure 60.

[0243] A more preferred embodiment of the present invention provides crystalline form B of the isethionate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is such that 2θ is 5.9±0.2°, 16.7±0.2°, and 2 The diffraction pattern includes at least one diffraction peak at 1.2±0.2°, preferably two diffraction peaks selected from those, and more preferably three diffraction peaks selected from those; optionally, it may further include at least one diffraction peak at 2θ = 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°, preferably two, three, four, or five diffraction peaks selected from those.

[0244] For example, the X-ray powder diffraction pattern of isethionate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 5.9±0.2° and 19.5±0.2°; Alternatively, 5.9±0.2°, 19.5±0.2°, and 22.5±0.2°; Alternatively, 5.9±0.2°, 19.5±0.2°, 22.5±0.2°, and 10.0±0.2°; Alternatively, 5.9±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°.

[0245] The X-ray powder diffraction pattern of crystalline form B of isethionate further optionally includes one or more diffraction peaks at 2θ of 15.5±0.2°, 17.5±0.2°, 20.1±0.2°, 17.7±0.2°, 26.2±0.2°, 16.9±0.2°, and 27.6±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0246] For example, the X-ray powder diffraction pattern of isethionate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 15.5±0.2°, and 17.5±0.2°; Alternatively, 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 15.5±0.2°, 17.5±0.2°, 20.1±0.2°, and 17.7±0.2°.

[0247] The X-ray powder diffraction pattern of crystalline form B of isethionate contains one or more diffraction peaks at 2θ of 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, 24.3±0.2°, 15.5±0.2°, 17.5±0.2°, 20.1±0.2°, 17.7±0.2°, 26.2±0.2°, 16.9±0.2°, and 27.6±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which can be selected from these.

[0248] For example, the X-ray powder diffraction pattern of isethionate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°; Alternatively, 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, 24.3±0.2°, 15.5±0.2°, and 17.5±0.2°.

[0249] The X-ray powder diffraction patterns of isethionate in crystalline form B are as follows: 2θ = 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, 24.3±0.2°, 15.5±0.2°, 17.5±0.2°, 20.1±0.2°, 17.7±0.2°, 26.2±0.2°, 16.9±0.2°, 27.6±0.2°, 18.9±0.2°, 25.8 The diffraction peaks include one or more at ±0.2°, 30.4±0.2°, 25.1±0.2°, and 22.1±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0250] For example, the X-ray powder diffraction pattern of isethionate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°; Alternatively, 5.9±0.2°, 16.7±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, 24.3±0.2°, 15.5±0.2°, and 17.5±0.2°; Alternatively, 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, 24.3±0.2°, 15.5±0.2°, and 17.5±0.2°.

[0251] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 24. [Table 24]

[0252] More preferably, the crystalline form B of the isethionate is substantially as shown in Figure 61; its DSC pattern is substantially as shown in Figure 62; and its TGA pattern is substantially as shown in Figure 63.

[0253] A more preferred embodiment of the present invention provides crystalline form A of the 1,5-napadisylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[5,7]cyclooctyl[1,2,3-cd]indene-11-carboxamide, where the number of acids is 1, and its X-ray powder diffraction pattern is 2θ = 21.3±0.2°, 10.2±0.2°. , and including at least one diffraction peak at 9.5±0.2°, preferably including two diffraction peaks selected from there, more preferably including three diffraction peaks selected from there; optionally, further including at least one diffraction peak at 2θ = 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 4.5±0.2°, preferably including two, three, four, or five diffraction peaks selected from there.

[0254] For example, the X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate has diffraction peaks where 2θ is less than or equal to: 21.3±0.2° and 17.1±0.2°; Alternatively, 21.3±0.2°, 17.1±0.2°, and 9.9±0.2°; Alternatively, 21.3±0.2°, 17.1±0.2°, 9.9±0.2°, and 16.7±0.2°; Alternatively, 21.3±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 5.7±0.2°.

[0255] The X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate optionally includes one or more diffraction peaks at 2θ of 8.0±0.2°, 23.7±0.2°, 23.0±0.2°, 18.2±0.2°, 19.9±0.2°, 12.2±0.2°, and 13.7±0.2°; preferably includes at least any 2-3, 4-5, or 6-7 diffraction peaks selected from there, and more preferably includes any 2, 3, 4, 6, or 7 diffraction peaks selected from there.

[0256] For example, the X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate has diffraction peaks where 2θ is less than or equal to: 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.0±0.2°, and 23.7±0.2°; Alternatively, 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.0±0.2°, 23.7±0.2°, 23.0±0.2°, and 18.2±0.2°.

[0257] The X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate includes one or more diffraction peaks at 2θ of 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, 5.7±0.2°, 8.0±0.2°, 23.7±0.2°, 23.0±0.2°, 18.2±0.2°, 19.9±0.2°, 12.2±0.2°, and 13.7±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions.

[0258] For example, the X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate has diffraction peaks where 2θ is less than or equal to: 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 5.7±0.2°; Alternatively, 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, 5.7±0.2°, 8.0±0.2°, and 23.7±0.2°.

[0259] The X-ray powder diffraction patterns of crystalline form A of 1,5-napadisylate are as follows, with 2θ values ​​of 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, 5.7±0.2°, 8.0±0.2°, 23.7±0.2°, 23.0±0.2°, 18.2±0.2°, 19.9±0.2°, 12.2±0.2°, 13.7±0.2°, 22.3±0.2°, and 14. The diffraction peaks include one or more at 4±0.2°, 13.4±0.2°, 24.3±0.2°, and 29.1±0.2°; preferably, the diffraction peaks include at least any 2-3, 4-5, 7-8, 10-12, or 15-18 positions selected from there; more preferably, the diffraction peaks include at any 2, 3, 4, 6, 8, 10, 12, 16, or 18 positions selected from there.

[0260] For example, the X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate has diffraction peaks where 2θ is less than or equal to: 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 5.7±0.2°; Alternatively, 21.3±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 23.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 12.2±0.2°; Alternatively, 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, 5.7±0.2°, 8.0±0.2°, and 23.7±0.2°.

[0261] Most preferably, the X-ray characteristic diffraction peaks, expressed by the 2θ angle and interplanar spacing d using Cu-Kα radiation, are as shown in Table 25. [Table 25]

[0262] More preferably, the X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate is substantially as shown in Figure 64; its DSC pattern is substantially as shown in Figure 65; and its TGA pattern is substantially as shown in Figure 66.

[0263] In a more preferred embodiment of the present invention, the crystalline forms A of ethyl sulfonate, B of ethyl sulfonate, A of tosylate, B of tosylate, A of hydrochloride, B of hydrochloride, C of hydrochloride, A of sulfate, B of sulfate, C of sulfate, D of sulfate, E of sulfate, F of sulfate, G of sulfate, A of p-tosylate, B of p-tosylate, C of p-tosylate, D of p-tosylate, E of p-tosylate, and A of besylate. The 2θ errors between diffraction peaks having the top 10 relative peak intensities in the X-ray powder diffraction patterns of besilate crystalline form B, besilate crystalline form C, isethionate crystalline form A, isethionate crystalline form B, and 1,5-napadisylate crystalline form A, and the 2θ errors between diffraction peaks at the corresponding positions in Figures 1, 4, 7, 10, 12, 15, 16, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 54, 57, 60, 61, and 64 are, respectively, ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0264] In preferred embodiments of the present invention, the crystalline form of any one acidic salt of the compound of formula (I) is a hydrate or an anhydrous; if the crystalline form of the acidic salt is a hydrate, the number of water molecules is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, more preferably 0.5, 1, 2, or 3; furthermore, the water molecules in the hydrate are pipe water or crystal water, or a combination thereof.

[0265] In a preferred embodiment of the present invention, the crystalline form of any one acidic salt of the compounds of formula (I) is an anhydrous.

[0266] As is well known to those skilled in the art, XRPDs can exhibit specific shift and intensity deviations due to the detection method, conditions, and equipment. A specific example of the crystal morphology of the present invention is shown in pattern X. However, those skilled in the art will understand that if the 2θ shift of key feature peaks varies within ±0.5, particularly around ±0.2, they can be identified as the same crystal morphology.

[0267] The present invention further provides a method for preparing the crystalline form of an acidic salt of a compound represented by formula (I), the method comprising the following steps: 1) Weigh out an appropriate amount of free base and dissolve the free base in a suitable solvent; 2) Weighing out an appropriate amount of acid and optionally dissolving the acid in an organic solvent; preferably, the amount of acid is 1.0 to 1.5 equivalents; 3) Combine the two solutions above and stir for precipitation, or add a poor solvent dropwise and then stir for precipitation; and 4) The obtained system is rapidly centrifuged or allowed to stand and dried to obtain the target product; (Here, The good solvents are acetone, toluene, acetonitrile, methanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl formate, isopropyl acetate, toluene, ethyl acetate, 2-methyltetrahydrofuran, 2-butanone, n-butanol, 1,4-dioxane, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, or tert-butanol; preferably selected from toluene, ethyl acetate, acetone, methanol, or acetonitrile; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably selected from methanol, ethanol, or acetonitrile; the above good solvents and organic solutions must be soluble in each other when used; The poor solvent is selected from heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, ethyl acetate, acetone, or acetonitrile; preferably selected from water, methyl tert-butyl ether, or isopropyl ether.) Or more specifically, it includes the following steps: 1) Weigh out an appropriate amount of free base and suspend the free base in a poor solvent; 2) Weighing out an appropriate amount of acid and dissolving the acid in an organic solvent; preferably, the amount of acid is 1.0 to 1.5 equivalents; 3) Add the solution from step 2) above to the suspension from step 1) above while stirring; and 4) The obtained system is rapidly centrifuged or allowed to stand and dried to obtain the target product. (Here, The poor solvent is selected from ethanol, acetone, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tert-butyl ether, methanol, 1,4-dioxane, 2-butanone, 2-methyltetrahydrofuran, anisole, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol, or 3-pentanone; preferably, selected from ethanol, 2-methyltetrahydrofuran, acetonitrile, methanol, or ethyl acetate; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably selected from methanol, ethanol, or acetonitrile; the above good solvents and organic solutions must be soluble in each other when used; The acid in question is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, decyclating acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, milk Acids, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethylsulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphor acid, maleic acid, malonic acid, methylsulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, Selected from pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably, hydrobromic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methylsulfonic acid, benzenesulfonic acid, oxalic acid, acetic acid, ethylsulfonic acid, maleic acid, phosphoric acid, fumaric acid, succinic acid, malonic acid, adipic acid, malic acid, tartaric acid, 1,5-naphthalenedisulfonic acid, isethionic acid Selected from citric acid, hippuric acid, lactic acid, benzoic acid, palmitic acid, or salicylic acid; more preferably selected from hydrobromic acid, ethyl sulfonic acid, methyl sulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid, 1,5-naphthalenedisulfonic acid, maleic acid, fumaric acid, succinic acid, malic acid, or tartaric acid; even more preferably selected from ethyl sulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid, or 1,5-naphthalenedisulfonic acid).

[0268] The present invention further provides a method for preparing the crystalline form of an acidic salt of a compound represented by formula (I), the method comprising the following steps: 1) Weigh out an appropriate amount of the compound salt and suspend the salt in a poor solvent; 2) Shake the suspension from step 1); 3) Rapidly centrifuge the suspension from step 2), remove the supernatant, and dry the residual solid to a certain weight to obtain the target product. (Here, The poor solvent is selected from methanol, ethanol, dichloromethane, 1,4-dioxane, acetonitrile, dichloromethane, chlorobenzene, chloroform, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tert-butyl ether, n-heptane, tert-butanol, or 2-butanone.

[0269] An object of the present invention is to further provide a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) in crystalline form and one or more pharmaceutically acceptable carriers or excipients.

[0270] The present invention further provides the use of an acidic salt or crystalline form of the compound represented by formula (I) or a pharmaceutical composition in the production of a tyrosine kinase activator that inhibits a protein selected from Ebelson protein (ABL1), Ebelson-associated protein (ABL2), and the chimeric protein BCR-ABL1.

[0271] The present invention further provides the use of an acidic salt or crystalline form of a compound represented by formula (I) or a pharmaceutical composition in the manufacture of a drug for the treatment of leukemia-related diseases, wherein the leukemia is preferably chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL); more preferably, the CML is resistant to treatment with one or more standard therapies such as imatinib, nilotinib, and dasatinib, and the AML is secondary AML that develops in conjunction with myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0272] The present invention further provides the use of an acidic salt or crystalline form of a compound represented by formula (I) or a pharmaceutical composition in the manufacture of a drug for the treatment of cancer-related diseases, wherein the cancer is preferably selected from melanoma, hereditary leiomyomatosis, renal cell carcinoma (HLRCC), brain cancer, glioblastoma, or other solid tumors.

[0273] The present invention further provides the use of an acidic salt or crystalline form of the compound represented by formula (I) or a pharmaceutical composition in the manufacture of a drug for the treatment of a disease related to a disorder of the central nervous system, wherein the disease related to a disorder of the central nervous system is preferably a stroke, traumatic brain or spinal cord injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, or motor neuron disease.

[0274] Detailed description of the invention Terms used in this specification and in the claims have the following meanings unless otherwise specified.

[0275] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 Examples include 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and if substituted, it may be substituted with a substituent at any available bond site, where the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, oxo, carboxyl, or carboxylate, and in the present invention, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterium alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0276] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing a pair of adjacent carbon atoms) group having a conjugated π-electron system, preferably a 6- to 10-membered group, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclil, or cycloalkyl ring, which includes a benzo-3 to 8-membered cycloalkyl, a benzo-3 to 8-membered heteroalkyl, preferably a benzo-3 to 6-membered cycloalkyl, or a benzo-3 to 6-membered heteroalkyl, where the heterocyclil is a heterocyclic group containing 1 to 3 nitrogen atoms, an oxygen atom, and a sulfur atom, or a 3-membered nitrogen-containing fused ring containing a benzene ring, and the ring connected to the parent structure is an aryl ring.

[0277] The aryl group may be substituted or unsubstituted. If substituted, it is preferably substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0278] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, the heteroatoms being selected from oxygen, sulfur, and nitrogen. Heteroaryls are preferably 5 to 10-membered, more preferably 5 or 6-membered, and include, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, or pyrazinyl, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring.

[0279] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and if substituted, preferably with substituents that are one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0280] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above. The term "haloalkoxy" refers to an alkoxy compound substituted with one or more halogens, where alkoxy is defined above.

[0281] "Hydroxyl" refers to the -OH group.

[0282] "Carboxyl" refers to -C(O)OH.

[0283] The phrases "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all express the same meaning, that is, X can be one or more of A, B, and C.

[0284] The hydrogen atoms described in this invention can be replaced with their isotopic hydrogen atoms, and any hydrogen atom in the exemplary compounds involved in this invention can also be replaced with a deuterium atom.

[0285] "Optional" or "at willing discretion" means that the event or situation described below may occur but is not necessarily required, and that the description includes both cases in which the event or situation occurs and cases in which it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be present but is not required, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0286] "Substitutable" means that one or more hydrogen atoms in the group, preferably up to five, more preferably one to three, are independently substituted with a corresponding number of substituents. Needless to say, substituents exist only in possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) without excessive effort. For example, amino or hydroxyl compounds with free hydrogen can become unstable when bonded to a carbon atom by an unsaturated bond (such as an olefin bond). Any substituents include one or more of deuterium, halogens, amino, hydroxyl, cyano, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, preferably deuterium, halogens, amino, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 They are aryl and 5- to 14-membered heteroaryls.

[0287] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and to promote the absorption of the active ingredient in order to exert biological activity.

[0288] Identical samples of the same crystal morphology typically have the same major XRPD characteristic peaks, although they may have certain operational errors. When a person skilled in the art detects a sample of the same crystal morphology obtained using the corresponding method, using the same instruments and detection methods, the characteristic peak error is usually within ±0.2°. (However, a person skilled in the art using different instruments may sometimes have some characteristic peaks with errors exceeding this range. For example, errors within ±0.5° or ±0.3° should be considered XRPD characteristic peaks of the same crystal morphology.) Therefore, all peaks with characteristic peak errors within ±0.5°, ±0.3°, or ±0.2° are construed to be included within the scope of protection of the present invention. [Brief explanation of the drawing]

[0289] [Figure 1] XRPD, DSC, and TGA patterns of crystalline form A of ethyl sulfonate are shown. [Figure 2] XRPD, DSC, and TGA patterns of crystalline form A of ethyl sulfonate are shown. [Figure 3] XRPD, DSC, and TGA patterns of crystalline form A of ethyl sulfonate are shown. [Figure 4] The XRPD, DSC, and TGA patterns of crystalline form B of ethyl sulfonate are shown. [Figure 5] The XRPD, DSC, and TGA patterns of crystalline form B of ethyl sulfonate are shown. [Figure 6] The XRPD, DSC, and TGA patterns of crystalline form B of ethyl sulfonate are shown. [Figure 7]The XRPD, DSC, and TGA patterns of crystalline form A of the mesylate are shown. [Figure 8] The XRPD, DSC, and TGA patterns of crystalline form A of the mesylate are shown. [Figure 9] The XRPD, DSC, and TGA patterns of crystalline form A of the mesylate are shown. [Figure 10] The XRPD and DSC patterns of crystalline form B of the mesylate are shown. [Figure 11] The XRPD and DSC patterns of crystalline form B of the mesylate are shown. [Figure 12] The XRPD, DSC, and TGA patterns of crystalline morphology A of the hydrochloride salt are shown. [Figure 13] The XRPD, DSC, and TGA patterns of crystalline morphology A of the hydrochloride salt are shown. [Figure 14] The XRPD, DSC, and TGA patterns of crystalline morphology A of the hydrochloride salt are shown. [Figure 15] The XRPD pattern of crystalline form B of the hydrochloride salt is shown. [Figure 16] The XRPD pattern of crystalline form C of the hydrochloride salt is shown. [Figure 17] The XRPD, DSC, and TGA patterns of crystalline form A of the sulfate are shown. [Figure 18] The XRPD, DSC, and TGA patterns of crystalline form A of the sulfate are shown. [Figure 19] The XRPD, DSC, and TGA patterns of crystalline form A of the sulfate are shown. [Figure 20] The XRPD, DSC, and TGA patterns of crystalline form B of the sulfate are shown. [Figure 21] The XRPD, DSC, and TGA patterns of crystalline form B of the sulfate are shown. [Figure 22] The XRPD, DSC, and TGA patterns of crystalline form B of the sulfate are shown. [Figure 23] The XRPD, DSC, and TGA patterns of the crystalline form C of sulfate are shown. [Figure 24] The XRPD, DSC, and TGA patterns of the crystalline form C of sulfate are shown. [Figure 25] The XRPD, DSC, and TGA patterns of the crystalline form C of sulfate are shown. [Figure 26] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology D are shown. [Figure 27] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology D are shown. [Figure 28] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology D are shown. [Figure 29] The XRPD, DSC, and TGA patterns of crystalline morphology E of the sulfate are shown. [Figure 30] The XRPD, DSC, and TGA patterns of crystalline morphology E of the sulfate are shown. [Figure 31] The XRPD, DSC, and TGA patterns of crystalline morphology E of the sulfate are shown. [Figure 32] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology F are shown. [Figure 33] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology F are shown. [Figure 34] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology F are shown. [Figure 35] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology G are shown. [Figure 36] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology G are shown. [Figure 37] The XRPD, DSC, and TGA patterns of the sulfate crystal morphology G are shown. [Figure 38] The XRPD, DSC, and TGA patterns of crystalline form A of p-tosylate are shown. [Figure 39] The XRPD, DSC, and TGA patterns of crystalline form A of p-tosylate are shown. [Figure 40] The XRPD, DSC, and TGA patterns of crystalline form A of p-tosylate are shown. [Figure 41] The XRPD, DSC, and TGA patterns of crystalline form B of the p-tosylate are shown. [Figure 42] The XRPD, DSC, and TGA patterns of crystalline form B of the p-tosylate are shown. [Figure 43] The XRPD, DSC, and TGA patterns of crystalline form B of the p-tosylate are shown. [Figure 44] The XRPD, DSC, and TGA patterns of the crystalline form C of the p-tosylate are shown. [Figure 45] The XRPD, DSC, and TGA patterns of the crystalline form C of the p-tosylate are shown. [Figure 46] The XRPD, DSC, and TGA patterns of the crystalline form C of the p-tosylate are shown. [Figure 47] The XRPD, DSC, and TGA patterns of crystalline form D of p-tosylate are shown. [Figure 48] The XRPD, DSC, and TGA patterns of crystalline form D of p-tosylate are shown. [Figure 49] The XRPD, DSC, and TGA patterns of crystalline form D of p-tosylate are shown. [Figure 50] The XRPD, DSC, and TGA patterns of crystalline morphology E of p-tosylate are shown. [Figure 51] The XRPD, DSC, and TGA patterns of crystalline morphology E of p-tosylate are shown. [Figure 52] The XRPD, DSC, and TGA patterns of crystalline morphology E of p-tosylate are shown. [Figure 53] This shows the XRPD pattern of crystalline form A of the besylate. [Figure 54] The XRPD, DSC, and TGA patterns of crystalline form B of the besylate are shown. [Figure 55] The XRPD, DSC, and TGA patterns of crystalline form B of the besylate are shown. [Figure 56] The XRPD, DSC, and TGA patterns of crystalline form B of the besylate are shown. [Figure 57] The XRPD, DSC, and TGA patterns of the crystalline form C of the besylate are shown. [Figure 58]The XRPD, DSC, and TGA patterns of the crystalline form C of the besylate are shown. [Figure 59] The XRPD, DSC, and TGA patterns of the crystalline form C of the besylate are shown. [Figure 60] This shows the XRPD pattern of crystalline form A of isethionate salt. [Figure 61] The XRPD, DSC, and TGA patterns of crystalline morphology B of isethionate are shown. [Figure 62] The XRPD, DSC, and TGA patterns of crystalline morphology B of isethionate are shown. [Figure 63] The XRPD, DSC, and TGA patterns of crystalline morphology B of isethionate are shown. [Figure 64] XRPD, DSC, and TGA patterns of crystalline morphology A of 1,5-napadisylate are shown. [Figure 65] XRPD, DSC, and TGA patterns of crystalline morphology A of 1,5-napadisylate are shown. [Figure 66] XRPD, DSC, and TGA patterns of crystalline morphology A of 1,5-napadisylate are shown. [Modes for carrying out the invention]

[0290] I. Preparation of Compounds The present invention will be further described below with reference to examples, but these examples are not intended to limit the scope of the present invention. [Examples]

[0291] Example 1: p-tosylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide [ka]

[0292] In a 500 mL reaction flask, 20 g of methyl 4-amino-3-bromo-5-nitrobenzoic acid (compound 1), 5.30 g of cetyltrimethylammonium bromide, 20.07 g of potassium carbonate, and 200 mL of acetonitrile were added. A solution of (S)-2-chloro-1-propanol in acetonitrile (10.3 g / 50 mL) was added dropwise at room temperature with stirring. After the addition was complete, the mixture was heated under reflux and reacted for 8 hours. After the reaction was complete, the reaction mixture was concentrated to dryness, and ethyl acetate and water were added to the residue to extract the mixture. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The system was filtered, and the filtrate was purified by column chromatography to obtain 13.32 g of compound 3 in 55% yield.

[0293] In a 100 mL reaction flask, 10 g of methyl(R)-3-bromo-4-[(1-hydroxyisopropan-2-yl)amino]-5-nitrobenzoic acid (compound 3) and 38 mL of difluoroacetic acid were added. 16.76 g of iron powder was added at room temperature, and the mixture was heated to 40-50°C and reacted for 3 hours. The reaction system was cooled, and ethyl acetate was added. The reaction system was filtered. The filtrate was washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and added directly to the next reaction step.

[0294] In a 250 mL three-necked flask, 15 g of methyl(R)-7-bromo-2-(difluoromethyl)-1-[1-hydroxypropa-2-yl]-1H-benzo[d]imidazole-5-carboxylate (compound 4), 16.2 g of potassium acetate, 7.9 g of potassium fluoride, 105 mL of 1,4-dioxane, and 15 mL of water were added, and the system was subjected to nitrogen purging three times. 2.4 g of Pd(PPh3)4 was added, and nitrogen purging was performed three times. The system was heated to 80 °C, and a solution of 5-pyrimidineboronic acid in tetrahydrofuran (6.1 g / 15 mL) was added dropwise. After the dropwise addition was complete, the reaction was stirred for a further 5 hours, and after TLC monitoring indicated that the starting materials had reacted completely, the system was cooled to room temperature. 250 mL of water, 120 mL of ethyl acetate, and 3 g of N-acetylcysteine ​​were added to the reaction system. The system was stirred for 0.5 hours, and then 3 L of saturated sodium bicarbonate solution was added. The system was separated into phases, and the aqueous phase was extracted with 120 mL of ethyl acetate. The organic phases were combined, washed with 5 L of saturated sodium chloride solution, concentrated to dryness, and purified by column chromatography to obtain 10.3 g of compound 6 in 69% yield.

[0295] In a 250 mL reaction flask, 10 g of compound 6, 5.8 g of 4-(chlorodifluoromethoxy)aniline, and 100 mL of tetrahydrofuran were added, and 44 mL of lithium bistrimethylsilylamide (1.0 M in THF) was added dropwise at 5–10°C. After the addition was complete, the system was stirred at room temperature for 15 hours to allow the reaction to proceed. The reaction was quenched by adding 100 mL of saturated aqueous ammonium chloride to the reaction mixture dropwise, and the organic phase was extracted with 200 mL of ethyl acetate and concentrated to dryness. 100 mL of ethyl acetate was added to the concentrate, and the concentrate was heated to 50°C and stirred for 0.5 hours, and 50 mL of n-heptane was slowly added dropwise. The system was stirred for a further 0.5 hours, then cooled to 20–30°C and stirred for 3 hours, filtered, and dried under vacuum to obtain 9.1 g of off-white solid in 82% yield.

[0296] 11HNMR (400Hz, acetone-d6) δ10.13(s,1H),9.51(s,1H),9.37(s,1H),9.09-9.10(d,J=2.4Hz,1H),7.90-7.92(m,3H),7.7.81(s,1H),7.74(t,J=52.4Hz,1H),7.27-7.29(d,J=8.4Hz,2H),6.04(s,1H),4.66-4.67(m,1H),3.98-4.04(m,1H),3.73-3.77(m,1H),1.56-1.58(d,J=6.8Hz,3H). [ka]

[0297] 9 g of compound 8 was weighed and 90 mL of acetonitrile was added. The system was heated to 50°C and stirred at this temperature for 30 minutes. An ethanol solution of p-toluenesulfonic acid (4 g / 20 mL) was added. After the addition was complete, the system was held at this temperature for 22-24 hours for the reaction. The system was filtered, and the filtered cake was dried under vacuum at 50°C for 24 hours to obtain the product (10.1 g, yield: 84%).

[0298] Other compounds and salts were prepared in reference to Example 1.

[0299] Biological testing and evaluation The present invention will be further described and interpreted below with reference to the test examples, but these examples are not intended to limit the scope of the present invention.

[0300] (I) Study on the inhibitory activity of the compounds of the present invention against ABL1 WT kinase. 1. Test Objectives The purpose of this study was to evaluate the in vitro inhibitory activity of the compound of the present invention against ABL1 WT kinase.

[0301] 2. Test Method Capillary electrophoresis was used to detect the phosphorylation conversion rate of substrate peptides and to determine the IC50 of test compounds that inhibit kinase (ABL1-WT). 50The values ​​were determined. The maximum concentration of the compounds tested in this study was 1000 nM, a 3-fold dilution, for a total of 12 concentrations (1000~0.0056 nM). First, an enzymatic reaction system was prepared (enzyme ABL1-WT concentration of 1.3 nM, substrate FLPeptide2 concentration of 1.5 μM, reaction factor of 10 mM MgCl2). After incubation at room temperature for 30 minutes, 5 μL of 4×ATP solution was added to initiate the enzymatic reaction. After reacting at room temperature for 90 minutes, the reaction was stopped by adding stop buffer (containing 0.5 M EDTA). The samples were analyzed using an EZ reader (analysis conditions: pressure -1.5 PSI, maximum voltage / current -2250 V, minimum voltage / current -500 V, separation time 40 seconds, system delay 100.0 seconds).

[0302] 3. Data Processing The residual activity was calculated from the conversion rate read by the EZ Reader according to the following formula.

number

[0303] I C 50 This is calculated using XLfit, and IC 50 This was calculated using Equation 201 as the fitting formula.

[0304] 4. Test Results [Table 26]

[0305] In vitro enzyme assays have shown that the compounds of the present invention exhibit good inhibitory activity against ABL1 WT kinase.

[0306] (II) Inhibitory activity against the proliferation of BaF3 cell lines overexpressing different BCR-ABL1 fusion mutations 1. Test Objectives The purpose of this study was to evaluate the inhibitory activity of the compounds of the present invention on the proliferation of Ba / F3 BCR-ABL1-T315I, Ba / F3 BCR-ABL1-E255K, Ba / F3 BCR-ABL1-E255V, and Ba / F3 BCR-ABL1-G250E mutant models of mice cultured in vitro with primary B cells.

[0307] 2. Cell lines [Table 27]

[0308] 3. Test Method The CellTiter-Glo® Luminescent Cell Viability Assay was used to detect the inhibitory effects of drugs on tumor cell proliferation and growth. Logarithmic growth phase cells cultured overnight were directly harvested, pipetted and dispensed, mixed and counted, and the cell density was adjusted according to various cell density requirements. The cells were prepared as cell suspensions and seeded in 96-well plates. Different concentrations of the drug were added, and three replication wells were set up for each concentration to create corresponding vehicle controls. The maximum test concentration in Ba / F3 BCR-ABL1-T315I and Ba / F3 BCR-ABL1-E255K cells was 10,000 nM, with a 3.16-fold gradient dilution, totaling nine concentrations (10,000 to 1.0058 nM). The maximum concentration of the compound detected in other cells was 500 nM, with a 3.16-fold gradient dilution, totaling nine concentrations (500 to 0.0503 nM). Cells treated with the compound were cultured at 37°C and 5% CO2 for a further 72 hours. The culture plate and its contents were equilibrated to room temperature, CellTiter-Glo® reagent was added, and the contents were mixed on a shaker for 5 minutes to induce cell lysis. The culture plate was incubated in the dark at room temperature for a further 20 minutes, and the luminescence was read using a microplate reader.

[0309] 4. Test Results [Table 28]

[0310] The compounds of the present invention can significantly inhibit the proliferation of Ba / F3 BCR-ABL1-T315I, E255K, E255V, and G250E mutant cells.

[0311] (III) Study on inhibitory activity against proliferation of tumor cell lines carrying BCR-ABL1 fusion mutations 1. Test Objectives The purpose of this study was to evaluate the inhibitory activity of the compounds of the present invention on the proliferation of human erythroleukemia cells K562, human peripheral blood basophilic leukemia cells Ku812, and human chronic granulocytic leukemia cells KCL22-s and KCL22-r cultured in vitro.

[0312] 2. Cell lines [Table 29]

[0313] 3. Test Method The CellTiter-Glo® Luminescent Cell Viability Assay was used to detect the inhibitory effects of drugs on tumor cell proliferation and growth. Logarithmic growth phase cells cultured overnight were directly harvested, pipetted, mixed, and counted. Cell density was adjusted according to various cell density requirements, and the cells were prepared as cell suspensions and seeded in 96-well plates. Different concentrations of the drug were added, with three replication wells set up for each concentration and corresponding solvent controls. The maximum concentration of the compound detected was 500 nM, followed by a 3-fold gradient dilution, for a total of nine concentrations (500–0.076 nM). Cells treated with the compound were further cultured at 37°C and 5% CO2 for 72 hours. The culture plate and its contents were equilibrated to room temperature, CellTiter-Glo® reagent was added, and the contents were mixed on a shaker for 3 minutes to induce cell lysis. The culture plate was then incubated in the dark at room temperature for a further 10 minutes, and the chemiluminescence signal value was determined using a microplate reader (BioTek SynergyH1).

[0314] 4. Test Results [Table 30]

[0315] The test results indicate that the compound of the present invention can significantly inhibit the proliferation of tumor cells carrying the BCR-ABL1 fusion mutation.

[0316] (IV) Research on the efficacy of the human chronic myeloid leukemia cell line KCL22-s in a xenograft tumor model. 1. Experimental Objective: The purpose of this experiment was to evaluate the efficacy of the test compound against a BALB / c nude mouse subcutaneous xenograft tumor model of the human chronic myeloid leukemia cell line KCL22-s.

[0317] 2. Experimental Procedures and Data Processing: 2.1 Animals BALB / c nude mice, 8-10 weeks old.

[0318] 2.2 Preparation of cell culture medium and cell suspension a. The KCL22-s cell line was extracted from the cell bank and resuscitated in RPMI-1640 medium (RPMI-1640 + 10% FBS + 1% P / S). The resuscitated cells were placed in cell culture flasks (with the cell type, date, culturer's name etc. written on the flask wall), and then incubated in a CO2 incubator (incubator temperature 37°C, CO2 concentration 5%).

[0319] b. The cells were passaged. After passage, the cells were continued to be cultured in a CO2 incubator. This process was repeated until the cell count met the in vivo efficacy requirements.

[0320] c. Cultured cells were collected and counted using a fully automated cell counter. The cells were resuspended in PBS according to the counting results to form a cell suspension (5 × 10⁻¹⁴). 7 A solution (with a density of / mL) was prepared and placed on an ice pack for later use.

[0321] 2.3 Cell inoculation a. Before vaccination, nude mice were labeled with disposable ear tags for mice and rats.

[0322] b. During inoculation, the cell suspension was uniformly mixed, 0.1 to 1 mL of the cell suspension was taken using a 1 mL syringe, air bubbles were removed, and the syringe was placed on an ice pack for later use.

[0323] c. The nude mouse was held in place with the left hand, and the area near the right shoulder on the right side of the nude mouse's back (the injection site) was disinfected with 75% alcohol. Injection was started 30 seconds later.

[0324] d. The cells were inoculated sequentially into nude laboratory mice (0.1 mL of cell suspension was inoculated into each mouse).

[0325] 2.4 Tumor measurement, grouping, and administration of tumor-carrying mice a. Based on tumor growth, the tumor was measured 15 days after vaccination and the tumor size was calculated.

[0326] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2

[0327] b. Mice were grouped using a randomized grouping method based on their body weight and tumor size.

[0328] c. Based on the group assignment results, administration of the study drug was initiated (route of administration: oral; dose: 1.5, 3, and 7.5 mg / kg; dosage: 10 mL / kg; frequency of administration: 1-2 times / day; administration cycle: 15 days; solvent: 0.5% HPMC K4M).

[0329] d. After the start of administration of the study drug, tumors were measured and weighed twice a week.

[0330] e. The animals were euthanized after the experiment.

[0331] f. Data was processed using Excel and other software. Calculation of the tumor inhibition rate TGI (%) of the compound: If no tumor regression is observed, TGI (%) = [1 - (average tumor volume at the end of treatment in the treatment group - average tumor volume at the start of treatment in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%. If tumor regression is observed, TGI (%) = [1 - (average tumor volume at the end of treatment in the specific treatment group - average tumor volume at the start of treatment in that treatment group) / average tumor volume at the start of treatment in that treatment group] × 100%.

[0332] 3. Experimental results: [Table 31]

[0333] The compounds of the present invention have a significant antitumor effect against the human chronic granulocyte leukemia cell line KCL22-s xenograft tumor model.

[0334] II. Tests concerning the salt and crystalline form of compounds 1. Laboratory equipment 1.1 Several parameters of physicochemical detection instruments [Table 32-1] [Table 32-2]

[0335] 2. Tests on the crystalline form of the salt of the compound. 2.1 Tests on the crystalline form of salts of compounds 2.1.1 Experimental Objective: The purpose of this experiment was to screen for compound salts in crystalline form.

[0336] 2.1.2 Experimental Steps: 1) Equipment and devices [Table 33]

[0337] 2) Tests on the crystalline form of salt (1) Formation of salt crystals by solvent removal or suspension 10 mg of the free base from Example 1 was weighed and added to 100 μL of different reaction solvents. Different counterionic acid solutions (base:acid = 1:1.2 molar reaction ratio) were added at 50°C to react, and the results were as follows: [Table 34-1] [Table 34-2] [Table 35-1] [Table 35-2]

[0338] (2) Slurry formation 10 mg of p-tosylate crystalline form A was weighed, 100 μL (100 μL pipette) of a different slurrying solvent was added, and the system was stirred at room temperature for 2 weeks to obtain a solid. This solid was then centrifuged, dried, and characterized by XRD. Specifically, the following was performed: [Table 36]

[0339] (3)Natural drying Appropriate amounts of crystalline form A of the p-tosylate were weighed and completely dissolved in different solvents by sonication or heating. The system was filtered and air-dried at room temperature to obtain a solid, which was then centrifuged, dried, and characterized by XRD. Specifically, the following was performed: [Table 37]

[0340] (4) Antisolvent method Appropriate amounts of crystalline form A of the p-tosylate were weighed and completely dissolved in different solvents by heating. The system was filtered, an antisolvent was added, and the presence of a precipitate was observed. The system with precipitates was centrifuged, dried, and then characterized. Specifically, the following was performed: [Table 38] [Table 39]

[0341] 2.1.3 Experimental Results: Screening experiments on the crystalline morphology of salts show that sulfates, p-tosylates, ethylsulfonates, and methylsulfonates are the most favorable based on the degree of crystallinity of the salt morphology and the difficulty of the crystallization process.

[0342] 2.2 Screening of the crystalline form of compounds 2.2.1 Experimental Objective: The purpose of this experiment was to screen the crystalline forms of compound salts.

[0343] 2.2.2 Experimental Steps: (1) Equipment and devices [Table 40]

[0344] (2) Operating Procedure 1) Preparation of crystalline form A of ethyl sulfonate 140 mg of the free base from Example 1 was weighed and completely dissolved in 3.5 mL of acetone by heating at 50°C. The system was filtered for use as stock solution. 250 μL of the stock solution was taken, and 22.9 μL of 1.0 M ethyl sulfonic acid solution in methanol was slowly added to the system. The system was stirred at 45°C to precipitate a large amount of solid, which was immediately centrifuged and dried under vacuum to obtain crystalline form A of ethyl sulfonate. Detection and analysis showed that it had the XRPD pattern shown in Figure 1, the DSC pattern shown in Figure 2, and the TGA pattern shown in Figure 3.

[0345] 2) Preparation of crystalline form B of ethyl sulfonate 100 mg of the free base from Example 1 was weighed, 1 mL of acetonitrile was added, and the system was heated with stirring at 50°C. 229 μL of 1.0 M ethyl sulfonic acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, it was vacuum-dried to obtain crystalline form B of the ethyl sulfonate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 4, the DSC pattern shown in Figure 5, and the TGA pattern shown in Figure 6.

[0346] 3) Preparation of mesylate crystal form A 10 mg of the free base from Example 1 was weighed, 100 μL of ethyl acetate was added, and the system was heated with stirring at 50°C. 22.9 μL of 1.0 M methylsulfonic acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain crystalline form A of the mesylate. Detection and analysis revealed that it possessed the XRPD pattern shown in Figure 7, the DSC pattern shown in Figure 8, and the TGA pattern shown in Figure 9.

[0347] 4) Preparation of mesylate crystalline form B 10 mg of the free base from Example 1 was weighed, 100 μL of methanol was added, and the system was heated with stirring at 50°C. 22.9 μL of 1.0 M methylsulfonic acid solution in ethanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, it was vacuum-dried to obtain crystalline form B of the mesylate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 10 and the DSC pattern shown in Figure 11.

[0348] 5) Preparation of crystalline form B of hydrochloride 10 mg of the free base from Example 1 was weighed, 100 μL of acetonitrile was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M hydrochloric acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, it was vacuum-dried to obtain crystalline form A of the hydrochloride salt. Detection and analysis revealed that it had the XRPD pattern shown in Figure 12, the DSC pattern shown in Figure 13, and the TGA pattern shown in Figure 14.

[0349] 6) Preparation of crystalline form B of hydrochloride 10 mg of the free base from Example 1 was weighed, 100 μL of methanol was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M hydrochloric acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain crystalline form B of the hydrochloride salt. Detection and analysis revealed that it had the XRPD pattern shown in Figure 15.

[0350] 7) Preparation of crystalline form C of hydrochloride salt 10 mg of the free base from Example 1 was weighed, 100 μL of dichloromethane was added, and the system was stirred at room temperature. 22.9 μL of 1 M hydrochloric acid solution in methanol was slowly added to the system until completely dissolved. After the addition of MTBE, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain the crystalline form C of the hydrochloride salt. Detection and analysis revealed that it had the XRPD pattern shown in Figure 16.

[0351] 8) Preparation of crystalline form A of sulfate 10 mg of the free base from Example 1 was weighed, 100 μL of acetonitrile was added, and the system was stirred at room temperature. 22.9 μL of 1 M sulfuric acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, it was vacuum-dried to obtain crystalline form A of the sulfate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 17, the DSC pattern shown in Figure 18, and the TGA pattern shown in Figure 19.

[0352] 9) Preparation of crystalline form B of sulfate 10 mg of the free base from Example 1 was weighed, 100 μL of methanol was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M sulfuric acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain crystalline form B of the sulfate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 20, the DSC pattern shown in Figure 21, and the TGA pattern shown in Figure 22.

[0353] 10) Preparation of crystalline form C of sulfate 10 mg of the free base from Example 1 was weighed, 100 μL of chloroform was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M sulfuric acid solution in methanol was slowly added to the system until it was completely dissolved. After the addition of MTBE, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain the sulfate crystalline form C. Detection and analysis revealed that it had the XRPD pattern shown in Figure 23, the DSC pattern shown in Figure 24, and the TGA pattern shown in Figure 25.

[0354] 11) Preparation of crystalline form D of sulfate 10 mg of the free base from Example 1 was weighed, 100 μL of acetone was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M sulfuric acid solution in methanol was slowly added to the system until it was completely dissolved. After the addition of MTBE, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain crystalline form D of the sulfate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 26, the DSC pattern shown in Figure 27, and the TGA pattern shown in Figure 28.

[0355] 12) Preparation of crystalline form E of sulfate 10 mg of the free base from Example 1 was weighed, 100 μL of dichloromethane was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M sulfuric acid solution in methanol was slowly added to the system until completely dissolved. After the addition of MTBE, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain crystalline form E of the sulfate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 29, the DSC pattern shown in Figure 30, and the TGA pattern shown in Figure 31.

[0356] 13) Preparation of the crystalline form F of sulfate 10 mg of the free base from Example 1 was weighed, 100 μL of 2-butanone was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M sulfuric acid solution in methanol was slowly added to the system until completely dissolved. After the addition of MTBE, a large amount of solid precipitated. After centrifugation, the mixture was vacuum-dried to obtain the sulfate crystalline form F. Detection and analysis revealed that it had the XRPD pattern shown in Figure 32, the DSC pattern shown in Figure 33, and the TGA pattern shown in Figure 34.

[0357] 14) Preparation of crystalline form G of sulfate 100 mg of the free base from Example 1 was weighed and 1 mL was added. The system was heated at 50°C with stirring, and 229 μL of 1 M sulfuric acid solution in methanol was slowly added to the system until it was completely dissolved. After the addition of MTBE, a large amount of solid precipitated. The system was stirred for 4 hours, then centrifuged, and dried under vacuum to obtain crystalline form D of the sulfate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 35, the DSC pattern shown in Figure 36, and the TGA pattern shown in Figure 37.

[0358] 15) Preparation of crystalline form A of p-tosylate 10 mg of the free base from Example 1 was weighed, 100 μL of acetonitrile was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M p-toluenesulfonic acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, it was vacuum-dried to obtain crystalline form A of the p-tosylate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 38, the DSC pattern shown in Figure 39, and the TGA pattern shown in Figure 40.

[0359] 16) Preparation of crystalline form B of p-tosylate 10 mg of the free base from Example 1 was weighed, 100 μL of methanol was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M p-toluenesulfonic acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After centrifugation, it was vacuum-dried to obtain crystalline form B of the p-tosylate. Detection and analysis revealed that it had the XRPD pattern shown in Figure 41, the DSC pattern shown in Figure 42, and the TGA pattern shown in Figure 43.

[0360] 17) Preparation of crystalline form C of p-tosylate 10 mg of the free base from Example 1 was weighed, 100 μL of acetonitrile was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M p-toluenesulfonic acid solution in methanol was slowly added to the system. After complete dissolution, a large amount of solid precipitated. After immediate centrifugation and vacuum drying, the crystalline form C of the p-tosylate was obtained. Detection and analysis revealed that it had the XRPD pattern shown in Figure 44, the DSC pattern shown in Figure 45, and the TGA pattern shown in Figure 46.

[0361] 18) Preparation of crystalline form D of p-tosylate 50 mg of p-tosylate in crystalline form A was weighed, and 15 mL of 2-butanone was added. The system was heated or sonicated to completely dissolve the substance. The system was filtered for use as stock solution. 4 mL of the stock solution was taken, and isopropyl ether, an antisolvent, was slowly added to the system, and the system was stirred for precipitation. After centrifugation and vacuum drying, p-tosylate in crystalline form D was obtained. Detection and analysis revealed that it had the XRPD pattern shown in Figure 47, the DSC pattern shown in Figure 48, and the TGA pattern shown in Figure 49.

[0362] 19) Preparation of crystalline form E of p-tosylate 12 mg of p-tosylate crystalline form A was weighed, 0.5 mL of methanol was added, and the system was heated or sonicated to completely dissolve it. The system was filtered and air-dried at room temperature to obtain p-tosylate crystalline form E. Detection and analysis revealed that it had the XRPD pattern shown in Figure 50, the DSC pattern shown in Figure 51, and the TGA pattern shown in Figure 52.

[0363] 20) Preparation of besylate crystalline form A 240 mg of the free base from Example 1 was weighed, 6 mL of tetrahydrofuran was added, and the system was heated or sonicated to completely dissolve it. The system was filtered for use as stock solution. 250 μL of the stock solution was taken, and 22.9 μL of 1 M benzenesulfonic acid solution in methanol was slowly added to the system. The system was air-dried at room temperature to obtain crystalline form A of the besylate. Detection and analysis showed that it had the XRPD pattern shown in Figure 53.

[0364] 21) Preparation of besylate crystal form B 10 mg of the free base from Example 1 was weighed, 100 μL of acetonitrile was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M benzenesulfonic acid solution in methanol was slowly added to the system. After the addition of MTBE, a large amount of solid precipitated. After centrifugation and vacuum drying, crystalline form B of the besilate was obtained. Detection and analysis revealed that it had the XRPD pattern shown in Figure 54, the DSC pattern shown in Figure 55, and the TGA pattern shown in Figure 56.

[0365] 22) Preparation of the crystalline form C of besylates 10 mg of the free base from Example 1 was weighed, 100 μL of methanol was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M benzenesulfonic acid solution in methanol was slowly added to the system. After the addition of MTBE, a large amount of solid precipitated. After centrifugation and vacuum drying, the crystalline form C of the besilate was obtained. Detection and analysis revealed that it had the XRPD pattern shown in Figure 57, the DSC pattern shown in Figure 58, and the TGA pattern shown in Figure 59.

[0366] 23) Preparation of crystalline form A of isethionate salt 240 mg of the free base from Example 1 was weighed, 6 mL of tetrahydrofuran was added, and the system was heated or sonicated to completely dissolve it. The system was filtered for use as stock solution. 250 μL of the stock solution was taken, and 22.9 μL of 1 M isethionic acid solution in methanol was slowly added to the system. The system was air-dried at room temperature to obtain crystalline form A of the isethionate salt. Detection and analysis showed that it had the XRPD pattern shown in Figure 60.

[0367] 24) Preparation of crystalline form B of isethionate salt 10 mg of the free base from Example 1 was weighed, 100 μL of methanol was added, and the system was heated with stirring at 50°C. 22.9 μL of 1 M isethionic acid solution in methanol was slowly added to the system. After the addition of MTBE, a large amount of solid precipitated. After centrifugation and vacuum drying, crystalline form B of the isethionate salt was obtained. Detection and analysis revealed that it had the XRPD pattern shown in Figure 61, the DSC pattern shown in Figure 62, and the TGA pattern shown in Figure 63.

[0368] 25) Preparation of crystalline form A of 1,5-napadisylate 10 mg of the free base from Example 1 was weighed, 100 μL of methanol was added, and the system was heated with stirring at 50°C. 183 μL of 0.125 M 1,5-naphthalenedisulfonic acid in ethanol was slowly added to the system. After the addition of MTBE, a large amount of solid precipitated. After centrifugation and vacuum drying, crystalline form A of 1,5-napadisylate was obtained. Detection and analysis revealed that it had the XRPD pattern shown in Figure 64, the DSC pattern shown in Figure 65, and the TGA pattern shown in Figure 66.

[0369] 3. Quantitative studies on the salts of compounds 3.1 Quantitative studies on the salts of compounds 3.1.1 Experimental Objective: The objective of this experiment was to quantify the number of conjugated acids in each sulfate of the compound using HPLC-ELSD.

[0370] 3.1.2 Experimental Steps: Appropriate amounts of ammonium sulfate were weighed, and a series of linear solutions of varying concentrations were prepared using acetonitrile-water (50:50) as a diluent. Appropriate amounts of ammonium sulfate were weighed from different batches, and each was prepared as a 2 mg / mL sulfate solution using acetonitrile-water (50:50) as a diluent.

[0371] The above solutions were collected. The linear solution and sulfate sample were filtered and then subjected to HPLC-ELSD. Specific HPLC-ELSD analysis method: [Table 41]

[0372] 3.1.3 Experimental Results: [Table 42]

[0373] 3.1.4 Conclusions of the experiment: SO4 in sulfates from different batches 2- Verification from the content calculations shows that the number of bonded sulfuric acid molecules in crystalline form D of the sulfate salt of the compound is 1.

[0374] 3.2 Quantification of p-tosylates of compounds 3.2.1 Experimental Objective: The objective of this experiment was to quantify the number of bound acids in the p-tosylate of a compound using HPLC-ELSD.

[0375] 3.2.2 Experimental Steps: Appropriate amounts of toluene-4-sulfonic acid (monohydrate) were weighed, and a series of linear solutions of varying concentrations were prepared using acetonitrile-water (50:50) as a diluent. Appropriate amounts of p-tosylate from different batches were weighed, and each was prepared as a 2 mg / mL p-tosylate solution using acetonitrile-water (50:50) as a diluent.

[0376] The above solutions were collected. The linear solution and p-tosylate samples were filtered and then subjected to HPLC-ELSD. Specific HPLC-ELSD analysis method: [Table 43]

[0377] 3.2.3 Experimental Results: [Table 44]

[0378] 3.2.4 Conclusions of the experiment: Verification from calculations of the p-toluenesulfonic acid content in p-tosylates of different batches confirms that the number of bound p-toluenesulfonic acid molecules in crystalline form A of the p-tosylate of the compound is 1.

[0379] 4. Solid Stability Experiment 4.1 Experimental Objective: The purpose of this experiment was to investigate the physicochemical stability of the crystalline form of the compound under conditions of illumination below 5000 lx, high temperature of 60°C, high humidity of 92.5% RH, and high temperature and high humidity of 50°C and 75% RH, in order to provide a basis for storing the compound.

[0380] 4.2 Equipment and Liquid Chromatography Conditions 4.2.1 Equipment and devices: [Table 45]

[0381] 4.2.2 Chromatography conditions: [Table 46]

[0382] 4.3 Experimental solution: To measure the content using HPLC and external standard methods, and to calculate the changes in related substances by chromatographic peak area normalization, approximately 1 mg each of crystalline forms of different salts of the compound was collected and investigated for 7 and 14 days under conditions of illumination below 5000 lx, high temperature of 60°C, high humidity of 92.5% RH, and high temperature and high humidity of 50°C and 75% RH.

[0383] 4.4 Experimental Results: [Table 47]

[0384] 4.5 Conclusions of the experiment: The data above suggests that the crystalline form of the compound's salt remains stable under conditions of illumination, high temperature, high humidity, and high temperature and humidity without a significant increase in impurities.

[0385] 5. Dynamic vapor adsorption experiment 5.1 Experimental Objective: The purpose of this experiment was to investigate the water vapor adsorption of the crystalline morphology of compound salts under various relative humidity conditions, and to provide a basis for screening and preserving the crystalline morphology of compound salts.

[0386] 5.2 Experimental solution: Crystallized form A of the p-tosylate of the compound was placed in saturated water vapor at different relative humidities, and dynamic equilibrium was reached between the compound and the water vapor. The rate of increase in the moisture-absorbing weight of the compound after equilibrium was then calculated.

[0387] 5.3 Experimental Results: Crystal morphology A of the p-tosylate of the compound showed a 0.3545% increase in moisture-absorbing weight at 80% RH. After two moisture absorption-desorption cycles at relative humidity 0–95%, the XRPD pattern of crystal morphology A of the p-tosylate remained unchanged, i.e., the crystal morphology remained unchanged.

[0388] 5.4 Conclusions of the experiment: Crystal morphology A of p-tosylate is stable in a humid environment.

[0389] 6. Thermodynamic stability experiment 6.1 Experimental Objective: The objective of this experiment was to obtain a thermodynamically stable crystal form through polymorph screening and competitive experiments of crystal forms.

[0390] 6.2 Experimental solution: An organic solvent with specific solubility was selected, and crystalline form A of the p-tosylate of the compound was suspended in the solvent system. The resulting system was stirred at room temperature for two weeks to form a slurry, which was then centrifuged. The supernatant was removed. The solid was dried under vacuum at 50°C (-0.1 MPa) for 16 hours, and the XRPD pattern of the solid was measured and compared with that of the salt of the starting compound.

[0391] 6.3 Experimental Results: [Table 48]

[0392] 6.4 Conclusions of the experiment: To obtain a total of five crystalline forms of p-tosylates, namely crystalline form A, crystalline form B, crystalline form C, crystalline form D, and crystalline form E, the crystallization solvent and crystallization method were modified by slurrying. As can be determined from the comparison of the DSC patterns of the different crystalline forms, crystalline form A of p-tosylate is the thermodynamically stable crystalline form among these forms and is an anhydrous form.

[0393] 7. Pharmacokinetic studies in rats 7.1. Experimental Objective: The purpose of this experiment was to investigate the pharmacokinetic parameters of the crystalline form A of the compound p-tosylate in rats through animal PK testing.

[0394] 7.2 Laboratory equipment and reagents [Table 49]

[0395] 7.3 Laboratory animals: [Table 50]

[0396] 7.4 Test compound: Crystal form A of the p-tosylate salt of the compound

[0397] 7.5 Experimental solution: The crystalline form A of the p-tosylate of the compound was completely suspended in an aqueous solution of 0.5% HPMC (hydroxypropyl methylcellulose) K4M, and then administered orally to rats at doses of 10 mg / kg and 30 mg / kg. Three rats were used in each parallel experiment. The amount of compound was completely converted to the equivalent amount of free base.

[0398] 7.6 Experimental Results: [Table 51]

[0399] 7.7 Conclusions of the experiment: As can be seen from the results of the rat pharmacokinetic experiments shown in the table, crystalline form A of the p-tosylate of the compound in the present invention exhibits good metabolic properties at a dose of 30 mg / kg.

[0400] 8. Pharmacokinetic studies in dogs 8.1. Experimental Objective: The purpose of this experiment was to investigate the pharmacokinetic parameters of crystalline form A of p-tosylate in dogs.

[0401] 8.2 Laboratory equipment and reagents [Table 52]

[0402] 8.3 Laboratory animals: [Table 53]

[0403] 8.4 Test compound: Crystal form A of the p-tosylate salt of the compound.

[0404] 8.5 Experimental solution: The crystalline form A of the p-tosylate of the compound was completely suspended in an aqueous solution of 0.5% HPMC (hydroxypropyl methylcellulose) K4M, and then force-administered to beagle dogs at doses of 20 mg / kg and 5 mL / kg. Three dogs were used in each parallel experiment. The amount of compound was completely converted to the equivalent amount of free base.

[0405] 8.6 Experimental Results: [Table 54]

[0406] 8.7 Conclusions of the experiment: As can be seen from the results of pharmacokinetic experiments in dogs shown in the table, crystalline form A of p-tosylate exhibits significant improvements in favorable metabolic properties, exposure, and bioavailability.

[0407] Furthermore, a comparison of pharmacokinetic experiment results in rats showed that the bioavailability of the compound was significantly higher in dogs than in rats, suggesting a significant difference between species. However, exposure levels of crystalline form A of p-tosylate in rats and dogs showed a consistent relative trend.

Claims

1. The crystalline form of the acidic salt of the compound represented by formula (I), 【Chemistry 1】 During the ceremony, Ring A is C ６－１０ They are aryl or 5-6 member heteroaryl; R １ is selected from C １－３ alkyl, C １－３ deuterated alkyl, C １－３ haloalkyl, C １－３ hydroxyalkyl, C １－３ alkoxy, C １３ alkylthio, or C １－３ haloalkoxy; M １ is selected from N or CH; M ２ is NH or CH ２ Selected from; M ３ is selected from N or CH; R ２ or R ３ Each of them is independent of C １－３ Alkyl, C １－３ Alkyl deuterated, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Alkoxy, C １－３ Alkylthio, or C １－３ Selected from haloalkoxys; The crystalline form of the acidic salt, wherein the acidic salt is selected from ethyl sulfonate, mesylate, sulfate, hydrochloride, p-tosylate, besylate, isethionate, or 1,5-napadisylate.

2. The crystalline form of the acidic salt of the compound represented by formula (I-a) is: 【Chemistry 2】 During the ceremony, Ring A is phenyl or pyridyl; R １ C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ Selected from haloalkoxys; M １ is N; M ２ is NH; M ３ is N; R ２ or R ３ These are, independently, hydrogen and C １－３ Alkyl, or C １－３ Selected from haloalkyls; The crystalline form of the acidic salt, wherein the acidic salt is selected from ethyl sulfonate, mesylate, sulfate, hydrochloride, p-tosylate, besylate, isethionate, or 1,5-napadisylate.

3. The specific structure of the compound represented by formula (I) is as follows, in the crystalline form of the acidic salt according to claim 1 or 2: 【Transformation 3】

4. The crystalline form is one of crystalline forms A-B of the ethyl sulfonate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide; In the formula, the X-ray powder diffraction pattern of the crystalline form A of the ethyl sulfonate has diffraction peaks at 5.9 ± 0.2°; or at 17.7 ± 0.2°; or at 22.3 ± 0.2°; or at 16.7 ± 0.2°; or at 21.0 ± 0.2°; or at 18.0 ± 0.2°; or at 5.6 ± 0.2°; or at 29.7 ± 0.2°; or at 23.8 ± 0.2°; or at 12.2 ± 0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks B selected from thereto; The X-ray powder diffraction pattern of crystalline form B of the ethyl sulfonate has diffraction peaks at 5.6±0.2°; or at 16.5±0.2°; or at 8.4±0.2°; or at 10.0±0.2°; or at 17.6±0.2°; or at 23.7±0.2°; or at 27.7±0.2°; or at 15.2±0.2°; or at 28.9±0.2°; or at 12.8±0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; Alternatively, the crystalline form is one of crystalline forms A-B of the mesylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide; In the formula, the X-ray powder diffraction pattern of crystalline form A of the mesylate has diffraction peaks at 6.0 ± 0.2°; or at 17.8 ± 0.2°; or at 21.4 ± 0.2°; or at 16.5 ± 0.2°; or at 22.4 ± 0.2°; or at 12.2 ± 0.2°; or at 24.3 ± 0.2°; or at 23.5 ± 0.2°; or at 29.8 ± 0.2°; or at 19.8 ± 0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form B of the mesylate has diffraction peaks at 6.0 ± 0.2°; or at 18.0 ± 0.2°; or at 22.6 ± 0.2°; or at 30.1 ± 0.2°; or at 6.6 ± 0.2°; or at 12.2 ± 0.2°; or at 13.2 ± 0.2°; or at 15.5 ± 0.2°; or at 21.4 ± 0.2°; or at 24.0 ± 0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; Alternatively, the crystalline form is one of the crystalline forms A-G of the sulfate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide; In the formula, the X-ray powder diffraction pattern of the crystalline form A of the sulfate has diffraction peaks at 5.8 ± 0.2°; or at 21.6 ± 0.2°; or at 17.6 ± 0.2°; or at 19.7 ± 0.2°; or at 16.5 ± 0.2°; or at 12.0 ± 0.2°; or at 12.3 ± 0.2°; or at 17.2 ± 0.2°; or at 13.6 ± 0.2°; or at 25.9 ± 0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of crystalline form B of the sulfate has diffraction peaks at 5.7±0.2°; or at 16.9±0.2°; or at 17.4±0.2°; or at 22.5±0.2°; or at 19.3±0.2°; or at 9.9±0.2°; or at 20.1±0.2°; or at 13.8±0.2°; or at 11.1±0.2°; or at 18.6±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form C of the sulfate has diffraction peaks at 5.6±0.2°; or at 16.7±0.2°; or at 8.3±0.2°; or at 12.7±0.2°; or at 15.3±0.2°; or at 17.6±0.2°; or at 10.0±0.2°; or at 15.5±0.2°; or at 13.1±0.2°; or at 21.0±0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form D of the sulfate has diffraction peaks at 17.3±0.2°; or at 24.3±0.2°; or at 20.6±0.2°; or at 26.2±0.2°; or at 22.1±0.2°; or at 18.6±0.2°; or at 15.1±0.2°; or at 12.9±0.2°; or at 25.9±0.2°; or at 18.0±0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form E of the sulfate has diffraction peaks at 5.8±0.2°; or at 17.2±0.2°; or at 9.8±0.2°; or at 13.8±0.2°; or at 20.0±0.2°; or at 22.6±0.2°; or at 19.2±0.2°; or at 22.2±0.2°; or at 11.1±0.2°; or at 26.2±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form F of the sulfate has diffraction peaks at 6.0 ± 0.2°; or at 16.0 ± 0.2°; or at 22.4 ± 0.2°; or at 17.3 ± 0.2°; or at 20.0 ± 0.2°; or at 18.5 ± 0.2°; or at 20.5 ± 0.2°; or at 14.4 ± 0.2°; or at 24.9 ± 0.2°; or at 24.4 ± 0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form G of the sulfate has diffraction peaks at 5.9 ± 0.2°; or at 16.7 ± 0.2°; or at 17.6 ± 0.2°; or at 5.6 ± 0.2°; or at 16.9 ± 0.2°; or at 22.2 ± 0.2°; or at 29.5 ± 0.2°; or at 27.7 ± 0.2°; or at 25.1 ± 0.2°; or at 10.2 ± 0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; Alternatively, the crystalline form is one of crystalline forms A-C of the hydrochloride salt of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide; In the formula, the X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt has diffraction peaks at 22.4 ± 0.2°; or at 14.0 ± 0.2°; or at 17.1 ± 0.2°; or at 6.2 ± 0.2°; or at 19.4 ± 0.2°; or at 25.2 ± 0.2°; or at 17.5 ± 0.2°; or at 21.6 ± 0.2°; or at 19.8 ± 0.2°; or at 23.4 ± 0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt has diffraction peaks at 6.7±0.2°; or at 27.0±0.2°; or at 23.4±0.2°; or at 13.4±0.2°; or at 11.0±0.2°; or at 24.1±0.2°; or at 15.6±0.2°; or at 4.5±0.2°; or at 20.0±0.2°; or at 10.2±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form C of the hydrochloride salt has diffraction peaks at 16.5±0.2°; or at 20.4±0.2°; or at 22.2±0.2°; or at 9.7±0.2°; or at 17.8±0.2°; or at 5.3±0.2°; or at 17.5±0.2°; or at 6.0±0.2°; or at 14.3±0.2°; or at 21.7±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; Alternatively, the crystalline form is one of crystalline forms A-E of the p-tosylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide; In the formula, the X-ray powder diffraction pattern of crystalline form A of the p-tosylate has diffraction peaks at 16.8±0.2°; or at 19.9±0.2°; or at 5.7±0.2°; or at 22.5±0.2°; or at 21.8±0.2°; or at 24.9±0.2°; or at 22.3±0.2°; or at 20.8±0.2°; or at 26.6±0.2°; or at 12.4±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of crystalline form B of the p-tosylate has diffraction peaks at 5.5 ± 0.2°; or at 19.9 ± 0.2°; or at 13.2 ± 0.2°; or at 21.9 ± 0.2°; or at 28.1 ± 0.2°; or at 14.1 ± 0.2°; or at 10.9 ± 0.2°; or at 17.6 ± 0.2°; or at 9.5 ± 0.2°; or at 20.4 ± 0.2°; preferably including any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably including any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form C of the p-tosylate has diffraction peaks at 5.8±0.2°; or at 17.3±0.2°; or at 16.7±0.2°; or at 22.0±0.2°; or at 19.6±0.2°; or at 23.1±0.2°; or at 22.4±0.2°; or at 20.1±0.2°; or at 29.0±0.2°; or at 12.8±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form D of the p-tosylate has diffraction peaks at 4.9±0.2°; or at 5.7±0.2°; or at 17.2±0.2°; or at 22.0±0.2°; or at 19.5±0.2°; or at 28.9±0.2°; or at 25.5±0.2°; or at 12.7±0.2°; or at 14.8±0.2°; or at 23.0±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form E of the p-tosylate has diffraction peaks at 5.4±0.2°; or at 16.1±0.2°; or at 9.9±0.2°; or at 16.7±0.2°; or at 8.4±0.2°; or at 23.1±0.2°; or at 26.9±0.2°; or at 25.7±0.2°; or at 25.2±0.2°; or at 28.2±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; Alternatively, the crystalline form is one of crystalline forms A-C of the besylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide; Here, the X-ray powder diffraction pattern of the crystalline form A of the besylate has diffraction peaks at 5.7±0.2°; or at 17.2±0.2°; or at 21.8±0.2°; or at 5.5±0.2°; or at 16.6±0.2°; or at 23.0±0.2°; or at 17.6±0.2°; or at 20.3±0.2°; or at 27.3±0.2°; or at 28.8±0.2°; preferably, it includes any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably, it includes any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form B of the besylate has diffraction peaks at 19.7±0.2°; or 17.4±0.2°; or 13.6±0.2°; or 22.6±0.2°; or 9.7±0.2°; or 5.7±0.2°; or 14.2±0.2°; or 29.1±0.2°; or 12.8±0.2°; or 23.7±0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of the crystalline form C of the besylate has diffraction peaks at 5.4±0.2°; or at 16.6±0.2°; or at 16.9±0.2°; or at 15.0±0.2°; or at 12.7±0.2°; or at 19.4±0.2°; or at 8.3±0.2°; or at 20.9±0.2°; or at 13.8±0.2°; or at 9.9±0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; Alternatively, the crystalline form is one of crystalline forms A-B of the isethionate salt of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide; Here, the X-ray powder diffraction pattern of the crystalline form A of the isethionate salt has diffraction peaks at 5.4 ± 0.2°; or at 16.1 ± 0.2°; or at 20.9 ± 0.2°; or at 20.0 ± 0.2°; or at 25.2 ± 0.2°; or at 15.1 ± 0.2°; or at 16.7 ± 0.2°; or at 25.7 ± 0.2°; or at 12.7 ± 0.2°; or at 19.5 ± 0.2°; preferably, comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; The X-ray powder diffraction pattern of crystalline form B of the isethionate salt has diffraction peaks at 5.9 ± 0.2°; or at 16.7 ± 0.2°; or at 21.2 ± 0.2°; or at 19.5 ± 0.2°; or at 22.5 ± 0.2°; or at 10.0 ± 0.2°; or at 13.0 ± 0.2°; or at 24.3 ± 0.2°; or at 15.5 ± 0.2°; or at 17.5 ± 0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto; Alternatively, the crystalline form is crystalline form A of 1,5-napadisylate of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide, wherein the X-ray powder diffraction pattern of crystalline form A of 1,5-napadisylate is a diffraction peak at 21.3±0.2°; or a diffraction peak at 10.2±0.2°; or a diffraction peak at 9.5±0.2°; or 17.1±0.2° The crystalline form of the acidic salt according to any one of claims 1 to 3, having a diffraction peak at °; or a diffraction peak at 9.9 ± 0.2°; or a diffraction peak at 16.7 ± 0.2°; or a diffraction peak at 25.8 ± 0.2°; or a diffraction peak at 5.7 ± 0.2°; or a diffraction peak at 8.0 ± 0.2°; or a diffraction peak at 23.7 ± 0.2°; preferably comprising any 2 to 5, 3 to 5, 3 to 6, 3 to 8, 5 to 8, or 6 to 8 of the above diffraction peaks, and more preferably comprising any 6, 7, or 8 diffraction peaks selected from thereto.

5. The crystalline form of the acidic salt according to claim 4, wherein the X-ray powder diffraction pattern of the crystalline form A of the ethyl sulfonate includes at least one diffraction peak at 2θ of 5.9±0.2°, 17.7±0.2°, and 22.3±0.2°, preferably including two diffraction peaks selected from there, and more preferably including three diffraction peaks selected from there; optionally, it may further include at least one diffraction peak at 2θ of 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, and 29.7±0.2°, preferably including two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form A of the ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, and 21.0±0.2°, Or 5.9±0.2°, 16.7±0.2°, 5.6±0.2°, and 29.7±0.2°, or 5.9±0.2°, 17.7±0.2°, 16.7±0.2°, 21.0±0.2°, 5.6±0.2°, and 29.7±0.2°, Alternatively, 17.7±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, and 29.7±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the ethyl sulfonate contains at least one diffraction peak at 2θ of 5.6±0.2°, 16.5±0.2°, and 8.4±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, and 15.2±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form B of the ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 10.0±0.2°, and 17.6±0.2°, Or 5.6±0.2°, 10.0±0.2°, 17.6±0.2°, and 23.7±0.2°, Alternatively, 5.6±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, and 15.2±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the mesylate contains at least one diffraction peak at 2θ of 6.0±0.2°, 17.8±0.2°, and 21.4±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the mesylate in crystalline form A has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 17.8±0.2°, and 16.5±0.2°, or 6.0±0.2°, 17.8±0.2°, 16.5±0.2°, and 22.4±0.2°, or 6.0±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°, or 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the mesylate contains at least one diffraction peak at 2θ = 6.0 ± 0.2°, 18.0 ± 0.2°, and 22.6 ± 0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ = 30.1 ± 0.2°, 6.6 ± 0.2°, 12.2 ± 0.2°, 13.2 ± 0.2°, and 15.5 ± 0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the mesylate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 30.1±0.2°, and 6.6±0.2°, or 6.0±0.2°, 30.1±0.2°, 12.2±0.2°, and 13.2±0.2°, or 18.0±0.2°, 30.1±0.2°, 6.6±0.2°, and 12.2±0.2°, or 22.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°, or 6.0±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°, or 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the sulfate contains at least one diffraction peak at 2θ of 5.8±0.2°, 21.6±0.2°, and 17.6±0.2°, preferably two diffraction peaks selected from there, and more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form A of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 19.7±0.2°, and 16.5±0.2°, Or 21.6±0.2°, 16.5±0.2°, and 12.0±0.2°, Or 5.8±0.2°, 19.7±0.2°, 16.5±0.2°, and 12.0±0.2°, or 5.8±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°, Alternatively, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the sulfate contains at least one diffraction peak at 2θ of 5.7±0.2°, 16.9±0.2°, and 17.4±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of crystalline form B of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 22.5±0.2°, and 19.3±0.2°, Or 5.7±0.2°, 22.5±0.2°, 19.3±0.2°, and 20.1±0.2°, or 5.7±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°, Alternatively, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the sulfate contains at least one diffraction peak at 2θ of 5.6±0.2°, 16.7±0.2°, and 8.3±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form C of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 12.7±0.2°, and 15.3±0.2°, Or 5.6±0.2°, 15.3±0.2°, 17.6±0.2°, and 15.5±0.2°, or 5.6±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°, Alternatively, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°; The X-ray powder diffraction pattern of the crystalline form D of the sulfate contains at least one diffraction peak at 2θ = 17.3±0.2°, 24.3±0.2°, and 20.6±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ = 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form D of the sulfate has diffraction peaks where 2θ is less than or equal to: 17.3±0.2°, 26.2±0.2°, and 12.9±0.2°, or 24.3±0.2°, 26.2±0.2°, 22.1±0.2°, and 18.6±0.2°, or 17.3±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°, or 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°; The X-ray powder diffraction pattern of the crystalline form E of the sulfate contains at least one diffraction peak at 2θ of 5.8±0.2°, 17.2±0.2°, and 9.8±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form E of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 13.8±0.2°, and 22.6±0.2°, or 5.8±0.2°, 13.8±0.2°, 20.0±0.2°, and 22.6±0.2°, or 5.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°, or 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°; The X-ray powder diffraction pattern of the crystalline form F of the sulfate contains at least one diffraction peak at 2θ = 6.0 ± 0.2°, 16.0 ± 0.2°, and 22.4 ± 0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ = 17.3 ± 0.2°, 20.0 ± 0.2°, 18.5 ± 0.2°, 20.5 ± 0.2°, and 14.4 ± 0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form F of the sulfate has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 17.3±0.2°, and 14.4±0.2°, Or 6.0±0.2°, 17.3±0.2°, 20.0±0.2°, and 18.5±0.2°, or 6.0±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°, or 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, and 14.4±0.2°; The X-ray powder diffraction pattern of the crystalline form G of the sulfate contains at least one diffraction peak at 2θ of 5.9±0.2°, 16.7±0.2°, and 17.6±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form G of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 5.6±0.2°, and 16.9±0.2°, Or 5.9±0.2°, 5.6±0.2°, 16.9±0.2°, and 27.7±0.2°, Or 5.9±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°, Alternatively, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the hydrochloride salt contains at least one diffraction peak at 2θ = 22.4±0.2°, 14.0±0.2°, and 17.1±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ = 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form A of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 22.4±0.2°, 6.2±0.2°, and 19.4±0.2°, or 22.4±0.2°, 6.2±0.2°, 19.4±0.2°, and 25.2±0.2°, or 22.4±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°, Alternatively, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the hydrochloride salt contains at least one diffraction peak at 2θ of 6.7±0.2°, 27.0±0.2°, and 23.4±0.2°, preferably two diffraction peaks selected from there, and more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form B of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 6.7±0.2°, 13.4±0.2°, and 1.0±0.2°, or 6.7±0.2°, 13.4±0.2°, 11.0±0.2°, and 24.1±0.2°, or 6.7±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°, or 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the hydrochloride salt contains at least one diffraction peak at 2θ of 16.5±0.2°, 20.4±0.2°, and 22.2±0.2°, preferably two diffraction peaks selected from there, and more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form C of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 16.5±0.2°, 9.7±0.2°, and 17.8±0.2°, Or 16.5±0.2°, 17.8±0.2°, 5.3±0.2°, and 6.0±0.2°, Alternatively, 16.5±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°, Alternatively, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the p-tosylate contains at least one diffraction peak at 2θ of 16.8±0.2°, 19.9±0.2°, and 5.7±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, and 20.8±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form A of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 16.8±0.2°, 19.9±0.2°, and 5.7±0.2°, or 16.8±0.2°, 22.5±0.2°, 21.8±0.2°, and 24.9±0.2°, or 16.8±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, and 20.8±0.2°, Alternatively, 5.7±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, and 20.8±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the p-tosylate contains at least one diffraction peak at 2θ of 5.5±0.2°, 19.9±0.2°, and 13.2±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, and 17.6±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form B of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.5±0.2°, 21.9±0.2°, and 28.1±0.2°, Or 5.5±0.2°, 21.9±0.2°, 28.1±0.2°, and 14.1±0.2°, or 5.5±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, and 17.6±0.2°, Alternatively, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, and 17.6±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the p-tosylate contains at least one diffraction peak at 2θ of 5.8±0.2°, 17.3±0.2°, and 16.7±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form C of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 22.0±0.2°, and 19.6±0.2°, Or 5.8±0.2°, 22.0±0.2°, 19.6±0.2°, and 23.1±0.2°, or 17.3±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°, or 5.8±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°, or 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°; The X-ray powder diffraction pattern of the crystalline form D of the p-tosylate contains at least one diffraction peak at 2θ of 4.9±0.2°, 5.7±0.2°, and 17.2±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form D of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 4.9±0.2°, 22.0±0.2°, and 19.5±0.2°, Or 4.9±0.2°, 22.0±0.2°, 19.5±0.2°, and 28.9±0.2°, or 4.9±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°, Alternatively, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°; The X-ray powder diffraction pattern of the crystalline form E of the p-tosylate contains at least one diffraction peak at 2θ of 5.4±0.2°, 16.1±0.2°, and 9.9±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form E of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.7±0.2°, and 8.4±0.2°, Or 5.4±0.2°, 16.7±0.2°, 8.4±0.2°, and 23.1±0.2°, Or 9.9±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°, Or 5.4±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°, Alternatively, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the besylate contains at least one diffraction peak at 2θ of 5.7±0.2°, 17.2±0.2°, and 21.8±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the besylate in crystalline form A has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 5.5±0.2°, and 16.6±0.2°, Or 5.7±0.2°, 5.5±0.2°, 16.6±0.2°, and 23.0±0.2°, or 5.7±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°, Alternatively, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the besylate contains at least one diffraction peak at 2θ of 19.7±0.2°, 17.4±0.2°, and 13.6±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the besylate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 19.7±0.2°, 22.6±0.2°, and 9.7±0.2°, Or 19.7±0.2°, 22.6±0.2°, 9.7±0.2°, and 5.7±0.2°, or 19.7±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°, Alternatively, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the besylate contains at least one diffraction peak at 2θ of 5.4±0.2°, 16.6±0.2°, and 16.9±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the besylate in crystalline form C has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 15.0±0.2°, and 12.7±0.2°, Or 5.4±0.2°, 15.0±0.2°, 12.7±0.2°, and 19.4±0.2°, Alternatively, 5.4±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°, Alternatively, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the isethionate salt contains at least one diffraction peak at 2θ of 5.4±0.2°, 16.1±0.2°, and 20.9±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the isethionate salt in crystalline form A has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 20.0±0.2°, and 25.2±0.2°, Or 5.4±0.2°, 20.0±0.2°, 25.2±0.2°, and 15.1±0.2°, or 5.4±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°, or 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the isethionate salt contains at least one diffraction peak at 2θ of 5.9±0.2°, 16.7±0.2°, and 21.2±0.2°, preferably two diffraction peaks selected from there, and more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ of 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the isethionate salt in crystalline form B has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 19.5±0.2°, and 22.5±0.2°, Or 5.9±0.2°, 19.5±0.2°, 22.5±0.2°, and 10.0±0.2°, or 5.9±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°, or 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the 1,5-napadisylate salt contains at least one diffraction peak at 2θ = 21.3±0.2°, 10.2±0.2°, and 9.5±0.2°, preferably two diffraction peaks selected from there, more preferably three diffraction peaks selected from there; optionally, it may further contain at least one diffraction peak at 2θ = 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 5.7±0.2°, preferably two, three, four, or five diffraction peaks selected from there. For example, the X-ray powder diffraction pattern of the crystalline form A of the 1,5-napadisylate has diffraction peaks where 2θ is less than or equal to: 21.3±0.2°, 17.1±0.2°, and 9.9±0.2°, Or 21.3±0.2°, 17.1±0.2°, 9.9±0.2°, and 16.7±0.2°, Alternatively, 21.3±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 5.7±0.2°, Alternatively, the crystalline form of the acidic salt is 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 5.7±0.2°.

6. The crystalline form of the acidic salt according to claim 4, wherein the X-ray powder diffraction pattern of the crystalline form A of the ethyl sulfonate includes one or more diffraction peaks at 2θ of 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, 28.0±0.2°, 24.9±0.2°, 10.0±0.2°, and 11.8±0.2°; preferably, a diffraction peak at positions 4, 6, 8, or 10, which are selected from there, is included. For example, the X-ray powder diffraction pattern of the crystalline form A of the ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, and 16.7±0.2°, or 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, and 18.0±0.2°, Alternatively, 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, and 29.7±0.2°, or 5.9±0.2°, 22.3±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, and 12.2±0.2°, Alternatively, 5.9±0.2°, 17.7±0.2°, 22.3±0.2°, 16.7±0.2°, 21.0±0.2°, 18.0±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, and 12.2±0.2°, Alternatively, 17.7±0.2°, 16.7±0.2°, 5.6±0.2°, 29.7±0.2°, 23.8±0.2°, 12.2±0.2°, 18.4±0.2°, 28.0±0.2°, 24.9±0.2°, and 10.0±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the ethyl sulfonate includes one or more diffraction peaks at 2θ of 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 12.8±0.2°, 13.8±0.2°, 21.1±0.2°, 11.8±0.2°, 18.6±0.2°, and 13.1±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these; For example, the X-ray powder diffraction pattern of the crystalline form B of the ethyl sulfonate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, and 10.0±0.2°, or 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, and 23.7±0.2°, or 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, and 15.2±0.2°, or 5.6±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, and 12.8±0.2°, Alternatively, 5.6±0.2°, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, and 12.8±0.2°, Alternatively, 16.5±0.2°, 8.4±0.2°, 10.0±0.2°, 17.6±0.2°, 23.7±0.2°, 27.7±0.2°, 15.2±0.2°, 28.9±0.2°, 12.8±0.2°, and 13.8±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the mesylate contains one or more diffraction peaks at 2θ of 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, 16.7±0.2°, 25.8±0.2°, 14.8±0.2°, 28.0±0.2°, and 33.9±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the mesylate in crystalline form A has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, and 16.5±0.2°, or 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, and 12.2±0.2°, or 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, and 23.5±0.2°, or 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, and 29.8±0.2°, or 6.0±0.2°, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, and 19.8±0.2°, Alternatively, 17.8±0.2°, 21.4±0.2°, 16.5±0.2°, 22.4±0.2°, 12.2±0.2°, 24.3±0.2°, 23.5±0.2°, 29.8±0.2°, 19.8±0.2°, and 16.7±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the mesylate contains one or more diffraction peaks at 2θ of 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, 24.0±0.2°, 12.0±0.2°, 10.1±0.2°, 24.6±0.2°, 16.6±0.2°, and 19.8±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the mesylate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, and 30.1±0.2°, or 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, and 12.2±0.2°, or 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, and 15.5±0.2°, or 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, and 21.4±0.2°, or 6.0±0.2°, 18.0±0.2°, 22.6±0.2°, 30.1±0.2°, 6.6±0.2°, 12.2±0.2°, 13.2±0.2°, 15.5±0.2°, 21.4±0.2°, and 24.0±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the sulfate includes one or more diffraction peaks at 2θ of 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, 25.9±0.2°, 23.5±0.2°, 21.8±0.2°, 14.4±0.2°, 10.4±0.2°, and 24.7±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form A of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, and 19.7±0.2°, or 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, and 12.0±0.2°, or 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, and 17.2±0.2°, Alternatively, 5.8±0.2°, 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, and 25.9±0.2°, or 21.6±0.2°, 17.6±0.2°, 19.7±0.2°, 16.5±0.2°, 12.0±0.2°, 12.3±0.2°, 17.2±0.2°, 13.6±0.2°, 25.9±0.2°, and 23.5±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the sulfate includes one or more diffraction peaks at 2θ of 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, 11.1±0.2°, 18.6±0.2°, 27.2±0.2°, 26.8±0.2°, 24.2±0.2°, 25.4±0.2°, and 23.7±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form B of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, and 22.5±0.2°, or 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, and 20.1±0.2°, or 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, and 13.8±0.2°, Alternatively, 5.7±0.2°, 16.9±0.2°, 17.4±0.2°, 22.5±0.2°, 19.3±0.2°, 9.9±0.2°, 20.1±0.2°, 13.8±0.2°, 11.1±0.2°, and 18.6±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the sulfate includes one or more diffraction peaks at 2θ of 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, 21.0±0.2°, 25.7±0.2°, 25.3±0.2°, 19.5±0.2°, 20.1±0.2°, and 18.6±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form C of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, and 12.7±0.2°, or 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, and 17.6±0.2°, or 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, and 15.5±0.2°, Alternatively, 5.6±0.2°, 16.7±0.2°, 8.3±0.2°, 12.7±0.2°, 15.3±0.2°, 17.6±0.2°, 10.0±0.2°, 15.5±0.2°, 13.1±0.2°, and 21.0±0.2°; The X-ray powder diffraction pattern of the crystalline form D of the sulfate includes one or more diffraction peaks at 2θ of 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, 25.9±0.2°, 18.0±0.2°, 25.8±0.2°, 22.9±0.2°, 29.1±0.2°, 6.8±0.2°, and 11.4±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form D of the sulfate has diffraction peaks where 2θ is less than or equal to: 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, and 26.2±0.2°, or 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, and 18.6±0.2°, or 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, and 12.9±0.2°, Alternatively, 17.3±0.2°, 24.3±0.2°, 20.6±0.2°, 26.2±0.2°, 22.1±0.2°, 18.6±0.2°, 15.1±0.2°, 12.9±0.2°, 25.9±0.2°, and 18.0±0.2°; The X-ray powder diffraction pattern of the crystalline form E of the sulfate includes one or more diffraction peaks at 2θ of 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, 26.2±0.2°, 24.3±0.2°, 20.6±0.2°, 18.6±0.2°, 19.7±0.2°, and 15.1±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form E of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, and 13.8±0.2°, or 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, and 22.6±0.2°, or 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, and 22.2±0.2°, or 5.8±0.2°, 17.2±0.2°, 9.8±0.2°, 13.8±0.2°, 20.0±0.2°, 22.6±0.2°, 19.2±0.2°, 22.2±0.2°, 11.1±0.2°, and 26.2±0.2°; The X-ray powder diffraction pattern of the crystalline form F of the sulfate includes one or more diffraction peaks at 2θ of 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 24.9±0.2°, 24.4±0.2°, 17.5±0.2°, 26.2±0.2°, 18.0±0.2°, 27.5±0.2°, and 21.5±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these; For example, the X-ray powder diffraction pattern of the crystalline form F of the sulfate has diffraction peaks where 2θ is less than or equal to: 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, and 17.3±0.2°, or 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, and 18.5±0.2°, or 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, and 20.5±0.2°, or 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, and 24.9±0.2°, or 6.0±0.2°, 16.0±0.2°, 22.4±0.2°, 17.3±0.2°, 20.0±0.2°, 18.5±0.2°, 20.5±0.2°, 14.4±0.2°, 24.9±0.2°, and 24.4±0.2°; The X-ray powder diffraction pattern of the crystalline form G of the sulfate includes one or more diffraction peaks at 2θ of 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 25.1±0.2°, 10.2±0.2°, 24.4±0.2°, 8.4±0.2°, 12.1±0.2°, 24.2±0.2°, and 15.4±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these; For example, the X-ray powder diffraction pattern of the crystalline form G of the sulfate has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, and 5.6±0.2°, Or 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, and 22.2±0.2°, or 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, and 27.7±0.2°, Alternatively, 5.9±0.2°, 16.7±0.2°, 17.6±0.2°, 5.6±0.2°, 16.9±0.2°, 22.2±0.2°, 29.5±0.2°, 27.7±0.2°, 25.1±0.2°, and 10.2±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the hydrochloride salt includes one or more diffraction peaks at 2θ of 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, 21.6±0.2°, 19.8±0.2°, 23.4±0.2°, 10.6±0.2°, 30.5±0.2°, 12.4±0.2°, 9.8±0.2°, and 11.1±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form A of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, and 6.2±0.2°, or 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, and 25.2±0.2°, or 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, and 21.6±0.2°, or 22.4±0.2°, 14.0±0.2°, 17.1±0.2°, 6.2±0.2°, 19.4±0.2°, 25.2±0.2°, 17.5±0.2°, 21.6±0.2°, 19.8±0.2°, and 23.4±0.2°, The X-ray powder diffraction pattern of the crystalline form B of the hydrochloride salt includes one or more diffraction peaks at 2θ of 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, 20.0±0.2°, 10.2±0.2°, 14.3±0.2°, 10.0±0.2°, 20.5±0.2°, 23.0±0.2°, and 31.0±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form B of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, and 13.4±0.2°, or 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, and 24.1±0.2°, or 6.0±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, and 4.5±0.2°, or 6.7±0.2°, 27.0±0.2°, 23.4±0.2°, 13.4±0.2°, 11.0±0.2°, 24.1±0.2°, 15.6±0.2°, 4.5±0.2°, 20.0±0.2°, and 10.2±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the hydrochloride salt includes one or more diffraction peaks at 2θ of 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, 14.3±0.2°, 21.7±0.2°, 24.6±0.2°, 10.9±0.2°, 27.2±0.2°, 20.8±0.2°, and 19.7±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form C of the hydrochloride salt has diffraction peaks where 2θ is less than or equal to: 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, and 9.7±0.2°, or 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, and 5.3±0.2°, or 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, and 6.0±0.2°, Alternatively, 16.5±0.2°, 20.4±0.2°, 22.2±0.2°, 9.7±0.2°, 17.8±0.2°, 5.3±0.2°, 17.5±0.2°, 6.0±0.2°, 14.3±0.2°, and 21.7±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the p-tosylate contains one or more diffraction peaks at 2θ of 16.8±0.2°, 19.9±0.2°, 5.7±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, 26.6±0.2°, 12.4±0.2°, 15.1±0.2°, 13.8±0.2°, 21.3±0.2°, 27.7±0.2°, and 20.5±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form A of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 16.8±0.2°, 19.9±0.2°, 5.7±0.2°, and 22.5±0.2°, or 16.8±0.2°, 19.9±0.2°, 5.7±0.2°, 22.5±0.2°, 21.8±0.2°, and 24.9±0.2°, or 16.8±0.2°, 19.9±0.2°, 5.7±0.2°, 12.4±0.2°, 13.8±0.2°, 22.5±0.2°, 21.8±0.2°, and 20.8±0.2°, Alternatively, 19.9±0.2°, 5.7±0.2°, 22.5±0.2°, 21.8±0.2°, 24.9±0.2°, 22.3±0.2°, 20.8±0.2°, 26.6±0.2°, 12.4±0.2°, and 15.1±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the p-tosylate contains one or more diffraction peaks at 2θ of 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, 17.6±0.2°, 9.5±0.2°, 20.4±0.2°, 17.8±0.2°, 22.1±0.2°, 21.5±0.2°, 16.3±0.2°, and 26.5±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form B of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, and 21.9±0.2°, or 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, and 14.1±0.2°, or 5.5±0.2°, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, and 17.6±0.2°, Alternatively, 19.9±0.2°, 13.2±0.2°, 21.9±0.2°, 28.1±0.2°, 14.1±0.2°, 10.9±0.2°, 17.6±0.2°, 9.5±0.2°, 20.4±0.2°, and 17.8±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the p-tosylate contains one or more diffraction peaks at 2θ of 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, 20.1±0.2°, 29.0±0.2°, 12.8±0.2°, 21.6±0.2°, 11.5±0.2°, 13.8±0.2°, 27.4±0.2°, and 20.9±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form C of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, and 22.0±0.2°, or 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, and 23.1±0.2°, or 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, and 20.1±0.2°, Alternatively, 5.8±0.2°, 17.3±0.2°, 16.7±0.2°, 22.0±0.2°, 19.6±0.2°, 23.1±0.2°, 22.4±0.2°, 20.1±0.2°, 29.0±0.2°, and 12.8±0.2°; The X-ray powder diffraction pattern of the crystalline form D of the p-tosylate contains one or more diffraction peaks at 2θ of 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, 12.7±0.2°, 14.8±0.2°, 23.0±0.2°, 20.6±0.2°, 27.3±0.2°, 30.4±0.2°, 24.8±0.2°, and 27.7±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form D of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, and 22.0±0.2°, Alternatively, 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, and 28.9±0.2°, Alternatively, 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, and 12.7±0.2°, Alternatively, 4.9±0.2°, 5.7±0.2°, 17.2±0.2°, 22.0±0.2°, 19.5±0.2°, 28.9±0.2°, 25.5±0.2°, 12.7±0.2°, 14.8±0.2°, and 23.0±0.2°; The X-ray powder diffraction pattern of the crystalline form E of the p-tosylate contains one or more diffraction peaks at 2θ of 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, 25.2±0.2°, 28.2±0.2°, 18.5±0.2°, 16.9±0.2°, 32.4±0.2°, 11.6±0.2°, and 15.1±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form E of the p-tosylate has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, and 16.7±0.2°, or 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, and 23.1±0.2°, or 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, and 25.7±0.2°, Alternatively, 5.4±0.2°, 16.1±0.2°, 9.9±0.2°, 16.7±0.2°, 8.4±0.2°, 23.1±0.2°, 26.9±0.2°, 25.7±0.2°, 25.2±0.2°, and 28.2±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the besylate contains one or more diffraction peaks at 2θ of 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, 20.3±0.2°, 27.3±0.2°, 28.8±0.2°, 11.5±0.2°, 13.8±0.2°, 25.5±0.2°, 19.9±0.2°, and 21.3±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the besylate in crystalline form A has diffraction peaks where 2θ is less than or equal to: 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, and 5.5±0.2°, Alternatively, 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, and 23.0±0.2°, or 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, and 20.3±0.2°, Alternatively, 55.7±0.2°, 17.2±0.2°, 21.8±0.2°, 5.5±0.2°, 16.6±0.2°, 23.0±0.2°, 17.6±0.2°, 20.3±0.2°, 27.3±0.2°, and 28.8±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the besylate contains one or more diffraction peaks at 2θ of 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, 29.1±0.2°, 12.8±0.2°, 23.7±0.2°, 26.4±0.2°, 27.3±0.2°, 24.0±0.2°, 20.7±0.2°, and 21.6±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the besylate in crystalline form B has diffraction peaks where 2θ is less than or equal to: 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, and 22.6±0.2°, or 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, and 5.7±0.2°, or 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, and 29.1±0.2°, Alternatively, 19.7±0.2°, 17.4±0.2°, 13.6±0.2°, 22.6±0.2°, 9.7±0.2°, 5.7±0.2°, 14.2±0.2°, 29.1±0.2°, 12.8±0.2°, and 23.7±0.2°; The X-ray powder diffraction pattern of the crystalline form C of the besylate contains one or more diffraction peaks at 2θ of 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, 20.9±0.2°, 13.8±0.2°, 9.9±0.2°, 25.6±0.2°, 25.2±0.2°, 16.2±0.2°, 18.5±0.2°, and 19.9±0.2°; preferably, it contains diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the besylate in crystalline form C has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, and 15.0±0.2°, or 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, and 19.4±0.2°, or 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, and 20.9±0.2°, Alternatively, 5.4±0.2°, 16.6±0.2°, 16.9±0.2°, 15.0±0.2°, 12.7±0.2°, 19.4±0.2°, 8.3±0.2°, 20.9±0.2°, 13.8±0.2°, and 9.9±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the isethionate salt includes one or more diffraction peaks at 2θ of 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, 25.7±0.2°, 12.7±0.2°, 19.5±0.2°, 22.1±0.2°, 8.4±0.2°, 23.7±0.2°, 28.3±0.2°, and 9.9±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the isethionate salt in crystalline form A has diffraction peaks where 2θ is less than or equal to: 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, and 20.0±0.2°, or 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, and 15.1±0.2°, or 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, and 25.7±0.2°, Alternatively, 5.4±0.2°, 16.1±0.2°, 20.9±0.2°, 20.0±0.2°, 25.2±0.2°, 15.1±0.2°, 16.7±0.2°, 25.7±0.2°, 12.7±0.2°, and 19.5±0.2°; The X-ray powder diffraction pattern of the crystalline form B of the isethionate salt includes one or more diffraction peaks at 2θ of 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, 24.3±0.2°, 15.5±0.2°, 17.5±0.2°, 20.1±0.2°, 17.7±0.2°, 26.2±0.2°, 16.9±0.2°, and 27.6±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the isethionate salt in crystalline form B has diffraction peaks where 2θ is less than or equal to: 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, and 19.5±0.2°, or 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, and 10.0±0.2°, or 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, and 24.3±0.2°, or 5.9±0.2°, 16.7±0.2°, 21.2±0.2°, 19.5±0.2°, 22.5±0.2°, 10.0±0.2°, 13.0±0.2°, 24.3±0.2°, 15.5±0.2°, and 17.5±0.2°; The X-ray powder diffraction pattern of the crystalline form A of the 1,5-napadisylate salt includes one or more diffraction peaks at 2θ of 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, 5.7±0.2°, 8.0±0.2°, 23.7±0.2°, 23.0±0.2°, 18.2±0.2°, 19.9±0.2°, 12.2±0.2°, and 13.7±0.2°; preferably, it includes diffraction peaks at positions 4, 6, 8, or 10, which are selected from these positions. For example, the X-ray powder diffraction pattern of the crystalline form A of the 1,5-napadisylate has diffraction peaks where 2θ is less than or equal to: 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, and 17.1±0.2°, or 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, and 16.7±0.2°, Alternatively, 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, and 5.7±0.2°, Alternatively, the crystalline form of the acidic salt is 21.3±0.2°, 10.2±0.2°, 9.5±0.2°, 17.1±0.2°, 9.9±0.2°, 16.7±0.2°, 25.8±0.2°, 5.7±0.2°, 8.0±0.2°, and 23.7±0.2°.

7. The crystalline form of the acidic salt according to claim 4, The crystalline form A of the ethyl sulfonate has an X-ray powder diffraction pattern as shown in Figure 1, or a DSC pattern as shown in Figure 2, or a TGA pattern as shown in Figure 3; The crystalline form B of the ethyl sulfonate has an X-ray powder diffraction pattern as shown in Figure 4, or a DSC pattern as shown in Figure 5, or a TGA pattern as shown in Figure 6; The crystalline form A of the mesylate has the X-ray powder diffraction pattern shown in Figure 7, or the DSC pattern shown in Figure 8, or the TGA pattern shown in Figure 9; The crystalline form B of the mesylate has the X-ray powder diffraction pattern shown in Figure 10, or the DSC pattern shown in Figure 11; The crystalline form A of the sulfate has an X-ray powder diffraction pattern as shown in Figure 17, or a DSC pattern as shown in Figure 18, or a TGA pattern as shown in Figure 19; The crystalline form B of the sulfate has an X-ray powder diffraction pattern as shown in Figure 20, or a DSC pattern as shown in Figure 21, or a TGA pattern as shown in Figure 22; The crystalline form C of the sulfate has either the X-ray powder diffraction pattern shown in Figure 23, the DSC pattern shown in Figure 24, or the TGA pattern shown in Figure 25; The crystalline form D of the sulfate has either the X-ray powder diffraction pattern shown in Figure 26, the DSC pattern shown in Figure 27, or the TGA pattern shown in Figure 28; The crystalline form E of the sulfate has either the X-ray powder diffraction pattern shown in Figure 29, the DSC pattern shown in Figure 30, or the TGA pattern shown in Figure 31; The crystalline form F of the sulfate has either the X-ray powder diffraction pattern shown in Figure 32, the DSC pattern shown in Figure 33, or the TGA pattern shown in Figure 34; The crystalline form G of the sulfate has either the X-ray powder diffraction pattern shown in Figure 35, the DSC pattern shown in Figure 36, or the TGA pattern shown in Figure 37; The crystalline form A of the hydrochloride salt has an X-ray powder diffraction pattern as shown in Figure 12, or a DSC pattern as shown in Figure 13, or a TGA pattern as shown in Figure 14; The crystalline form B of the hydrochloride salt has the X-ray powder diffraction pattern shown in Figure 15; The crystalline form C of the hydrochloride salt has the X-ray powder diffraction pattern shown in Figure 16; The crystalline form A of the p-tosylate has an X-ray powder diffraction pattern as shown in Figure 38, or a DSC pattern as shown in Figure 39, or a TGA pattern as shown in Figure 40; The crystalline form B of the p-tosylate has an X-ray powder diffraction pattern as shown in Figure 41, or a DSC pattern as shown in Figure 42, or a TGA pattern as shown in Figure 43; The crystalline form C of the p-tosylate has an X-ray powder diffraction pattern as shown in Figure 44, or a DSC pattern as shown in Figure 45, or a TGA pattern as shown in Figure 46; The crystalline form D of the p-tosylate has an X-ray powder diffraction pattern as shown in Figure 47, or a DSC pattern as shown in Figure 48, or a TGA pattern as shown in Figure 49; The crystalline form E of the p-tosylate has an X-ray powder diffraction pattern as shown in Figure 50, or a DSC pattern as shown in Figure 51, or a TGA pattern as shown in Figure 52; The crystalline form A of the besylate salt has the X-ray powder diffraction pattern shown in Figure 53; The crystalline form B of the besylate salt has either the X-ray powder diffraction pattern shown in Figure 54, the DSC pattern shown in Figure 55, or the TGA pattern shown in Figure 56; The crystalline form C of the besylate has either the X-ray powder diffraction pattern shown in Figure 57, the DSC pattern shown in Figure 58, or the TGA pattern shown in Figure 59; The crystalline form A of the isethionate salt has the X-ray powder diffraction pattern shown in Figure 60; The crystalline form B of the isethionate salt has an X-ray powder diffraction pattern as shown in Figure 61, or a DSC pattern as shown in Figure 62, or a TGA pattern as shown in Figure 63; The crystalline form A of the 1,5-napadisylate salt has an X-ray powder diffraction pattern as shown in Figure 64; or a DSC pattern as shown in Figure 65; or a TGA pattern as shown in Figure 66, which is the crystalline form of the acidic salt.

8. The crystalline form of the acidic salt of the compound according to any one of claims 1 to 7, wherein the number of acids is 0.2 to 3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3; more preferably 0.5, 1, 2, or 3; and even more preferably 1.

9. The crystalline form of the acidic salt is a hydrate or an anhydrous; if the crystalline form of the acidic salt is a hydrate, the number of water molecules is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, more preferably 0.5, 1, 2, or 3; furthermore, the water molecules in the hydrate are pipe water or crystal water, or a combination thereof, the crystalline form of the acidic salt of the compound according to any one of claims 1 to 8.

10. A method for preparing the crystalline form of an acidic salt of a compound according to any one of claims 1 to 9, comprising the following steps: 1) Weigh an appropriate amount of free base and dissolve the free base in a suitable solvent; 2) Weigh out an appropriate amount of acid and optionally dissolve the acid in an organic solvent; preferably, the amount of acid is 1.0 to 1.5 equivalents; 3) Combine the two solutions and stir for precipitation, or add a poor solvent dropwise and then stir for precipitation; and 4) The obtained system is rapidly centrifuged, or the system is allowed to stand and dried to obtain the target product; (Here, The aforementioned good solvents are acetone, toluene, acetonitrile, methanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl formate, isopropyl acetate, toluene, ethyl acetate, 2-methyltetrahydrofuran, 2-butanone, n-butanol, 1,4-dioxane, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, or tert-butanol; preferably selected from toluene, ethyl acetate, acetone, methanol, or acetonitrile; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably selected from methanol, ethanol, or acetonitrile; the above-mentioned good solvents and organic solutions must be soluble in each other when used; The poor solvent is selected from heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, ethyl acetate, acetone, or acetonitrile; preferably selected from water, methyl tert-butyl ether, or isopropyl ether. Or more specifically, it includes the following steps: 1) Weigh out an appropriate amount of free base and suspend the free base in a poor solvent; 2) Weighing out an appropriate amount of acid and dissolving the acid in an organic solvent; preferably, the amount of acid is 1.0 to 1.5 equivalents; 3) Adding the solution from step 2) to the suspension from step 1) while stirring; and 4) The obtained system is rapidly centrifuged, or the system is allowed to stand and dried to obtain the target product; (In the formula, The poor solvent is selected from ethanol, acetone, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tert-butyl ether, methanol, 1,4-dioxane, 2-butanone, 2-methyltetrahydrofuran, anisole, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol, or 3-pentanone; preferably, selected from ethanol, 2-methyltetrahydrofuran, acetonitrile, methanol, or ethyl acetate; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably selected from methanol, ethanol, or acetonitrile; the above-mentioned good solvents and organic solutions must be soluble in each other when used; The acid is selected from ethylsulfonic acid, methylsulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid, or 1,5-naphthalenedisulfonic acid;) Or more specifically, it includes the following steps: 1) Weigh out an appropriate amount of the compound salt and suspend the salt in a poor solvent; 2) Rapidly centrifuge the suspension from step 1), remove the supernatant, and dry the residual solid to a certain weight to obtain the target product; (In the formula, The poor solvent is selected from methanol, ethanol, dichloromethane, 1,4-dioxane, acetonitrile, dichloromethane, chlorobenzene, chloroform, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tert-butyl ether, n-heptane, tert-butanol, or 2-butanone), and the method.

11. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of an acidic salt of a compound according to any one of claims 1 to 9, and one or more pharmaceutically acceptable carriers or excipients.

12. The use of the crystalline form of an acidic salt of the compound according to any one of claims 1 to 9, and the pharmaceutical composition according to claim 11, in the production of a tyrosine kinase activator that inhibits a protein selected from Ebelson protein, Ebelson-related protein, and the chimeric protein BCR-ABL1.

13. Use in the manufacture of a crystalline form of an acidic salt of a compound according to any one of claims 1 to 9, and a pharmaceutical composition according to claim 11, for the treatment of a hematological disease, wherein preferably the leukemia is chronic myeloid leukemia, acute myeloid leukemia, or acute lymphoblastic leukemia; more preferably the chronic myeloid leukemia is resistant to treatment with one or more standard therapies such as imatinib, nilotinib, and dasatinib, and the acute myeloid leukemia is secondary acute myeloid leukemia that develops as a result of myelodysplastic syndrome or myeloproliferative neoplasm.

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