CN117736176A

CN117736176A - Pharmaceutically acceptable salts of androgen receptor antagonists and polymorphs thereof, methods of preparation and use

Info

Publication number: CN117736176A
Application number: CN202311228759.0A
Authority: CN
Inventors: 童友之
Original assignee: Suzhou Kintor Pharmaceuticals Inc
Current assignee: Suzhou Kintor Pharmaceuticals Inc
Priority date: 2022-09-22
Filing date: 2023-09-22
Publication date: 2024-03-22

Abstract

The invention belongs to the technical field of pharmaceutical crystal chemistry, and particularly relates to three different medicinal salts of androgen receptor antagonists, polymorphs, a preparation method and medical application thereof. In particular, the present invention provides compounds of formula IHydrochloride, mesylate and hydrobromide salts and polymorphs thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the prevention, alleviation and/or treatment of diseases or conditions associated with androgen receptor activity. The medicinal salt and the polymorphic substance thereof have excellent properties in the aspects of solubility, hygroscopicity, particle size, stability and the like, and have better patent medicine property and higher bioavailability.

Description

Pharmaceutically acceptable salts of androgen receptor antagonists and polymorphs thereof, methods of preparation and use

Technical Field

The invention belongs to the technical field of pharmaceutical crystal chemistry, and particularly relates to three pharmaceutically acceptable salts of androgen receptor antagonists, polymorphs, a preparation method and medical application thereof.

Background

Androgen receptor (androgen receptor, AR) is a 110kDa steroid nuclear receptor, one of its key functions being androgen-activated gene transcription. Androgen receptor plays an important role in a variety of androgen-associated diseases or conditions, such as prostate cancer, benign prostatic hyperplasia, androgenic alopecia, muscle loss, acne, and hirsutism.

Chinese patent No. CN102757389B discloses a small molecule AR receptor antagonist (chemical name 4- (4, 4-dimethyl-3- (6-methylpyridin-3-yl) -5-oxo-2-thioimidazolidin-1-yl) -3-fluoro-2-methoxybenzonitrile (shown in formula I), currently in clinical research phase) prepared from intermediates 3a and 6e by microwave assisted cyclization reaction and purified by silica gel column chromatography to give a substantially colloidal or viscous state on a small scale.

The patent application PCT/CN 2022/08274 describes four different anhydrous polymorphs of a compound of formula I, as defined above, which are form A, form B, form C and form D of the free base of the compound of formula I, suitable as potential pharmaceutical forms, especially form B or form D of the free base. The inventors found in the subsequent studies of the anhydrous polymorph of the free base of the compound of formula I that the anhydrous polymorph is poorly soluble in water, e.g. form D of the compound of formula I has a dynamic solubility in water of about 0.0046mg/mL (1 h assay) to about 0.0056mg/mL (24 h assay) at room temperature and normal pressure, and poor water solubility, which is disadvantageous for the preparation of conventional pharmaceutical dosage forms, e.g. oral solid formulations or dosage forms of aqueous systems. The free base form of the drug may also have poor stability, which may cause quality problems during storage of the drug, thereby affecting the effectiveness and safety of the drug.

Therefore, it is necessary to develop a salt form or a polymorph thereof which is stable and has more excellent physicochemical properties with respect to the above-mentioned compound of formula I, however, studies on a pharmaceutically acceptable salt form of the compound of formula I or a polymorph thereof have not been reported in the related literature so far.

Disclosure of Invention

Problems to be solved by the invention

The present invention aims to provide pharmaceutically acceptable salts of the compounds of formula I and polymorphs thereof which have excellent physicochemical properties such as good solubility, hygroscopicity, chemical stability and physical stability, as well as small particle size and which are capable of improving bioavailability. Meanwhile, the invention also aims to provide a preparation method of the medicinal salt or the polymorphic substance thereof and application in the field of medicines.

Solution for solving the problem

In a first aspect, the present invention provides a pharmaceutically acceptable acid addition salt of a compound of formula I, or a hydrate or solvate thereof,

wherein the acid is hydrochloric acid, methanesulfonic acid or hydrobromic acid, i.e. the present invention provides a hydrochloride, methanesulfonate or hydrobromide salt of a compound of formula I or a hydrate or solvate thereof.

Preferably, the molar ratio of the compound of formula I to the acid in the acid addition salt is 1 (0.2-5), more preferably 1 (0.5-3) or 1 (0.5-1.5), even more preferably 1 (0.8-1.2), most preferably 1 (0.8-1), such as 1:0.8, 1:0.9 or 1:1.

In a second aspect, the present invention provides a polymorph of a hydrochloride salt of a compound of formula I as described in the first aspect having a crystalline form a, an X-ray powder diffraction (XRPD) pattern comprising peaks at the following 2Θ values: 15.3 + -0.2 deg., 18.5 + -0.2 deg., and 24.7 + -0.2 deg..

Preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 20.9 + -0.2 deg., 22.0 + -0.2 deg., and 26.5 + -0.2 deg..

More preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 12.3±0.2°, 23.0±0.2° and 25.6±0.2°.

Further, the XRPD pattern of form a comprises peaks at the following 2θ values: 12.3.+ -. 0.2 °, 13.2.+ -. 0.2 °, 15.3.+ -. 0.2 °, 17.9.+ -. 0.2 °, 18.5.+ -. 0.2 °, 20.9.+ -. 0.2 °, 22.0.+ -. 0.2 °, 23.0.+ -. 0.2 °, 24.7.+ -. 0.2 °, 25.6.+ -. 0.2 °, 26.5.+ -. 0.2 ° and 30.6.+ -. 0.2 °.

Further preferably, the XRPD pattern of form a is substantially in accordance with figure 1.

Further, the thermogravimetric analysis (TGA) profile of form a shows a weight loss of about 1.3% at 130±1 ℃.

Preferably, the TGA profile of form a is substantially in accordance with figure 2.

Further, the DSC profile of form a shows endotherm at 174.8±2 ℃ and 204.8±2 ℃.

Preferably, the DSC profile of form a is substantially in accordance with figure 2.

Further, the molar ratio of the compound of formula I to the acid in the polymorph is 1:1.

In a third aspect, the present invention provides a method for preparing the crystal form a in the second aspect, which is selected from the group consisting of an antisolvent addition method, a slow volatilization method, a slow cooling method, a suspension stirring method, a cyclic temperature increasing and decreasing method, a gas-solid permeation method, a gas-liquid diffusion method, a polymer induction method, a grinding method and a reactive crystallization method; the antisolvent addition method, the slow volatilization method, the suspension stirring method, the cyclic temperature increase and decrease method, the gas-solid permeation method, the gas-liquid diffusion method, the high polymer induction method, the grinding method and the reactive crystallization method are preferable.

Preferably, the good solvent used in the anti-solvent addition method is alkyl ketone or alkyl alcohol, more preferably, the alkyl ketone is acetone, and the alkyl alcohol is methanol; the antisolvent used is an alkyl ester, an alkane, an ether or an aromatic hydrocarbon, more preferably, the alkyl ester is isopropyl acetate, the alkane is n-heptane, the ether is 2-methyltetrahydrofuran, and the aromatic hydrocarbon is toluene; further, the good solvent/antisolvent combination used in the antisolvent addition method is acetone/isopropyl acetate, acetone/n-heptane, methanol/isopropyl acetate, methanol/2-methyltetrahydrofuran, or acetone/toluene.

Preferably, the temperature of the anti-solvent addition process is room temperature or 5 ℃ to-20 ℃, preferably room temperature, 5 ℃ or-20 ℃.

Preferably, the solvent used in the slow volatilization method is alkyl ketone or linear or branched C2-C6 nitrile; more preferably, the alkyl ketone is acetone and the linear or branched C2-C6 nitrile is acetonitrile.

Preferably, the temperature of the suspension stirring method is room temperature or 40 ℃ to 60 ℃, preferably room temperature or 50 ℃.

Preferably, the solvent used in the suspension stirring method is alkyl alcohol, alkyl ketone, alkyl ester, ether, aromatic hydrocarbon, alkane, combination of alkyl alcohol and ether, combination of alkyl ketone and alkane, combination of alkyl alcohol and water, combination of haloalkane and alkane, combination of alkyl alcohol and alkane; more preferably, the alkyl alcohol is isopropanol or ethanol, the alkyl ketone is methyl isobutyl ketone or acetone, the alkyl ester is ethyl acetate or isopropyl acetate, the ether is methyl tert-butyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, the aromatic hydrocarbon is toluene, the alkane is n-heptane, the combination of alkyl alcohol and ether is a combination of methanol and methyl tert-butyl ether, the combination of alkyl ketone and alkane is a combination of acetone and n-heptane, the combination of alkyl alcohol and water is a combination of isopropanol and water, the combination of haloalkane and alkane is a combination of dichloromethane and n-heptane, and the combination of alkyl alcohol and alkane is a combination of ethanol and n-heptane.

Preferably, the temperature cycle parameters of the cyclic temperature increasing and decreasing method are as follows: and (3) cycling at 50-5 ℃ and a temperature change rate of 0.1 ℃/min and 2 cycles.

Preferably, the solvent used in the cyclic temperature increasing and reducing method is alkyl alcohol, alkyl ester, ether, aromatic hydrocarbon or a combination of cyclic amide and aromatic hydrocarbon; more preferably, the alkyl alcohol is isopropanol, the alkyl ester is ethyl acetate, the ether is tetrahydrofuran, the aromatic hydrocarbon is toluene, and the combination of the cyclic amide and the aromatic hydrocarbon is a combination of N-methylpyrrolidone and toluene.

Preferably, the solvent used in the gas-solid permeation method is alkyl alcohol, alkyl ester, ether, sulfoxide, water, aromatic hydrocarbon, alkyl ketone, alkane or cyclic amide; preferably, the alkyl alcohol is isopropanol or ethanol, the alkyl ester is ethyl acetate or isopropyl acetate, the ether is tetrahydrofuran, methyl tertiary butyl ether or 2-methyltetrahydrofuran, the sulfoxide is dimethyl sulfoxide, the aromatic hydrocarbon is toluene, the alkyl ketone is methyl isobutyl ketone, the alkane is N-heptane, and the cyclic amide is N-methylpyrrolidone.

Preferably, the good solvent used in the gas-liquid diffusion method is linear or branched C2-C6 nitrile, more preferably acetonitrile; the antisolvent used is an alkyl ketone, more preferably methyl isobutyl ketone.

Preferably, the solvent used in the polymer induction method is an alkyl ketone, more preferably acetone; the polymer used is any one or a mixture of more than one of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose, and more preferably an equal mass mixture of the polymers.

Preferably, the milling process is carried out in the absence of a solvent.

Preferably, the reactive crystallization process uses hydrochloric acid in an amount equimolar to the compound of formula I.

Preferably, the solvent used in the reactive crystallization method is alkyl alcohol, alkyl ketone, alkyl ester or ether; preferably, the alkyl alcohol is ethanol or isopropanol, the alkyl ketone is methyl isobutyl ketone, the alkyl ester is ethyl acetate, and the ether is 2-methyltetrahydrofuran.

In a fourth aspect, the present invention provides a polymorph of a hydrochloride salt of a compound of formula I as described in the first aspect having a form B, the XRPD pattern of which comprises peaks at the following 2Θ values: 12.2±0.2°, 17.4±0.2° and 21.4±0.2°.

Preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 10.7 ± 0.2 °, 13.7 ± 0.2 ° and 23.0 ± 0.2 °.

More preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 15.2 + -0.2 deg., 22.2 + -0.2 deg., and 25.5 + -0.2 deg..

Further, the XRPD pattern of form B comprises peaks at the following 2θ values: 10.7±0.2°, 12.2±0.2°, 13.7±0.2°, 15.2±0.2°, 15.9±0.2°, 17.4±0.2°, 20.4±0.2°, 21.4±0.2°, 22.2±0.2°, 23.0±0.2°, 25.5±0.2° and 27.5±0.2°.

Further preferably, the XRPD pattern of form B is substantially in accordance with figure 5.

Further, the TGA profile of form B shows a weight loss of about 0.6% at 120±1 ℃.

Preferably, the TGA profile of form B is substantially in accordance with figure 6.

Further, the DSC profile of form B shows an endotherm at 205.2±2 ℃.

Preferably, the DSC profile of form B is substantially in accordance with figure 6.

In a fifth aspect, the present invention provides a method for preparing the crystal form B described in the fourth aspect, which is selected from the group consisting of an antisolvent addition method, a slow volatilization method, a slow cooling method, a suspension stirring method, a cyclic temperature increasing and decreasing method, a gas-solid permeation method, a gas-liquid diffusion method, a polymer induction method, a grinding method, and a reactive crystallization method; the antisolvent addition method, the slow volatilization method, the slow cooling method, the suspension stirring method, the gas-liquid diffusion method and the reactive crystallization method are preferable.

Preferably, the good solvent used in the anti-solvent addition method is alkyl alcohol, linear or branched C2-C6 nitrile or halogenated alkane, more preferably, the alkyl alcohol is methanol, the linear or branched C2-C6 nitrile is acetonitrile, and the halogenated alkane is dichloromethane or chloroform; the antisolvent used is an ether, an alkyl ester, or an alkane, more preferably, the ether is methyl tert-butyl ether, the alkyl ester is isopropyl acetate, and the alkane is n-heptane; further, the good solvent/antisolvent combination used in the antisolvent addition method is methanol/methyl tert-butyl ether, acetonitrile/methyl tert-butyl ether, dichloromethane/isopropyl acetate, dichloromethane/n-heptane or chloroform/methyl tert-butyl ether.

Preferably, the temperature of the antisolvent addition method is room temperature.

Preferably, the solvent used in the slow volatilization process is a haloalkane, more preferably, the haloalkane is chloroform.

Preferably, the solvent used in the slow cooling method is an alkyl alcohol or an ether, more preferably, the alkyl alcohol is isopropanol, and the ether is 1, 4-dioxane.

Preferably, the temperature of the suspension stirring process is room temperature or 40 ℃ to 60 ℃, preferably 50 ℃.

Preferably, the solvent used in the suspension stirring method is an ether, more preferably, the ether is 1, 4-dioxane.

Preferably, the good solvent used in the gas-liquid diffusion method is alkyl alcohol, linear or branched C2-C6 nitrile, halogenated alkane or chain amide, more preferably, the alkyl alcohol is methanol, the linear or branched C2-C6 nitrile is acetonitrile, the halogenated alkane is chloroform, and the chain amide is N, N-dimethylformamide; the antisolvent used is an alkyl ester, an ether, an alkane or an aromatic hydrocarbon, more preferably, the alkyl ester is ethyl acetate or isopropyl acetate, the ether is methyl tert-butyl ether, the alkane is n-heptane, and the aromatic hydrocarbon is toluene; further, the good solvent/antisolvent combination used in the gas-liquid diffusion method is methanol/ethyl acetate, methanol/methyl tert-butyl ether, acetonitrile/isopropyl acetate, chloroform/N-heptane, chloroform/toluene or N, N-dimethylacetamide/methyl tert-butyl ether.

Preferably, the reactive crystallization process uses an amount of hydrochloric acid that is equimolar to the compound of formula I.

Preferably, the solvent used in the reactive crystallization method is alkyl ester or ether; preferably, the alkyl ester is isopropyl acetate and the ether is methyl tert-butyl ether or 1, 4-dioxane.

In a sixth aspect, the present invention provides a polymorph of a hydrate of a hydrochloride salt of a compound of formula I as described in the first aspect having a form D, the XRPD pattern of which comprises peaks at the following 2Θ values: 12.5±0.2°, 20.8±0.2° and 25.2±0.2°.

Preferably, the XRPD pattern of form D further comprises peaks at the following 2θ values: 13.0 + -0.2 deg., 10.7 + -0.2 deg., and 21.2 + -0.2 deg..

More preferably, the XRPD pattern of form D further comprises peaks at the following 2θ values: 8.4 + -0.2 deg., 22.6 + -0.2 deg., and 29.8 + -0.2 deg..

Further, the XRPD pattern of form D comprises peaks at the following 2θ values: 8.4.+ -. 0.2 °, 10.7.+ -. 0.2 °, 12.5.+ -. 0.2 °, 13.0.+ -. 0.2 °, 16.4.+ -. 0.2 °, 19.6.+ -. 0.2 °, 20.8.+ -. 0.2 °, 21.2.+ -. 0.2 °, 22.6.+ -. 0.2 °, 25.2.+ -. 0.2 °, 27.0.+ -. 0.2 ° and 29.8.+ -. 0.2 °.

Further preferably, the XRPD pattern of form D is substantially in accordance with figure 7.

Further, the TGA profile of form D shows a weight loss of about 2.6% at 100±1 ℃.

Preferably, the TGA profile of form D is substantially in accordance with figure 8.

Further, the DSC profile of form D shows endotherms at 84.7.+ -. 2 ℃, 144.9.+ -. 2 ℃, 163.7.+ -. 2 ℃ and 196.5.+ -. 2 ℃.

Preferably, the DSC profile of form D is substantially in accordance with figure 8.

Further, the molar ratio of water to the compound of formula I in the polymorph is (0.4-0.8): 1, preferably (0.5-0.7): 1, more preferably 0.6:1.

Further, the molar ratio of the compound of formula I to the acid in the polymorph is 1:0.8.

In a seventh aspect, the present invention provides a method for preparing the crystalline form D described in the sixth aspect, which is selected from the group consisting of an antisolvent addition method, a slow volatilization method, a slow cooling method, a suspension stirring method, a cyclic temperature increasing and decreasing method, a gas-solid permeation method, a gas-liquid diffusion method, a polymer induction method, a grinding method, and a reactive crystallization method; suspension stirring is preferred.

Preferably, the temperature of the suspension stirring method is room temperature.

Preferably, the solvent used in the suspension stirring method is a combination of alkyl alcohol and water, more preferably a combination of isopropyl alcohol and water, and even more preferably isopropyl alcohol/water (0.85:0.15, v/v).

In an eighth aspect, the present invention provides a polymorph of a hydrochloride salt of a compound of formula I as described in the first aspect having form F obtained by nitrogen purging of form D as described in the fifth aspect in a temperature swing XRPD test. The XRPD pattern of form F comprises peaks at the following 2θ values: 21.2±0.2°, 25.1±0.2° and 25.5±0.2°.

Preferably, the XRPD pattern of form F further comprises peaks at the following 2θ values: 12.5±0.2°, 13.1±0.2° and 21.5±0.2°.

More preferably, the XRPD pattern of form F further comprises peaks at the following 2θ values: 10.8 ± 0.2 °, 17.4 ± 0.2 ° and 23.0 ± 0.2 °.

Further, the XRPD pattern of form F comprises peaks at the following 2θ values: 8.4.+ -. 0.2 °, 10.8.+ -. 0.2 °, 12.5.+ -. 0.2 °, 13.1.+ -. 0.2 °, 15.1.+ -. 0.2 °, 17.4.+ -. 0.2 °, 19.4.+ -. 0.2 °, 21.2.+ -. 0.2 °, 21.5.+ -. 0.2 °, 23.0.+ -. 0.2 °, 25.1.+ -. 0.2 ° and 25.5.+ -. 0.2 °.

Further preferably, the XRPD pattern of form F is substantially in accordance with figure 13.

In a ninth aspect, the present invention provides a polymorph of a solvate of a hydrochloride salt of a compound of formula I as described in the first aspect, the solvent being 1, 4-dioxane, the polymorph having form E. The XRPD pattern of form E comprises peaks at the following 2θ values: 10.9 ± 0.2 °, 12.7 ± 0.2 ° and 21.4 ± 0.2 °.

Preferably, the XRPD pattern of form E further comprises peaks at the following 2θ values: 15.8 + -0.2 deg., 19.6 + -0.2 deg., and 23.1 + -0.2 deg..

More preferably, the XRPD pattern of form E further comprises peaks at the following 2θ values: 28.9 ± 0.2 °.

Further, the XRPD pattern of form E comprises peaks at the following 2θ values: 10.9±0.2°, 12.7±0.2°, 15.8±0.2°, 19.6±0.2°, 21.4±0.2°, 23.1±0.2° and 28.9±0.2°.

Further preferably, the XRPD pattern of form E is substantially in accordance with figure 14.

Further, the TGA profile of form E shows a weight loss of about 16.5% at 130±1 ℃.

Preferably, the TGA profile of form E is substantially in accordance with figure 15.

Further, the DSC profile of form E shows endotherms at 122.0±2 ℃ and 204.5±2 ℃.

Preferably, the DSC profile of form E is substantially in accordance with figure 15.

Further, the molar ratio of 1, 4-dioxane to the compound of formula I in the polymorph is (0.6-1.0): 1, preferably (0.7-0.9): 1, more preferably 0.8:1.

In a tenth aspect, the present invention provides a method for preparing the crystal form E in the ninth aspect, which is selected from the group consisting of an antisolvent addition method, a slow volatilization method, a slow cooling method, a suspension stirring method, a cyclic temperature increasing and decreasing method, a gas-solid permeation method, a gas-liquid diffusion method, a polymer induction method, a grinding method, and a reactive crystallization method; preferably, the method is a cyclic temperature raising and lowering method or a gas-solid permeation method.

Preferably, the solvent used in the cyclic temperature increasing and decreasing method is 1, 4-dioxane.

Preferably, the solvent used in the gas-solid permeation method is 1, 4-dioxane.

In an eleventh aspect, the present invention provides a polymorph of a mesylate salt of a compound of formula I as in the first aspect, having a form a whose XRPD pattern comprises peaks at the following 2Θ values: 12.7±0.2°, 14.7±0.2° and 15.6±0.2°.

Preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 11.6 + -0.2 deg., 21.1 + -0.2 deg., and 22.0 + -0.2 deg..

More preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 18.5±0.2°, 19.9±0.2° and 20.2±0.2°.

Further, the XRPD pattern of form a comprises peaks at the following 2θ values: 10.6±0.2°, 11.6±0.2°, 12.7±0.2°, 14.7±0.2°, 15.6±0.2°, 16.6±0.2°, 17.1±0.2°, 18.5±0.2°, 19.9±0.2°, 20.2±0.2°, 21.1±0.2° and 22.0±0.2°.

Further preferably, the XRPD pattern of form a is substantially in accordance with figure 18.

Further, the TGA profile of form a shows a weight loss of about 7.0% at 150±1 ℃.

Preferably, the TGA profile of form a is substantially in accordance with figure 19.

Further, the DSC profile of form a shows an endotherm at 102.9±2 ℃.

Preferably, the DSC profile of form a is substantially in accordance with figure 19.

Further, the molar ratio of the compound of formula I to the acid in the polymorph is 1:0.9.

In a twelfth aspect, the present invention provides a polymorph of a mesylate salt of a compound of formula I as in the first aspect, having a form B whose XRPD pattern comprises peaks at the following 2Θ values: 9.8 + -0.2 deg., 10.7 + -0.2 deg., and 11.4 + -0.2 deg..

Preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 12.6±0.2°, 21.3±0.2° and 25.7±0.2°.

More preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 13.1±0.2°, 14.8±0.2° and 17.8±0.2°.

Further, the XRPD pattern of form B comprises peaks at the following 2θ values: 9.8.+ -. 0.2 °, 10.7.+ -. 0.2 °, 11.4.+ -. 0.2 °, 12.6.+ -. 0.2 °, 13.1.+ -. 0.2 °, 14.8.+ -. 0.2 °, 17.8.+ -. 0.2 °, 20.3.+ -. 0.2 °, 21.3.+ -. 0.2 °, 22.3.+ -. 0.2 °, 24.0.+ -. 0.2 ° and 25.7.+ -. 0.2 °.

Further preferably, the XRPD pattern of form B is substantially in accordance with figure 21.

In a thirteenth aspect, the present invention provides a process for the preparation of form a as described in the eleventh aspect or form B as described in the twelfth aspect, which is a reactive crystallization process.

Preferably, the reactive crystallization process uses methanesulfonic acid in an amount equimolar to the compound of formula I.

Preferably, the solvent used in the reactive crystallization method is an alkyl alcohol, more preferably, the alkyl alcohol is ethanol.

Preferably, when preparing the crystalline form a, the temperature of the reactive crystallization process is from-20 ℃ to room temperature, preferably room temperature, 5 ℃ or-20 ℃; specifically, the preparation method of the crystal form A is any one of the following methods: (1) Equimolar amounts of the compound of formula I and methanesulfonic acid in an alkyl alcohol at 5℃for 3 days and at-20℃for 1 day; (2) Equimolar amounts of the compound of formula I and methanesulfonic acid in an alkyl alcohol are stirred for 5 days at-20 ℃; (3) Equimolar amounts of the compound of formula I and methanesulfonic acid are stirred in the alkyl alcohol at-20℃for 1 day and dried at elevated temperature (preferably 40-60℃such as 50 ℃) for preferably 3 days. Further preferably, the alkyl alcohol is ethanol.

Preferably, when preparing the form B, the temperature of the reactive crystallization process is-20 ℃; specifically, the preparation method of the crystal form B comprises the following steps: equimolar amounts of the compound of formula I and methanesulfonic acid in an alkyl alcohol are stirred for 1 day at-20 ℃. Further preferably, the alkyl alcohol is ethanol.

In a fourteenth aspect, the present invention provides a polymorph of a mesylate salt of a compound of formula I as in the first aspect, having a crystalline form C, the XRPD pattern of which comprises peaks at the following 2Θ values: 12.4±0.2°, 19.3±0.2° and 19.8±0.2°.

Preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 12.8±0.2°, 18.0±0.2° and 26.2±0.2°.

More preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 8.7 + -0.2 deg., 9.5 + -0.2 deg., and 24.9 + -0.2 deg..

Further, the XRPD pattern of form C comprises peaks at the following 2θ values: 8.2.+ -. 0.2 °, 8.7.+ -. 0.2 °, 9.5.+ -. 0.2 °, 11.5.+ -. 0.2 °, 12.4.+ -. 0.2 °, 12.8.+ -. 0.2 °, 16.8.+ -. 0.2 °, 18.0.+ -. 0.2 °, 19.3.+ -. 0.2 °, 19.8.+ -. 0.2 °, 24.9.+ -. 0.2 ° and 26.2.+ -. 0.2 °.

Further preferably, the XRPD pattern of form C is substantially in accordance with figure 22.

Further, the TGA profile of form C shows a weight loss of about 0.8% at 150±1 ℃.

Preferably, the TGA profile of form C is substantially in accordance with figure 23.

Further, the DSC profile of form C shows an endotherm at 186.3±2 ℃.

Preferably, the DSC profile of form C is substantially in accordance with figure 23.

The preparation method of the crystal form C is any one of the following methods: (1) Equimolar amounts of the compound of formula I and methanesulfonic acid in an alkyl alcohol, preferably ethanol, are stirred for 1 day at-20℃and dried at elevated temperature, preferably 40-60℃such as 50℃for preferably 2 hours; (2) The crystal form A of methanesulfonate is added with crystal form C of methanesulfonate in a mixed solvent of alkyl alcohol and alkane (preferably a mixed solvent of isopropyl alcohol and n-heptane, more preferably an equal volume of mixed solvent of isopropyl alcohol and n-heptane) at 50 ℃, stirred in suspension for 1 day, and dried in vacuum (preferably for 4 hours) at 40-60 ℃ (such as 50 ℃).

In a fifteenth aspect, the present invention provides a polymorph of a mesylate salt of a compound of formula I as in the first aspect, having a form D, the XRPD pattern of which comprises peaks at the following 2Θ values: 9.5 + -0.2 deg., 12.0 + -0.2 deg., and 19.9 + -0.2 deg..

Preferably, the XRPD pattern of form D further comprises peaks at the following 2θ values: 8.9 + -0.2 deg., 15.8 + -0.2 deg., and 20.3 + -0.2 deg..

More preferably, the XRPD pattern of form D further comprises peaks at the following 2θ values: 18.0±0.2°, 26.1±0.2° and 28.9±0.2°.

More preferably, the XRPD pattern of form D comprises peaks at the following 2θ values: 8.9.+ -. 0.2 °, 9.5.+ -. 0.2 °, 12.0.+ -. 0.2 °, 15.8.+ -. 0.2 °, 18.0.+ -. 0.2 °, 19.9.+ -. 0.2 °, 20.3.+ -. 0.2 °, 26.1.+ -. 0.2 ° and 28.9.+ -. 0.2 °.

Further preferably, the XRPD pattern of form D is substantially in accordance with figure 26.

Further, the TGA profile of form D shows a weight loss of about 7.1% at 150±1 ℃.

Preferably, the TGA profile of form D is substantially in accordance with figure 27.

Further, the DSC profile of form D shows endotherms at 106.0.+ -. 2 ℃, 117.7.+ -. 2 ℃ and 185.6.+ -. 2 ℃.

Preferably, the DSC profile of form D is substantially in accordance with figure 27.

The preparation method of the crystal form D comprises the following steps: suspending and stirring the mesylate crystal form A in a solvent to obtain the crystal form D. Preferably, the solvent is isopropanol, or a mixed solvent of isopropanol and n-heptane (such as a mixed solvent of isopropanol and n-heptane in a volume ratio of 1:1).

In a sixteenth aspect, the present invention provides a polymorph of a hydrobromide salt of a compound of formula I as described in the first aspect, having a form a whose XRPD pattern comprises peaks at the following 2Θ values: 12.0±0.2°, 17.7±0.2° and 20.9±0.2°.

Preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 10.4 ± 0.2 °, 13.6 ± 0.2 ° and 22.6 ± 0.2 °.

More preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 15.5 + -0.2 DEG and 23.2 + -0.2 deg.

Further, the XRPD pattern of form a comprises peaks at the following 2θ values: 10.4±0.2°, 12.0±0.2°, 13.6±0.2°, 15.5±0.2°, 17.7±0.2°, 20.9±0.2°, 22.6±0.2° and 23.2±0.2°.

Further preferably, the XRPD pattern of form a is substantially in accordance with figure 28.

Further, the TGA profile of form a shows a weight loss of about 7.4% at 150±1 ℃.

Preferably, the TGA profile of form a is substantially in accordance with figure 31.

Further, the DSC profile of form a shows an endotherm at 201.1±2 ℃.

Preferably, the DSC profile of form a is substantially in accordance with figure 31.

In a seventeenth aspect, the present invention provides a polymorph of a hydrobromide salt of a compound of formula I as described in the first aspect, having a form B whose XRPD pattern comprises peaks at the following 2Θ values: 22.3 + -0.2 deg., 23.9 + -0.2 deg., and 30.5 + -0.2 deg..

Preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 15.1 + -0.2 DEG, 20.1 + -0.2 DEG and 24.4 + -0.2 deg.

More preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 11.6 + -0.2 deg., 21.8 + -0.2 deg., and 29.8 + -0.2 deg..

Further, the XRPD pattern of form B comprises peaks at the following 2θ values: 11.6.+ -. 0.2 °, 14.5.+ -. 0.2 °, 15.1.+ -. 0.2 °, 15.7.+ -. 0.2 °, 16.4.+ -. 0.2 °, 20.1.+ -. 0.2 °, 21.8.+ -. 0.2 °, 22.3.+ -. 0.2 °, 23.9.+ -. 0.2 °, 24.4.+ -. 0.2 °, 29.8.+ -. 0.2 ° and 30.5.+ -. 0.2 °.

Further preferably, the XRPD pattern of form B is substantially in accordance with figure 29.

Further, the TGA profile of form B shows a weight loss of about 1.3% at 150±1 ℃.

Preferably, the TGA profile of form B is substantially in accordance with figure 32.

Further, the DSC profile of form B shows an endotherm at 196.4±2 ℃.

Preferably, the DSC profile of form B is substantially in accordance with figure 32.

In an eighteenth aspect, the present invention provides a polymorph of a hydrobromide salt of a compound of formula I as described in the first aspect, having a form C whose XRPD pattern comprises peaks at the following 2Θ values: 12.6 + -0.2 deg., 20.9 + -0.2 deg., and 25.6 + -0.2 deg..

Preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 13.1±0.2°, 19.8±0.2° and 25.2±0.2°.

More preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 10.6 ± 0.2 °, 17.6 ± 0.2 ° and 29.4 ± 0.2 °.

Further, the XRPD pattern of form C comprises peaks at the following 2θ values: 8.5.+ -. 0.2 °, 10.6.+ -. 0.2 °, 12.6.+ -. 0.2 °, 13.1.+ -. 0.2 °, 17.6.+ -. 0.2 °, 19.5.+ -. 0.2 °, 19.8.+ -. 0.2 °, 20.9.+ -. 0.2 °, 25.2.+ -. 0.2 °, 25.6.+ -. 0.2 °, 26.0.+ -. 0.2 ° and 29.4.+ -. 0.2 °.

Further preferably, the XRPD pattern of form C is substantially in accordance with figure 30.

Further, the TGA profile of form C shows a weight loss of about 1.2% at 150±1 ℃.

Preferably, the TGA profile of form C is substantially in accordance with figure 33.

Further, the DSC profile of form C shows an endotherm at 200.5±2 ℃.

Preferably, the DSC profile of form C is substantially in accordance with figure 33.

In a nineteenth aspect, the present invention provides a process for the preparation of crystalline form a as defined in the sixteenth aspect, crystalline form B as defined in the seventeenth aspect or crystalline form C as defined in the eighteenth aspect, which is a reactive crystallization process.

Preferably, the reactive crystallization process uses hydrobromic acid in an amount equimolar to the compound of formula I.

Preferably, the temperature of the reactive crystallization process is room temperature.

Preferably, the solvent used in the reactive crystallization method is an alkyl alcohol, alkyl ester or ether.

Preferably, the solvent used in preparing the above crystal form a by a reactive crystallization method is an alkyl alcohol, more preferably, the alkyl alcohol is ethanol.

Preferably, the solvent used in preparing the above crystal form B by a reactive crystallization method is an alkyl ester, more preferably, the alkyl ester is isopropyl acetate.

Preferably, the solvent used in preparing the above-mentioned form C by a reactive crystallization method is an ether, more preferably, the ether is methyl tert-butyl ether.

In a twentieth aspect, the present invention provides a polymorph of a hydrochloride salt of a compound of formula I (e.g. hydrochloride form a), a polymorph of a mesylate salt (e.g. mesylate form C) or a polymorph of a hydrobromide salt (e.g. hydrobromide form C) having a particle size of 5 to 100 μm, more preferably 10 to 90 μm, still more preferably 10 to 50 μm.

In a twenty-first aspect, the present invention also provides a polymorph of a compound of formula I having a crystalline form E, an XRPD pattern comprising peaks at the following 2Θ values: 9.5 + -0.2 deg., 10.7 + -0.2 deg., and 14.3 + -0.2 deg..

Preferably, the XRPD pattern of form E further comprises peaks at the following 2θ values: 4.8 + -0.2 deg., 12.9 + -0.2 deg., and 19.0 + -0.2 deg..

More preferably, the XRPD pattern of form E further comprises peaks at the following 2θ values: 17.2 + -0.2 deg., 21.8 + -0.2 deg., and 28.8 + -0.2 deg..

Further, the XRPD pattern of form E comprises peaks at the following 2θ values: 4.8±0.2°, 9.5±0.2°, 10.7±0.2°, 12.9±0.2°, 14.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.0±0.2°, 20.8±0.2°, 21.8±0.2°, 24.0±0.2° and 28.8±0.2°.

Further preferably, the XRPD pattern of form E is substantially in accordance with figure 34.

The preparation method of the crystal form E can be a suspension stirring method.

Preferably, the solvent used in the suspension stirring method is an alkyl ester, more preferably isopropyl acetate.

In a twenty-second aspect, the present invention also provides a pharmaceutical composition comprising (preferably a prophylactically, palliatively and/or therapeutically effective amount of) one or more of the acid addition salts of the compounds of formula I described above or a hydrate or solvate thereof or a polymorph thereof.

Preferably, the pharmaceutical composition further comprises one or more therapeutically active co-agents selected from one or more of barbitinib (barbitinib), jactinib (Jaktinib), ritlecritinib (PF-06651600), erasimod (Zehnder name ANB 030), daxdilimab (HZN-7734), SHR0302, minoxidil (minoxidil), deuterated ruxotinib (deuterated ruxolitinib, CTP-543), botulinum toxin (botulium toxin), clavazone (clascoterketone, CB-03-01), finasteride (finasteride), dutasteride (Ddutasteride), and latanoprost (latanoprost).

Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Preferably, the particle size of the polymorph is from 5 to 100 μm (preferably from 10 to 90 μm, more preferably from 10 to 50 μm).

Preferably, in the pharmaceutical composition, the weight percentage of the acid addition salt of the above-mentioned compound of formula I or a hydrate or solvate thereof or a polymorph thereof is 0.1% -99.0%, for example may be 0.1% -80%, 1% -80%, 10.0% -80.0%, 20% -80%, 25% -70%, 25% -65%, 25% -60%, 25% -55%, 25% -50%, 30% -50%, 35% -50% or 40% -50%.

In a twenty-third aspect, the present invention provides the pharmaceutical use of an acid addition salt of a compound of formula I as defined above, or a hydrate or solvate thereof, a polymorph as defined above, or a pharmaceutical composition as defined above.

First, the present invention provides the use of an acid addition salt as described above or a hydrate or solvate thereof, a polymorph as described above or a pharmaceutical composition as described above in the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease or condition associated with androgen receptor activity.

Further, the present invention provides the above acid addition salt or a hydrate or solvate thereof, the above polymorph or the above pharmaceutical composition, which can be used for preventing, alleviating and/or treating diseases or disorders related to androgen receptor activity.

Again, the present invention provides a method for preventing, alleviating and/or treating a disease or condition associated with androgen receptor activity, comprising the steps of: a prophylactically, palliatively and/or therapeutically effective amount of the above acid addition salt or a hydrate or solvate thereof, the above polymorph or the above pharmaceutical composition is administered to a subject in need thereof.

Wherein the androgen receptor activity associated disease or disorder is selected from the group consisting of prostate cancer, benign prostatic hyperplasia, acne, hirsutism, excessive sebum, and androgenic alopecia.

ADVANTAGEOUS EFFECTS OF INVENTION

The present invention surprisingly found that the compound of formula I can only form salts with hydrochloric acid, methanesulfonic acid and hydrobromic acid in a 51 salt form screening assay consisting of 17 acids, 3 solvent systems, thus providing three pharmaceutically acceptable salts of the compound of formula I as well as polymorphs thereof, in particular providing a plurality of different hydrochloride polymorphs. The pharmaceutically acceptable salts or polymorphs thereof of the present invention have improved solubility compared to the free base form, particularly greatly improved solubility in water. Meanwhile, the medicinal salt or the polymorphic substance thereof has less moisture absorption in a DVS test, shows that the particle size of a sample is small under a polarizing microscope, and has no obvious change in crystal form and chemical purity after being placed for one week under the conditions of 40 ℃/75%RH and 25 ℃/60%RH. The results show that the medicinal salt or the polymorphic substance thereof has good physicochemical property and excellent physical and chemical stability, and has better medicinal property and higher bioavailability.

Drawings

Fig. 1 is an XRPD pattern of a polymorph of the hydrochloride salt of a compound of formula I having form a.

FIG. 2 is a TGA/DSC spectrum of a polymorph of the hydrochloride salt of the compound of formula I having form A.

FIG. 3 is a polymorph of a hydrochloride salt of a compound of formula I having form A ¹ H NMR spectrum.

Fig. 4 is an XRPD pattern before and after heating of a polymorph with form a of the compound of formula I hydrochloride.

Fig. 5 is an XRPD pattern of a polymorph of the hydrochloride salt of the compound of formula I having form B.

FIG. 6 is a TGA/DSC spectrum of a polymorph of the hydrochloride salt of the compound of formula I having form B.

Fig. 7 is an XRPD pattern of polymorphs of form D of the hydrochloride hydrate of the compound of formula I.

FIG. 8 is a TGA/DSC spectrum of a polymorph of the hydrochloride hydrate of the compound of formula I having form D.

FIG. 9 is a polymorph of a hydrochloride hydrate of a compound of formula I having form D ¹ H NMR spectrum.

Fig. 10 is an XRPD pattern before and after heating of a polymorph with form D of the hydrochloride hydrate of the compound of formula I.

Fig. 11 is a temperature swing XRPD stack (1) of a polymorph with form D of the hydrochloride hydrate of the compound of formula I.

Fig. 12 is a temperature swing XRPD stack (2) of a polymorph with form D of the hydrochloride hydrate of the compound of formula I.

Fig. 13 is an XRPD pattern of a polymorph of the hydrochloride salt of the compound of formula I having form F.

FIG. 14 is an XRPD pattern for a polymorph of form E of the hydrochloride salt of the compound of formula I, the solvate of 1, 4-dioxane.

FIG. 15 is a TGA/DSC spectrum of a polymorph of form E of the hydrochloride 1, 4-dioxane solvate of a compound of formula I.

FIG. 16 is a polymorph of form E of a hydrochloride salt of a compound of formula I, 1, 4-dioxane solvate ¹ H NMR spectrum.

FIG. 17 is an XRPD pattern for a polymorph of the hydrochloride salt of the compound of formula I, 1, 4-dioxane solvate with form E before and after heating.

Fig. 18 is an XRPD pattern of a polymorph of the mesylate salt of compound I having form a.

FIG. 19 is a TGA/DSC spectrum of a polymorph of the mesylate salt of the compound of formula I having form A.

FIG. 20 is a polymorph of a mesylate salt of a compound of formula I having form A ¹ H NMR spectrum.

Fig. 21 is an XRPD pattern of a polymorph of the mesylate of compound I having form B.

Fig. 22 is an XRPD pattern of polymorphs of the mesylate salt of compound of formula I having form C.

FIG. 23 is a TGA/DSC spectrum of a polymorph of a mesylate salt of the compound of formula I having form C.

FIG. 24 is a polymorph of a mesylate salt of a compound of formula I having form C ¹ H NMR spectrum.

Fig. 25 is an XRPD pattern of polymorphs of the mesylate salt of formula I having form a after suspension stirring in different solvents.

Fig. 26 is an XRPD pattern of a polymorph of the mesylate of compound I having form D.

FIG. 27 is a TGA/DSC spectrum of a polymorph of a mesylate salt of the compound of formula I having form D.

Fig. 28 is an XRPD pattern of polymorphs of the hydrobromide salt of compound of formula I having form a.

Fig. 29 is an XRPD pattern of polymorphs of the hydrobromide salt of compound of formula I with form B.

Fig. 30 is an XRPD pattern of a polymorph of the hydrobromide salt of compound of formula I having form C.

Figure 31 is a TGA/DSC profile of a polymorph of the hydrobromide salt of a compound of formula I having form a.

Figure 32 is a TGA/DSC profile of a polymorph of the hydrobromide salt of a compound of formula I having form B.

Figure 33 is a TGA/DSC profile of a polymorph of the hydrobromide salt of a compound of formula I having form C.

Fig. 34 is an XRPD pattern of a polymorph of a compound of formula I having form E.

FIG. 35 is an XRPD overlay of the suspension competition test sample of Experimental example 1 (1).

Fig. 36 is an XRPD overlay of the suspension competition test sample of experimental example 1 (2).

FIG. 37 is an XRPD pattern (3) of the suspension competition test sample of Experimental example 1.

Fig. 38 is a graph of the interconversion relationship of polymorphs of the hydrochloride salt of the compound of formula I.

Fig. 39 is a DVS plot of a polymorph of the hydrochloride salt of the compound of formula I having form a.

Fig. 40 is an XRPD pattern of a polymorph with form a of the compound of formula I hydrochloride before and after DVS testing.

Fig. 41 is a DVS plot of a polymorph of the mesylate of compound I having form C.

Fig. 42 is a DVS plot of a polymorph of the hydrobromide salt of a compound of formula I having form C.

Fig. 43 is an XRPD pattern of a polymorph of a compound of formula I hydrobromide having form C before and after DVS testing.

Figure 44 is a DVS plot of a polymorph of a compound of formula I having form D.

Fig. 45 is an XRPD pattern of polymorphs of compound of formula I having form D before and after DVS testing.

Figure 46 is a PLM plot of the polymorph of form a of the hydrochloride salt of the compound of formula I.

Fig. 47 is a PLM plot of a polymorph of the mesylate of formula I having form C.

Fig. 48 is a PLM plot of a polymorph of the hydrobromide salt of a compound of formula I having form C.

Figure 49 is a PLM plot of a polymorph of a compound of formula I having form D.

Figure 50 is a graph of dynamic solubility curves of four polymorphs in water.

Figure 51 is a graph of dynamic solubility curves of four polymorphs in ethanol.

Fig. 52 is an XRPD pattern of a polymorph with form a of a compound of formula I hydrochloride salt of a sample during stability testing.

Figure 53 is an XRPD pattern of a polymorph of a mesylate salt of compound of formula I having form C as a sample during stability testing.

Fig. 54 is an XRPD pattern of a polymorph of a compound of formula I hydrobromide having form C as a sample during stability testing.

Fig. 55 is an XRPD pattern of a polymorph of a compound of formula I having form D as a sample during stability testing.

Detailed Description

Unless otherwise defined, scientific and technical terms herein have the meanings commonly understood by one of ordinary skill in the art.

Unless otherwise indicated, the singular forms herein, such as "a," "an," and "the," encompass the plural referents thereof unless the context clearly dictates otherwise. For example, when referring to "a" form or polymorph, one or more different forms or polymorphs are contemplated, and when referring to "the" method, equivalent steps and methods known to those of ordinary skill in the art are contemplated.

For the crystalline forms herein, only the characteristic peaks (i.e., the most characteristic, significant, unique and/or reproducible diffraction peaks) in the XRPD patterns are summarized, while other peaks may be obtained from the patterns by conventional methods. The characteristic peaks described above may be repeated within the margin of error (error range of + -0.2 deg.).

Unless otherwise indicated, the terms "comprises" and variations such as "comprising" and "includes" appearing herein mean that the collection encompasses not only the explicitly disclosed integer or integers, steps or combination thereof, but also does not exclude any other integer or step or combination thereof. Meanwhile, the term "comprising" appearing herein may be replaced by the term "containing", "including" or "having" in certain cases.

The term "effective amount" as used herein, unless otherwise indicated, means an amount of a pharmaceutically active ingredient sufficient to affect a disease or condition after administration to an individual/subject/patient in order to prevent, alleviate and/or treat the disease or condition. The "effective amount" may vary depending on factors such as the pharmaceutically active ingredient, the symptoms or severity of the disease or condition, the individual/subject/patient's personal condition (such as age, sex, weight, etc.), and the like.

Unless otherwise indicated, the term "about" as used herein means within + -10% of the specified value, e.g.: "about 1.3% weight loss" means "1.3% ± 1.3% x 10%", i.e. "1.17% -1.14%".

Unless otherwise indicated, the term "substantially in accordance with a drawing" as used herein with respect to an XRPD pattern means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the XRPD pattern of a polymorph are shown in the given XRPD pattern. Meanwhile, the variation of the representative peak position (2θ) and the relative peak intensity is taken into consideration. Peak positions will show some variation from instrument to instrument and sample to sample, typically up to 0.1 ° to 0.2 °. In addition, the relative peak intensities may also vary due to differences between instruments as well as the degree of crystallinity, preferred orientation, samples prepared, and other factors known to those skilled in the art.

The term "substantially in accordance with a drawing" as used herein with respect to a DSC or TGA profile is also intended to encompass variations known to those skilled in the art relating to such analytical techniques, unless otherwise indicated. For clearly defined peaks in the DSC pattern, the variation is typically up to + -0.2deg.C, even larger for broad peaks (up to + -1deg.C, or up to + -5deg.C). For mass loss in TGA profile, there is a slight difference in mass loss detected from instrument to instrument, typically up to ±1%, or up to ±2%, depending on many factors such as sample preparation and instrument.

The term "room temperature" as used herein refers to 23.+ -. 7 ℃ unless otherwise indicated.

Unless otherwise indicated, pharmaceutical compositions comprising polymorphs of the present invention may be administered to an individual/subject/patient in need thereof by oral, inhalation, rectal, parenteral or topical routes. For oral administration, the pharmaceutical composition may be a solid formulation (such as a tablet, powder, granule, capsule, etc.) or a liquid formulation (such as a water-based or oil-based suspension or other liquid formulation, such as a syrup, solution, etc.). For parenteral administration, the pharmaceutical compositions may be in the form of solutions, suspensions, lyophilized powders, and the like. The pharmaceutical composition may be a single unit with a precise dosage. In addition, the pharmaceutical composition may further comprise additional pharmaceutically active ingredients.

Pharmaceutically acceptable salts of compounds of formula I

The present invention provides pharmaceutically acceptable acid addition salts of compounds of formula I or a hydrate or solvate thereof,

wherein the acid is hydrochloric acid, methanesulfonic acid or hydrobromic acid, i.e., the acid addition salt is hydrochloride, methanesulfonate or hydrobromide.

In some embodiments, the acid addition salt has a molar ratio of the compound of formula I to the acid of 1 (0.2-5), preferably 1 (0.5-3) or 1 (0.5-1.5), more preferably 1 (0.8-1.2), even more preferably 1 (0.8-1), such as 1:0.8, 1:0.9 or 1:1.

Polymorphs of the hydrochloride salt of a compound of formula I

The present invention provides five polymorphs of the hydrochloride salt of the compound of formula I, form a, form B, form D, form E and form F, respectively. Wherein, form a and form B are anhydrous polymorphs, form D is a polymorph of hydrochloride hydrate, form F is an anhydrous polymorph obtained by nitrogen purging or heating dehydration of form D, form F is a polymorph of hydrochloride 1, 4-dioxane solvate, form E is a polymorph of hydrochloride, and form E is converted into form B after heating removal of solvent, and the conversion relationship of the five forms is shown in fig. 38.

The XRPD pattern of form a is substantially in accordance with figure 1. From its XRPD pattern, form a was found to have diffraction peaks with relatively high intensities at the following 2θ values: 15.3 + -0.2 deg., 18.5 + -0.2 deg., and 24.7 + -0.2 deg..

In addition, form a also has a diffraction peak with moderate relative intensity at the following 2θ values: 20.9 + -0.2 deg., 22.0 + -0.2 deg., and 26.5 + -0.2 deg..

In addition, form a also has diffraction peaks with relatively low intensities at the following 2θ values: 12.3±0.2°, 23.0±0.2° and 25.6±0.2°.

Further, form a has diffraction peaks at the following 2θ values: 12.3.+ -. 0.2 °, 13.2.+ -. 0.2 °, 15.3.+ -. 0.2 °, 17.9.+ -. 0.2 °, 18.5.+ -. 0.2 °, 20.9.+ -. 0.2 °, 22.0.+ -. 0.2 °, 23.0.+ -. 0.2 °, 24.7.+ -. 0.2 °, 25.6.+ -. 0.2 °, 26.5.+ -. 0.2 ° and 30.6.+ -. 0.2 °.

The XRPD pattern of form B is substantially in accordance with figure 5. From its XRPD pattern, form B was found to have diffraction peaks with relatively high intensities at the following 2θ values: 12.2±0.2°, 17.4±0.2° and 21.4±0.2°.

In addition, form B also has a diffraction peak with moderate relative intensity at the following 2θ values: 10.7 ± 0.2 °, 13.7 ± 0.2 ° and 23.0 ± 0.2 °.

In addition, form B also has diffraction peaks with relatively low intensities at the following 2θ values: 15.2 + -0.2 deg., 22.2 + -0.2 deg., and 25.5 + -0.2 deg..

Further, form B has diffraction peaks at the following 2θ values: 10.7±0.2°, 12.2±0.2°, 13.7±0.2°, 15.2±0.2°, 15.9±0.2°, 17.4±0.2°, 20.4±0.2°, 21.4±0.2°, 22.2±0.2°, 23.0±0.2°, 25.5±0.2° and 27.5±0.2°.

The XRPD pattern of form D is substantially in accordance with figure 7. From its XRPD pattern, form D was found to have diffraction peaks with relatively high intensities at the following 2θ values: 12.5±0.2°, 20.8±0.2° and 25.2±0.2°.

In addition, form D also has a diffraction peak with moderate relative intensity at the following 2θ values: 13.0 + -0.2 deg., 10.7 + -0.2 deg., and 21.2 + -0.2 deg..

In addition, form D also has diffraction peaks with relatively low intensities at the following 2θ values: 8.4 + -0.2 deg., 22.6 + -0.2 deg., and 29.8 + -0.2 deg..

Further, form D has diffraction peaks at the following 2θ values: 8.4.+ -. 0.2 °, 10.7.+ -. 0.2 °, 12.5.+ -. 0.2 °, 13.0.+ -. 0.2 °, 16.4.+ -. 0.2 °, 19.6.+ -. 0.2 °, 20.8.+ -. 0.2 °, 21.2.+ -. 0.2 °, 22.6.+ -. 0.2 °, 25.2.+ -. 0.2 °, 27.0.+ -. 0.2 ° and 29.8.+ -. 0.2 °.

The molar ratio of bound water to compound of formula I in the polymorph having form D is (0.4-0.8): 1, for example (0.5-0.7): 1 or 0.6:1.

The XRPD pattern of form F is substantially in accordance with figure 13. From its XRPD pattern, form F was found to have diffraction peaks with relatively high intensities at the following 2θ values: 21.2±0.2°, 25.1±0.2° and 25.5±0.2°.

In addition, form F also has a diffraction peak with moderate relative intensity at the following 2θ values: 12.5±0.2°, 13.1±0.2° and 21.5±0.2°.

In addition, form F also has diffraction peaks with relatively low intensities at the following 2θ values: 10.8 ± 0.2 °, 17.4 ± 0.2 ° and 23.0 ± 0.2 °.

Further, form F has diffraction peaks at the following 2θ values: 8.4.+ -. 0.2 °, 10.8.+ -. 0.2 °, 12.5.+ -. 0.2 °, 13.1.+ -. 0.2 °, 15.1.+ -. 0.2 °, 17.4.+ -. 0.2 °, 19.4.+ -. 0.2 °, 21.2.+ -. 0.2 °, 21.5.+ -. 0.2 °, 23.0.+ -. 0.2 °, 25.1.+ -. 0.2 ° and 25.5.+ -. 0.2 °.

The XRPD pattern of form E is substantially in accordance with figure 14. From its XRPD pattern, form E was found to have diffraction peaks with relatively high intensities at the following 2θ values: 10.9 ± 0.2 °, 12.7 ± 0.2 ° and 21.4 ± 0.2 °.

In addition, form E also has a diffraction peak with moderate relative intensity at the following 2θ values: 15.8 + -0.2 deg., 19.6 + -0.2 deg., and 23.1 + -0.2 deg..

In addition, form E also has diffraction peaks with relatively low intensities at the following 2θ values: 28.9 ± 0.2 °.

Further, form E has diffraction peaks at the following 2θ values: 10.9±0.2°, 12.7±0.2°, 15.8±0.2°, 19.6±0.2°, 21.4±0.2°, 23.1±0.2° and 28.9±0.2°.

The polymorph having crystalline form E of 1, 4-dioxane and (0.6-1.0) of a compound of formula I: 1, preferably (0.7-0.9): 1, more preferably 0.8:1.

Polymorphs of the mesylate salt of a compound of formula I

The present invention provides four polymorphs of the mesylate salt of the compound of formula I, form a, form B, form C and form D, respectively. Wherein, the crystal form D is obtained by suspending and stirring the crystal form A in a solvent (such as a mixed solvent of isopropanol, isopropanol and n-heptane).

The XRPD pattern of form a is substantially in accordance with figure 18. From its XRPD pattern, form a was found to have diffraction peaks with relatively high intensities at the following 2θ values: 12.7±0.2°, 14.7±0.2° and 15.6±0.2°.

In addition, form a also has a diffraction peak with moderate relative intensity at the following 2θ values: 11.6 + -0.2 deg., 21.1 + -0.2 deg., and 22.0 + -0.2 deg..

In addition, form a also has diffraction peaks with relatively low intensities at the following 2θ values: 18.5±0.2°, 19.9±0.2° and 20.2±0.2°.

Further, form a has diffraction peaks at the following 2θ values: 10.6±0.2°, 11.6±0.2°, 12.7±0.2°, 14.7±0.2°, 15.6±0.2°, 16.6±0.2°, 17.1±0.2°, 18.5±0.2°, 19.9±0.2°, 20.2±0.2°, 21.1±0.2° and 22.0±0.2°.

The XRPD pattern of form B is substantially in accordance with figure 21. From its XRPD pattern, form B was found to have diffraction peaks with relatively high intensities at the following 2θ values: 9.8 + -0.2 deg., 10.7 + -0.2 deg., and 11.4 + -0.2 deg..

In addition, form B also has a diffraction peak with moderate relative intensity at the following 2θ values: 12.6±0.2°, 21.3±0.2° and 25.7±0.2°.

In addition, form B also has diffraction peaks with relatively low intensities at the following 2θ values: 13.1±0.2°, 14.8±0.2° and 17.8±0.2°.

Further, form B has diffraction peaks at the following 2θ values: 9.8.+ -. 0.2 °, 10.7.+ -. 0.2 °, 11.4.+ -. 0.2 °, 12.6.+ -. 0.2 °, 13.1.+ -. 0.2 °, 14.8.+ -. 0.2 °, 17.8.+ -. 0.2 °, 20.3.+ -. 0.2 °, 21.3.+ -. 0.2 °, 22.3.+ -. 0.2 °, 24.0.+ -. 0.2 ° and 25.7.+ -. 0.2 °.

The XRPD pattern of form C is substantially in accordance with figure 22. From its XRPD pattern, form C was found to have diffraction peaks with relatively high intensities at the following 2θ values: 12.4±0.2°, 19.3±0.2° and 19.8±0.2°.

In addition, form C also has a diffraction peak with moderate relative intensity at the following 2θ values: 12.8±0.2°, 18.0±0.2° and 26.2±0.2°.

In addition, form C also has diffraction peaks with relatively low intensities at the following 2θ values: 8.7 + -0.2 deg., 9.5 + -0.2 deg., and 24.9 + -0.2 deg..

Further, form C has diffraction peaks at the following 2θ values: 8.2.+ -. 0.2 °, 8.7.+ -. 0.2 °, 9.5.+ -. 0.2 °, 11.5.+ -. 0.2 °, 12.4.+ -. 0.2 °, 12.8.+ -. 0.2 °, 16.8.+ -. 0.2 °, 18.0.+ -. 0.2 °, 19.3.+ -. 0.2 °, 19.8.+ -. 0.2 °, 24.9.+ -. 0.2 ° and 26.2.+ -. 0.2 °.

The XRPD pattern of form D is substantially in accordance with figure 26. From its XRPD pattern, form D was found to have diffraction peaks with relatively high intensities at the following 2θ values: 9.5 + -0.2 deg., 12.0 + -0.2 deg., and 19.9 + -0.2 deg..

In addition, form D also has a diffraction peak with moderate relative intensity at the following 2θ values: 8.9 + -0.2 deg., 15.8 + -0.2 deg., and 20.3 + -0.2 deg..

In addition, form D also has diffraction peaks with relatively low intensities at the following 2θ values: 18.0±0.2°, 26.1±0.2° and 28.9±0.2°.

Further, form D has diffraction peaks at the following 2θ values: 8.9.+ -. 0.2 °, 9.5.+ -. 0.2 °, 12.0.+ -. 0.2 °, 15.8.+ -. 0.2 °, 18.0.+ -. 0.2 °, 19.9.+ -. 0.2 °, 20.3.+ -. 0.2 °, 26.1.+ -. 0.2 ° and 28.9.+ -. 0.2 °.

Polymorphs of the hydrobromide salt of a compound of formula I

The present invention provides three polymorphs of the hydrobromide salt of a compound of formula I, form a, form B and form C, respectively.

The XRPD pattern of form a is substantially in accordance with figure 28. From its XRPD pattern, form a was found to have diffraction peaks with relatively high intensities at the following 2θ values: 12.0±0.2°, 17.7±0.2° and 20.9±0.2°.

In addition, form a also has a diffraction peak with moderate relative intensity at the following 2θ values: 10.4 ± 0.2 °, 13.6 ± 0.2 ° and 22.6 ± 0.2 °.

In addition, form a also has diffraction peaks with relatively low intensities at the following 2θ values: 15.5 + -0.2 DEG and 23.2 + -0.2 deg.

Further, form a has diffraction peaks at the following 2θ values: 10.4±0.2°, 12.0±0.2°, 13.6±0.2°, 15.5±0.2°, 17.7±0.2°, 20.9±0.2°, 22.6±0.2° and 23.2±0.2°.

The XRPD pattern of form B is substantially in accordance with figure 29. From its XRPD pattern, form B was found to have diffraction peaks with relatively high intensities at the following 2θ values: 22.3 + -0.2 deg., 23.9 + -0.2 deg., and 30.5 + -0.2 deg..

In addition, form B also has a diffraction peak with moderate relative intensity at the following 2θ values: 15.1 + -0.2 DEG, 20.1 + -0.2 DEG and 24.4 + -0.2 deg.

In addition, form B also has diffraction peaks with relatively low intensities at the following 2θ values: 11.6 + -0.2 deg., 21.8 + -0.2 deg., and 29.8 + -0.2 deg..

Further, form B has diffraction peaks at the following 2θ values: 11.6.+ -. 0.2 °, 14.5.+ -. 0.2 °, 15.1.+ -. 0.2 °, 15.7.+ -. 0.2 °, 16.4.+ -. 0.2 °, 20.1.+ -. 0.2 °, 21.8.+ -. 0.2 °, 22.3.+ -. 0.2 °, 23.9.+ -. 0.2 °, 24.4.+ -. 0.2 °, 29.8.+ -. 0.2 ° and 30.5.+ -. 0.2 °.

The XRPD pattern of form C is substantially in accordance with figure 30. From its XRPD pattern, form C was found to have diffraction peaks with relatively high intensities at the following 2θ values: 12.6 + -0.2 deg., 20.9 + -0.2 deg., and 25.6 + -0.2 deg..

In addition, form C also has a diffraction peak with moderate relative intensity at the following 2θ values: 13.1±0.2°, 19.8±0.2° and 25.2±0.2°.

In addition, form C also has diffraction peaks with relatively low intensities at the following 2θ values: 10.6 ± 0.2 °, 17.6 ± 0.2 ° and 29.4 ± 0.2 °.

Further, form C has diffraction peaks at the following 2θ values: : 8.5.+ -. 0.2 °, 10.6.+ -. 0.2 °, 12.6.+ -. 0.2 °, 13.1.+ -. 0.2 °, 17.6.+ -. 0.2 °, 19.5.+ -. 0.2 °, 19.8.+ -. 0.2 °, 20.9.+ -. 0.2 °, 25.2.+ -. 0.2 °, 25.6.+ -. 0.2 °, 26.0.+ -. 0.2 ° and 29.4.+ -. 0.2 °.

Preparation method

The acid addition salts of the present invention or a hydrate or solvate thereof or a polymorph thereof may be prepared by a process selected from the group consisting of: antisolvent addition method, slow volatilization method, slow cooling method, suspension stirring method, circulation temperature increasing and decreasing method, gas-solid permeation method, gas-liquid diffusion method, high polymer induction method, grinding method and reactive crystallization method.

In some embodiments, starting from the free base of the compound of formula I, the preparation of the target product may be carried out by reactive crystallization with the corresponding acid.

In some embodiments, when the acid addition salt of the compound of formula I is used as a raw material, the preparation of the target product may be performed by an antisolvent addition method, a slow volatilization method, a slow cooling method, a suspension stirring method, a cyclic temperature increase and decrease method, a gas-solid permeation method, a gas-liquid diffusion method, a polymer induction method, or a grinding method.

Pharmaceutical composition

The invention provides pharmaceutical compositions comprising one or more of the above-described acid addition salts of the compounds of formula I or a hydrate or solvate thereof or a polymorph thereof.

In some embodiments, the pharmaceutical composition comprises a prophylactically, palliatively and/or therapeutically effective amount of one or more of the above-described acid addition salts of the compound of formula I, or a hydrate or solvate thereof, or a polymorph thereof.

In some embodiments, the pharmaceutical composition may further comprise one or more therapeutically active co-agents. The therapeutically active co-agent may be selected from one or more of baratinib, jacktinib, ritlecitinib, etrasimod, daxdilimab, SHR0302, minoxidil, deuterated Lu Suoti, botulinum toxin, clavulanone, finasteride, dutasteride, and latanoprost.

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

In some embodiments, the particle size of the polymorph is 5-100 μm, e.g., 10-90 μm or 10-50 μm.

In some embodiments, the above-described acid addition salt of the compound of formula I, or a hydrate or solvate thereof, or a polymorph thereof, is 0.1% to 99.0% by weight, such as may be 0.1% to 80%, 1% to 80%, 10.0% to 80.0%, 20% to 80%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 30% to 50%, 35% to 50%, or 40% to 50% in the pharmaceutical composition.

Medical application

First, the present invention provides the use of an acid addition salt as described above, or a hydrate or solvate thereof, a polymorph or pharmaceutical composition thereof, for the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease or condition associated with androgen receptor activity.

Next, the present invention provides the above-mentioned acid addition salt or a hydrate or solvate thereof, a polymorph or a pharmaceutical composition thereof, which is used for preventing, alleviating and/or treating a disease or disorder associated with androgen receptor activity.

Again, the present invention provides a method for preventing, alleviating and/or treating a disease or condition associated with androgen receptor activity, comprising the steps of: a prophylactically, palliatively and/or therapeutically effective amount of an acid addition salt as described above, or a hydrate or solvate thereof, a polymorph or pharmaceutical composition thereof, is administered to a subject in need thereof.

In some embodiments, the disorder or condition associated with androgen receptor activity is selected from the group consisting of prostate cancer, benign prostatic hyperplasia, acne, hirsutism, excessive sebum, and androgenic alopecia.

The invention will be further illustrated by the following specific examples. The instruments, practices, materials, and the like used in the following examples are all available through conventional commercial means unless otherwise indicated.

Free base form D or free base form B

In the embodiment of the invention, the free base crystal form D or the free base crystal form B is an anhydrous polymorph of the compound with the formula I of the crystal form D or the crystal form B, and the microstructure characterization and the preparation method are described in patent application PCT/CN 2022/08274.

X-ray powder diffraction (XRPD)

XRPD patterns were collected on an X-ray powder diffraction analyzer produced by PANalytacal, and the scanning parameters are shown in table 1.

Table 1XRPD test parameters

In the table: "to" means "about".

Thermogravimetric analysis (TGA) and Differential Scanning Calorimeter (DSC)

TGA and DSC spectra were collected on a TA Q5000/5500 thermogravimetric analyzer and a TA Q200/Q2000/2500 differential scanning calorimeter, respectively, and the test parameters are listed in table 2.

TABLE 2DSC and TGA test parameters

Parameters (parameters)	TGA	DSC
			Method	Linear temperature rise	Linear temperature rise
Sample tray	Aluminum tray open	Aluminum plate, gland/not gland
			Temperature range	Room temperature-set end point temperature	25 ℃ to set the end point temperature
Scan Rate (. Degree. C/min)	10	10
			Protective gas	Nitrogen gas	Nitrogen gas

Dynamic moisture adsorption (DVS)

Dynamic moisture sorption (DVS) curves were collected on DVS intricic of SMS (Surface Measurement Systems). LiCl, mg (NO) ₃ ) ₂ And deliquescence point correction of KCl. DVS test parameters are listed in table 3.

TABLE 3DVS test parameters

Polarizing microscope (PLM)

Polarized microscopic data were collected by Axio lab. A1 front-facing microscope at room temperature.

Liquid nuclear magnetism (Solution NMR)

Liquid nuclear magnetic resonance spectra were collected on a Bruker 400M NMR apparatus with DMSO-d6 as solvent.

High performance liquid chromatography/ion chromatography (HPLC/IC)

Purity, dynamic solubility and stability in the test were tested by Agilent 1260/1100 high performance liquid chromatograph, chloride and bromide salt formation molar ratios were tested by ion chromatography, and the analytical conditions are shown in tables 4 and 5.

TABLE 4 high performance liquid chromatography test conditions

Table 5 ion chromatograph test conditions

Parameters (parameters)	Parameter value/set point
		Instrument for measuring and controlling the intensity of light	ThermoFisher ICS-1100
Chromatographic column	IonPac AS18 Analytical Column,250*4mm
		Mobile phase	25mM NaOH
Sample injection volume	25μL
		Flow rate	1.0mL/min
Temperature (temperature)	35℃
		Column temperature	35℃
Electric current	80mA
		Run time	Chloride ion is 6.0min, and bromide ion is 9.0min

In the invention, the mole ratio of acid to alkali of the salt of the compound of the formula I is calculated as follows:

chinese name contrast for solvent abbreviations

The abbreviations for solvents presented herein are compared to the corresponding chinese names in table 6 below.

TABLE 6 comparison of solvent English abbreviations and Chinese names

English abbreviations	Chinese character	English abbreviations	Chinese character
				MeOH	Methanol	2-MeTHF	2-methyltetrahydrofuran
EtOH	Ethanol	ACN	Acetonitrile
				IPA	Isopropyl alcohol	DCM	Dichloromethane (dichloromethane)
MIBK	Methyl isobutyl ketone	CHCl ₃	Trichloromethane
				EtOAc	Acetic acid ethyl ester	DMSO	Dimethyl sulfoxide
IPAc	Acetic acid isopropyl ester	DMAc	N, N-dimethylacetamide
				MTBE	Methyl tert-butyl ether	NMP	N-methylpyrrolidone
THF	Tetrahydrofuran (THF)	H ₂ O	Water and its preparation method

EXAMPLE 1 screening of different salts

(1) Solubility experiment

The solubility of the free base form D of the compound of formula I was experimentally determined before salt form screening, and the crude solubility of the free base form D was determined using 20 solvents at room temperature. Weighing about 2mg of the free base form D to a 3mL vial, and gradually adding the corresponding solvent until the solid is dissolved; if the sample was still undissolved after the addition of 2mL of solvent, no more solvent was added. The rough solubility range in the corresponding solvent was calculated based on the mass of the sample and the volume of solvent added, as shown in table 7, and based on this data, the solvent selection in the salt screening test was guided.

TABLE 7 crude solubility of free base form D at room temperature

Solvent(s)	Solubility (mg/mL)	Solvent(s)	Solubility (mg/mL)
				MeOH	11.0<S<22.0	1, 4-Dioxahexacyclic ring	S>44.0
EtOH	2.6<S<6.5	ACN	S>42.0
				IPA	1.2<S<2.3	CHCl ₃	S>56.0
Acetone (acetone)	S>50.0	DCM	S>38.0
				MIBK	13.0<S<26.0	N-heptane	S<1.3
EtOAc	21.0<S<42.0	Toluene (toluene)	13.5<S<27.0
				IPAc	7.0<S<14.0	DMAc	S>42.0
MTBE	1.4<S<2.7	DMSO	S>46.0
				THF	S>52.0	NMP	S>42.0
2-MeTHF	22.0<S<44.0	H ₂ O	S<1.1

(2) Salt screening

Through solubility data analysis of the free base form D of the compound of formula I, three solvents of different solubilities EtOH, IPAc and MTBE were selected as salt forming solvents for 51 salt form screening experiments with 17 acids in the above 3 solvent systems, respectively. The method comprises the following steps: after stirring about 15mg of the free base form D of the compound of formula I with equimolar acid in 0.5mL of solvent at room temperature for 3 days, the sample was centrifuged and the solid was subjected to XRPD characterization, the results are shown in table 8.

Table 8 summary of salt screening test results

Experimental results indicate that, although in theory the free base of the compound of formula I may form salts with organic or inorganic acids, in practice most acidic systems cannot form salts (remain in the free base form) or are colloidal, and that the compound of formula I is only able to form salts with hydrochloric acid, methanesulfonic acid and hydrobromic acid.

Wherein the free base of the compound of formula I forms a hydrochloride form a with hydrochloric acid in an ethanol solvent, and forms a hydrochloride form B in a solvent of isopropyl acetate and methyl tert-butyl ether; the free base of the compound of formula I and the mesylate form a mesylate in ethanol alone, and the remaining two solvents cannot form salts or gels; the free base of the compound of formula I forms hydrobromide form a with hydrobromic acid in ethanol, form B in isopropyl acetate, and form C in methyl tert-butyl ether.

The hydrochloride polymorphism of the compound of the formula I is further screened, in addition to the hydrochloride crystal form A and the hydrochloride crystal form B screened by the test, 100 hydrochloride polymorphism screening tests are set by the applicant by adopting various solid phase transformation and solution crystallization methods, and finally the hydrochloride crystal form D, the hydrochloride crystal form E, the hydrochloride crystal form F and the hydrochloride amorphous form are obtained.

EXAMPLE 2 preparation of Compound of formula I hydrochloride form A

Method 1: reactive crystallization process

About 15mg of the free base form D of the compound of formula I is weighed, 0.5ml of solvent is added, 3.25. Mu.l of hydrochloric acid (equimolar amount to the compound of formula I) is added, and the mixture is allowed to stand at room temperature with magnetic stirring (1000 rpm). After solid precipitation, the solid was collected by centrifugation (10000 rpm,2 min) and subjected to XRPD testing.

The results show that when the solvent is ethanol, IPA, MIBK, ethyl acetate or 2-MeTHF, both hydrochloride forms A are obtained.

XRPD patterns of hydrochloride form a and detailed data are shown in fig. 1 and table 9.

Table 9 XRPD pattern data for hydrochloride form a

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	10.42	5.83	17	23.04	15.59
2	10.91	7.15	18	23.34	13.67
						3	12.34	18.20	19	24.73	44.37
4	13.21	11.86	20	25.56	17.17
						5	14.12	2.89	21	26.45	18.67
6	14.94	10.52	22	27.03	7.59
						7	15.30	40.61	23	28.12	9.26
8	16.33	2.32	24	28.86	5.80
						9	16.99	6.96	25	29.64	11.59
10	17.88	13.17	26	30.55	12.27
						11	18.52	100.00	27	32.91	8.70
12	19.80	2.63	28	34.16	7.95
						13	20.43	5.12	29	35.12	3.68
14	20.94	35.16	30	36.02	1.99
						15	21.39	18.91	31	37.43	7.91
16	22.01	23.31	32	38.97	5.00

The TGA/DSC spectrum of hydrochloride form A is shown in FIG. 2. As can be seen from fig. 2, the sample loses about 1.3% weight when heated to 130 ℃ and has 2 endothermic peaks at 174.8 ℃ and 204.8 ℃ (peak temperature). Since the hydrochloride form a has a lower TGA weight loss, it is presumed to be the anhydrous form. ¹ The H NMR spectrum is shown in FIG. 3, and the result shows that no residual solvent was detected. HPLC/IC results show samplesThe molar ratio of acid to alkali is 1:1.

Method 2: antisolvent addition method

About 15mg of the hydrochloride form A of the compound of formula I is weighed, placed in a 20ml vial, and 0.2-2.4ml of good solvent is added to dissolve the solid completely. To the clear solution was added dropwise an antisolvent with stirring (1000 rpm) at room temperature until a solid precipitated. The precipitated solid was isolated and subjected to XRPD testing. The hydrochloride crystal form A can be obtained by identification under the condition that acetone is used as a good solvent and n-heptane is used as an anti-solvent at room temperature.

The invention also verifies that: if the sample is at room temperature and no solid is precipitated after the total volume of the anti-solvent is added to 15ml, the temperature is reduced to 5 ℃ and the suspension is stirred until the solid is precipitated. The precipitated solid was isolated and subjected to XRPD testing. It was identified that hydrochloride form a could be obtained at 5 ℃ with acetone or methanol as good solvent and IPAc as anti-solvent.

The invention further verifies that: if the sample still has no solid precipitation at 5 ℃, the temperature is reduced to-20 ℃ and the suspension is stirred until the solid precipitation exists. The precipitated solid was isolated and subjected to XRPD testing. The identification is carried out under the condition that methanol is taken as a good solvent and 2-MeTHF is taken as an antisolvent at the temperature of minus 20 ℃; or under the condition that acetone is a good solvent and toluene is an antisolvent, the hydrochloride crystal form A can be obtained.

Method 3: slow volatilization method

About 15mg of the hydrochloride form A of the compound of formula I is weighed, placed in a 3mL vial, dissolved in 0.4-1.0mL of solvent, the vial is sealed with a sealing film, 2 pinholes are punched therein, and left to evaporate slowly at room temperature. The resulting solid was collected and subjected to XRPD testing. It was identified that both hydrochloride forms a were obtained when the solvent was acetone or acetonitrile.

Method 4: room temperature suspension stirring method

About 15mg of the hydrochloride salt of the compound of formula I, form A, was weighed into an HPLC glass vial, 0.5mL of solvent was added, and placed under magnetic stirring (1000 rpm) at room temperature, after about 5-6 days, centrifuged (10000 rpm,2 min), the solid was collected and XRPD tested. It was identified that when the solvent was IPA, MIBK, ethyl acetate, MTBE,THF, toluene, meOH/MTBE (1:4), acetone/n-heptane (1:2), IPA/H ₂ O(0.98:0.02,a _w ～0.2)、IPA/H ₂ O(0.96:0.04,a _w ～0.4)、IPA/H ₂ O(0.92:0.08,a _w 0.6), ethanol, acetone, 2-MeTHF or DCM/n-heptane (1:4) to give the hydrochloride salt form A. In this specification, "to" means "about".

Method 5:50 ℃ suspension stirring method

About 15mg of the hydrochloride salt of the compound of formula I, form A, was weighed into an HPLC glass vial, 0.5mL of solvent was added, magnetically stirred (1000 rpm) at 50℃and after about 3 days, centrifuged (10000 rpm,2 min), the solid was collected and XRPD tested. It was identified that when the solvent was IPAc, 2-MeTHF, n-heptane, toluene or EtOH/n-heptane (1:9), both hydrochloride forms A were obtained.

Method 6: circulation temp. -increasing and-decreasing method

About 15mg of the hydrochloride salt of the compound of formula I, form A, was weighed into an HPLC glass vial, 0.5mL of solvent was added, magnetically stirred (1000 rpm) at temperature cycling (50 ℃ C. -5 ℃ C., 0.1 ℃ C./min, 2 cycles), centrifuged (10000 rpm,2 min), the solid was collected, and XRPD testing was performed. It was identified that when the solvent was IPA, ethyl acetate, THF, toluene or NMP/toluene (1:9), hydrochloride form A was obtained.

Method 7: gas-solid permeation method

About 15mg of the hydrochloride form A of the compound of formula I is weighed into a 3mL vial, about 3mL of solvent is added to a 20mL vial, the 3mL vial is placed in the 20mL vial with the opening, the 20mL vial is sealed, allowed to stand at room temperature for 8 days, the solid is collected, and XRPD testing is performed. It was identified that when the solvent was IPA, ethyl acetate, THF, DMSO, water, toluene, ethanol, MIBK, IPAc, MTBE, 2-MeTHF, n-heptane or NMP, hydrochloride form A was obtained.

Method 8: gas-liquid diffusion process

About 15mg of the hydrochloride form A of the compound of formula I is weighed into a 3mL vial, 0.1 to 0.3mL of good solvent is added for dissolution (undissolved PTFE filter head of 0.45 μm is used for filtration), about 3mL of antisolvent is added to another 20mL vial, the 3mL vial containing the clear solution is placed in the 20mL vial with its mouth open, the 20mL vial is sealed, and left at room temperature. The resulting solid was collected and subjected to XRPD testing. It was identified that when the good solvent was acetonitrile and the anti-solvent was MIBK, hydrochloride form a was obtained.

Method 9: high polymer induction method

About 15mg of the hydrochloride form A of the compound of formula I is weighed into a 3mL vial, 0.2-1.0 mL of solvent is added for dissolution, about 2mg of the mixed polymer is added, the vial is sealed with a sealing film, 4 pinholes are pricked on the vial, and the vial is left to evaporate slowly at room temperature. The resulting solid was collected and subjected to XRPD testing. It was identified that when the solvent was acetone, the conjunct polymers were: when polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (equal mass mixture) are mixed, hydrochloride crystal form A can be obtained.

The method 10 comprises the following steps: grinding method

About 15mg of the hydrochloride form a of the compound of formula I is weighed into a mortar and ground for about 2 minutes. The resulting solid was collected and subjected to XRPD testing. The solid obtained was identified to be still hydrochloride form a.

Example 3: temperature change XRPD test for hydrochloride form A

The hydrochloride form a was heated to 180 ℃ and cooled to room temperature, and the XRPD pattern, see fig. 4, was determined and the results showed no form transformation after heating.

Example 4: preparation of hydrochloride form B

Method 1: reactive crystallization process

About 15mg of the free base form D of the compound of formula I was weighed, then an equimolar amount of hydrochloric acid was added, 0.5ml of solvent was added, and left to stir at room temperature for 3 days, centrifuged, the solid was collected and subjected to XRPD testing. The results show that when the solvent is IPAc, MTBE or 1, 4-dioxane, both hydrochloride forms B are obtained.

XRPD patterns of hydrochloride form B and detailed data are shown in fig. 5 and table 10.

Table 10 XRPD diffraction peak data for hydrochloride form B

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	10.68	35.95	9	21.36	77.15
2	12.15	100.00	10	22.21	32.90
						3	13.71	56.60	11	23.03	61.94
4	15.24	20.44	12	25.53	22.40
						5	15.89	46.78	13	27.54	17.76
6	16.32	39.60	14	28.07	13.64
						7	17.42	80.05	15	29.74	6.68
8	20.38	19.25	16	32.40	9.94

The TGA/DSC spectrum of hydrochloride form B is shown in FIG. 6. As can be seen from fig. 6, the sample loses weight by about 0.6% when heated to 120 ℃, and the sample has a sharp endothermic peak at 205.2 ℃ (peak temperature). Since the hydrochloride form B has a lower TGA weight loss, it is presumed to be the anhydrous form. HPLC/IC results showed that the acid-base molar ratio of the samples was 1.0:1.

Method 2: antisolvent addition method

About 15mg of the hydrochloride form A of the compound of formula I is weighed, placed in a 20ml vial, and 0.2-2.4ml of good solvent is added to dissolve the solid completely. To the clear solution was added dropwise an antisolvent with stirring (1000 rpm) at room temperature until a solid precipitated. The precipitated solid was isolated and subjected to XRPD testing. The MTBE is identified as an anti-solvent under the condition that methanol, acetonitrile or chloroform is used as a good solvent at room temperature; or under the condition that DCM is used as a good solvent and IPAc is used as an antisolvent, the hydrochloride crystal form B can be obtained.

The invention also verifies that: if the sample is at room temperature and no solid is precipitated after the total volume of the anti-solvent is added to 15ml, the sample is placed at room temperature for volatilization until solid is precipitated. The precipitated solid was isolated and subjected to XRPD testing. The hydrochloride crystal form B can be obtained by identification under the condition that DCM is a good solvent and n-heptane is an anti-solvent.

Method 3: slow volatilization method

About 15mg of the hydrochloride form A of the compound of formula I is weighed, placed in a 3mL vial, dissolved in 0.4-1.0mL of solvent, the vial is sealed with a sealing film, 2 pinholes are punched therein, and left to evaporate slowly at room temperature. The resulting solid was collected and subjected to XRPD testing. When the solvent is chloroform, it was identified that hydrochloride form B can be obtained.

Method 4: slow cooling method

About 15mg of the hydrochloride form A of the compound of formula I is weighed into a 5mL vial, 3mL of solvent is added, the mixture is equilibrated at 50℃for about 1 hour, and the supernatant is filtered. The resulting supernatant was placed in a biological incubator, cooled from 50 ℃ to 5 ℃ at 0.1 ℃/min, kept at constant temperature at 5 ℃, and the precipitated solids were collected and subjected to XRPD testing. It was identified that when the solvent was 1, 4-dioxane, hydrochloride form B could be obtained.

The invention also verifies that: if the sample did not precipitate solids at a constant temperature of 5 ℃, the clear solution was transferred to a constant temperature of-20 ℃, the precipitated solids were collected and XRPD tested. It was identified that when the solvent was IPA, hydrochloride form B could be obtained.

Method 5:50 ℃ suspension stirring method

About 15mg of the hydrochloride salt of the compound of formula I, form A, was weighed into an HPLC glass vial, 0.5mL of solvent was added, and after magnetic stirring (1000 rpm) at 50℃for about 3 days, centrifuged (10000 rpm,2 min), the solid was collected and XRPD tested. It was identified that when the solvent was 1, 4-dioxane, hydrochloride form B could be obtained.

Method 6: gas-liquid diffusion process

About 15mg of the hydrochloride form A of the compound of formula I is weighed into a 3mL vial, 0.1 to 0.3mL of good solvent is added for dissolution (undissolved PTFE filter head of 0.45 μm is used for filtration), about 3mL of antisolvent is added to another 20mL vial, the 3mL vial containing the clear solution is placed in the 20mL vial with its mouth open, the 20mL vial is sealed, and left at room temperature. The resulting solid was collected and subjected to XRPD testing. The identification shows that when the good solvent is methanol and the anti-solvent is ethyl acetate or MTBE; or when the good solvent is acetonitrile and the anti-solvent is IPAc; or when the good solvent is chloroform and the anti-solvent is n-heptane or toluene; or when the good solvent is DMAc and the anti-solvent is MTBE; hydrochloride form B can be obtained.

Example 5: preparation of hydrochloride form D

Method 1: room temperature suspension stirring method

200mg of hydrochloride form A was placed in IPA/H at room temperature ₂ O(0.85：0.15,a _w And 0.8) and stirring for 4 days, and drying at room temperature in vacuum to obtain the hydrochloride crystal form D. XRPD patterns of hydrochloride form D and detailed data are shown in fig. 7 and table 11.

TABLE 11 XRPD diffraction peak data for hydrochloride form D

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	8.36	19.93	9	20.80	55.33
2	10.71	59.59	10	21.24	43.58
						3	12.50	100.00	11	22.61	17.08
4	13.00	66.43	12	25.17	42.24
						5	16.38	8.40	13	27.08	16.31
6	16.92	7.78	14	29.23	10.48
						7	19.06	7.77	15	29.77	18.27
8	19.60	9.85	16	31.18	8.25

The TGA/DSC spectrum of hydrochloride form D is shown in FIG. 8. As can be seen from fig. 8, the sample loses weight by about 2.6% when heated to 100 ℃, and the sample shows endothermic peaks at 84.7 ℃, 144.9 ℃, 163.7 ℃ and 196.5 ℃ (peak temperature).

¹ H NMR is shown in fig. 9, which shows a molar ratio of residual solvent IPA to API in the polymorph of hydrochloride form D of 0.03 (corresponding weight loss of 0.4%). HPLC/IC results showed the acid-base molar ratio of the samples to be 0.8:1.

Example 6: temperature change XRPD test for hydrochloride form D

To investigate the DSC signal of hydrochloride form D, a heating test was performed on it, the sample was heated to 100deg.C by DSC and cooled to room temperature, and then XRPD was tested in air exposure, see FIG. 10, and the results showed that the form was unchanged. To further investigate the DSC signal, a temperature swing XRPD test was performed and the results are shown in FIGS. 11 and 12. The results show that in the temperature swing XRPD test, the XRPD pattern changes after 20 minutes of nitrogen purge and the crystalline form does not change after heating to 100 ℃ under nitrogen atmosphere (the partial diffraction peak to peak position shift is presumed to be due to lattice expansion upon heating).

And by combining DSC heating test and variable temperature XRPD results, supposing that the hydrochloride crystal form D is a hydrate, dehydrating and converting the hydrate into a new crystal form (named as hydrochloride crystal form F) after nitrogen purging or heating, wherein the new crystal form is converted into the hydrochloride crystal form D again after absorbing water in the air. In the temperature-changing XRPD test, the hydrochloride crystal form D is converted into a free base crystal form D after being heated to 150 ℃ in nitrogen purging atmosphere, and the endothermic peak at 144.9 ℃ in the graph 8 is presumed to be a dehydrohydrochloric signal by combining TGA weight loss and DSC signals; heating to 165 deg.c, converting to free base form B, and cooling to 30 deg.c.

In combination with the TGA weight loss of 2.6% for hydrochloride form D in example 5, it can be speculated that the molar ratio of bound water to free base in hydrochloride form D is 0.6:1.

Hydrochloride form F was obtained after nitrogen purging in a temperature swing XRPD for 20 minutes, presumably as the anhydrous form, with XRPD spectra and detailed data shown in fig. 13 and table 12.

Table 12 XRPD pattern of hydrochloride form F

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	6.70	4.24	19	23.01	28.73
2	8.13	6.52	20	24.16	13.01
						3	8.42	19.26	21	25.10	44.27
4	10.56	31.12	22	25.53	59.23
						5	10.80	53.52	23	25.80	21.34
6	11.95	10.44	24	26.33	15.23
						7	12.46	89.95	25	27.30	19.45
8	13.06	79.34	26	27.86	11.75
						9	13.50	16.33	27	28.15	17.59
10	15.10	17.75	28	29.43	21.60
						11	16.36	15.86	29	30.22	23.12
12	17.40	29.29	30	31.11	15.15
						13	19.08	18.55	31	31.55	18.29
14	19.36	28.29	32	32.20	7.91
						15	19.73	28.06	33	33.22	8.02
16	20.28	15.47	34	34.25	7.90
						17	21.16	100.00	35	35.12	7.05
18	21.45	53.53

Example 7: preparation of hydrochloride form E

Method 1: gas-solid permeation method

About 15mg of the hydrochloride salt of the compound of formula I, form A, is weighed into a 3mL vial, about 3mL of solvent is added to a 20mL vial, the 3mL vial is placed in the 20mL vial with the opening, and the 20mL vial is sealed. The solid was collected and XRPD tested by standing for 8 days at room temperature. The results show that when the solvent is 1, 4-dioxane, hydrochloride form E can be obtained.

XRPD patterns of hydrochloride form E and detailed data are shown in fig. 14 and table 13.

TABLE 13 XRPD diffraction peak data for hydrochloride form E

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	10.93	44.69	5	21.41	100.00
2	12.68	86.08	6	23.11	26.79
						3	15.84	26.56	7	28.88	9.80
4	19.55	21.87

The TGA/DSC profile for hydrochloride form E is shown in figure 15, which shows that the sample loses weight by about 16.5% when heated to 130 ℃, with 2 endothermic peaks at 122.0 ℃ and 204.5 ℃ (peak temperature). ¹ The H NMR (spectrum see fig. 16) results show that the molar ratio of solvent 1, 4-dioxane to API in the polymorph of hydrochloride form E is 0.8:1 (corresponding to a weight loss of 14.3%). HPLC/IC results showed that the acid-base molar ratio of the samples was 1:1.

To investigate the TGA weight loss of hydrochloride form E, XRPD characterization was performed after heating the sample to 130 ℃ and cooling to room temperature. XRPD results (spectrum see fig. 17) show that the sample was converted to form B hydrochloride after heating. Since the hydrochloride form E is subjected to crystal transformation after heating, and combined with a TGA step curve, a corresponding DSC endothermic peak and 1, 4-dioxane detected in nuclear magnetism, the hydrochloride form E is presumed to be a 1, 4-dioxane solvate, and the molar ratio of the 1, 4-dioxane to the API is 0.8:1.

Method 2: circulation temp. -increasing and-decreasing method

About 15mg of the hydrochloride salt of the compound of formula I, form A, was weighed into an HPLC glass vial, 0.5mL of solvent was added, magnetically stirred (1000 rpm) at temperature cycling (50 ℃ C. -5 ℃ C., 0.1 ℃ C./min, 2 cycles), centrifuged (10000 rpm,2 min), the solid was collected, and XRPD testing was performed. It was identified that when the solvent was 1, 4-dioxane, hydrochloride form E was obtained.

Example 8: preparation of mesylate salt form A

Method 1: reactive crystallization process

About 15mg of the free base form D of the compound of formula I is weighed, then equimolar methanesulfonic acid is added, 0.5ml of solvent is added, and the mixture is left to stir at room temperature, 5 ℃ or-20 ℃, centrifuged, the solid is collected and subjected to XRPD testing. The results show that when the solvent is ethanol, mesylate form a is obtained under the following conditions: (1) stirring at room temperature for 3 days; (2) stirring at 5 ℃ for 3 days and at-20 ℃ for 1 day; (3) -20 ℃ stirring for 5 days; (4) -20 ℃ for 1 day, and drying at 50 ℃ for 3 days.

XRPD patterns and detailed data for mesylate form a are shown in fig. 18 and table 14.

TABLE 14 XRPD diffraction peak data for mesylate form A

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	8.31	16.20	16	20.15	44.57
2	9.20	7.81	17	20.72	11.11
						3	10.57	15.81	18	21.11	70.45
4	11.58	69.06	19	21.96	84.54
						5	12.67	68.76	20	23.02	19.46
6	13.56	4.14	21	24.12	36.74
						7	14.74	53.85	22	25.03	11.34
8	15.58	100.00	23	25.80	37.02
						9	16.55	35.92	24	26.61	25.50
10	17.13	34.79	25	27.91	24.21
						11	17.97	42.98	26	29.61	7.80
12	18.52	43.60	27	31.39	9.36
						13	18.93	29.35	28	32.42	15.21
14	19.48	16.80	29	34.46	6.69
						15	19.91	56.53

The TGA/DSC results for mesylate form a are shown in fig. 19, with a sample loss of weight of about 7.0% after heating to 150 ℃ and 1 sharp endothermic peak at 102.9 ℃ (peak temperature). ¹ The H NMR (spectrum see FIG. 20) results show that the acid-base molar ratio in the sample is 0.9:1, and the molar ratio of residual solvent EtOH to API is 0.9:1 (corresponding to a weight loss of 6.4%).

Example 9: preparation of mesylate Crystal forms B and C

The free base sample and methanesulfonic acid (molar ratio 1:1, acid/base) were used as starting materials and stirred in EtOH solvent system at-20℃for 1 day. The XRPD results are shown in fig. 21, which shows the wet sample as a new form, designated mesylate form B, and the sample was dried at 50 ℃ for two hours and then subjected to XRPD characterization, and the XRPD results are shown in fig. 22, which shows that the sample is transcrystalline, designated mesylate form C. Details of XRPD patterns of mesylate forms B and C are shown in tables 15 and 16.

Table 15 XRPD diffraction peak data for mesylate form B

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	9.80	11.94	8	20.34	8.59
2	10.68	100.00	9	21.26	25.35
						3	11.44	46.16	10	22.33	9.15
4	12.55	31.94	11	23.22	5.02
						5	13.12	9.29	12	23.95	5.64
6	14.76	9.88	13	25.73	12.00
						7	17.78	10.40

TABLE 16 XRPD diffraction peak data for mesylate form C

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	8.21	20.09	12	19.80	100.00
2	8.70	30.09	13	21.60	16.81
						3	9.48	23.38	14	22.44	15.01
4	11.52	22.17	15	24.89	27.75
						5	12.39	93.65	16	25.27	30.52
6	12.76	58.65	17	25.72	17.33
						7	16.46	22.40	18	26.21	45.94
8	16.82	23.12	19	26.90	17.08
						9	17.39	15.18	20	29.79	9.51
10	18.04	64.49	21	30.80	7.84
						11	19.34	79.16	22	33.90	5.30

TGA/DSC results for mesylate form C are shown in FIG. 23, which shows a weight loss of about 0.8% after heating the sample to 150℃and 1 sharp endothermic peak at 186.3 ℃ (peak temperature). ¹ The H NMR (spectrum see FIG. 24) results show that the acid-base molar ratio in the sample is 1:1 and the molar ratio of residual solvent EtOH to API is 0.1:1 (corresponding to a weight loss of 0.9%). Since the mesylate form C has less TGA weight loss, it is presumed to be the anhydrous form.

The preparation method of the mesylate crystal form C can also be as follows: the mesylate crystal form C crystal seeds are added into IPA/n-heptane (1:1, v/v) as a raw material at 50 ℃, suspended and stirred for 1 day, solids are separated, and the mixture is dried for 4 hours at 50 ℃ in vacuum, and the mesylate crystal form C is obtained after identification.

Example 10: preparation of mesylate form D

After suspending mesylate form a in 3 solvent systems (IPA, IPA/n-heptane (1:1, v/v) or IPAc/n-heptane (1:1, v/v)) at-20 ℃ for 1 day, the solids were isolated, XRPD was tested, the spectra summarized in fig. 25, and the results showed that the new crystalline or amorphous samples were obtained.

Of these, the new form was designated mesylate form D, its XRPD pattern and detailed data are shown in fig. 26 and table 17, its TGA/DSC results are shown in fig. 27, the sample loses weight about 7.1% when heated to 150 ℃, and there are 3 endothermic peaks at 106.0 ℃, 117.7 ℃ and 185.6 ℃ (peak temperature).

Table 17 XRPD diffraction peak data for mesylate form D

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	8.94	69.61	6	19.86	47.91
2	9.50	51.96	7	20.25	45.75
						3	11.98	100.00	8	26.11	18.51
4	15.80	20.28	9	28.92	10.97
						5	17.98	15.98

Example 11: preparation of hydrobromide crystalline form A/B/C

The hydrobromide crystal form A/B/C is prepared by taking a free base crystal form D and hydrobromic acid (molar ratio 1:1, acid/base) as raw materials and stirring the raw materials in a solvent system of EtOH, IPAc and MTBE at room temperature for 3 days. XRPD patterns and detailed data are shown in fig. 28-30 and tables 18-20.

Table 18 XRPD diffraction peak data for hydrobromide form a

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	10.42	75.24	5	17.72	100.00
2	12.03	81.45	6	20.91	84.10
						3	13.56	51.83	7	22.63	83.69
4	15.45	42.26	8	23.21	24.85

Table 19 XRPD diffraction peak data for hydrobromide form B

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	11.64	59.82	10	20.95	25.40
2	13.31	28.51	11	21.77	56.84
						3	13.87	30.91	12	22.30	100.00
4	14.53	46.73	13	22.83	48.70
						5	15.08	63.16	14	23.90	76.40
6	15.71	55.46	15	24.39	72.08
						7	16.37	42.06	16	27.68	55.24
8	17.79	22.36	17	29.84	59.48
						9	20.06	60.59	18	30.54	72.93

Table 20 XRPD diffraction peak data for hydrobromide form C

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	8.54	17.98	14	22.75	9.48
2	10.58	28.84	15	25.22	61.68
						3	11.11	13.82	16	25.63	65.96
4	12.57	100.00	17	26.01	24.71
						5	13.06	63.91	18	27.20	22.44
6	16.51	11.30	19	27.93	18.15
						7	17.63	37.89	20	29.38	35.35
8	19.50	24.00	21	30.39	10.97
						9	19.84	44.55	22	31.51	19.26
10	20.16	12.70	23	32.32	12.48
						11	20.90	94.85	24	33.65	14.80
12	21.84	8.45	25	34.45	7.35
						13	22.24	16.11

The TGA/DSC results of hydrobromide form A are shown in FIG. 31. The TGA results showed that the sample lost weight about 7.4% when heated to 150 ℃, and the DSC results showed that the sample had 1 endothermic peak with a peak temperature of 201.1 ℃. HPLC/IC results showed that the acid-base molar ratio of the samples was 1:1.

The TGA/DSC results of hydrobromide form B are shown in FIG. 32. The TGA results showed that the sample lost weight by about 1.3% when heated to 150 ℃, and the DSC results showed that the sample had 1 endothermic peak with a peak temperature of 196.4 ℃. HPLC/IC results showed that the acid-base molar ratio of the samples was 1:1.

The TGA/DSC results of hydrobromide form C are shown in FIG. 33. The TGA results showed that the sample lost weight by about 1.2% when heated to 150 ℃, and the DSC results showed that the sample had 1 endothermic peak with a peak temperature of 200.5 ℃. HPLC/IC results showed that the acid-base molar ratio of the samples was 1:1. Since the hydrobromide form C has less TGA weight loss, it is presumed to be the anhydrous form.

Example 12: preparation of free base form E

About 15mg of the free base form D of the compound of formula I was weighed, 0.5ml of solvent was added, left to stir at room temperature for 3 days, then stirred for 1 day at 5 ℃, then stirred for 1 day at-20 ℃, centrifuged, the solid was collected and subjected to XRPD testing. The results indicate that when the solvent is IPAc, the free base form E is obtained.

XRPD patterns of the free base form E and detailed data are shown in fig. 34 and table 21.

TABLE 21 XRPD diffraction peak data for form E free base

Sequence number	2θ(°)	Relative intensity (%)	Sequence number	2θ(°)	Relative intensity (%)
						1	4.80	13.29	9	20.82	4.11
2	9.53	100.00	10	21.81	7.10
						3	10.69	36.21	11	24.07	4.32
4	12.89	10.25	12	24.94	4.75
						5	14.29	13.30	13	27.03	5.24
6	17.16	6.41	14	28.78	7.03
						7	18.16	3.67	15	29.20	4.93
8	18.98	7.94

Experimental example 1: research on transformation relation of hydrochloride crystal forms

In order to study the conversion relation between the anhydrous hydrochloride crystal form A, B and the hydrate hydrochloride crystal form D, suspension competition stirring tests at the temperature of 50 ℃ are carried out on the hydrochloride crystal form A, the hydrochloride crystal form B and the hydrochloride crystal form D.

An amount of form a was weighed into an HPLC vial and 1.0mL of the different solvents were added. After stirring for 1.5 hours at room temperature/50 ℃, the sample was filtered using a PTFE filter membrane with a pore size of 0.45 μm, the filtrate was transferred to HPLC vials containing the different crystalline solids, and the solids XRPD were tested after stirring at room temperature and 50 ℃ respectively. The results are summarized in Table 22 and the XRPD results are shown in FIGS. 35-37. The results show that at room temperature water activities of 0.4 and below gave hydrochloride form a, water activities of 0.6 to 0.8 gave hydrochloride form D, which was bifidus to free base form B in pure water. And simultaneously, in anhydrous solvent, the crystal form A is obtained at room temperature and 50 ℃. According to the results, the crystal form A is an anhydrous crystal form which is more thermodynamically stable at room temperature and 50 ℃; meanwhile, the key water activity of the transformation of the anhydrous crystal form A and the hydrate crystal form D at room temperature is between 0.4 and 0.6.

Table 22 summary of suspension competition experiments

In the table: "to" means "about".

The conversion of hydrochloride forms A, B, D, E and F was summarized according to the above test results and examples 6-7, and the results are shown in FIG. 38.

Experimental example 2: moisture permeability

Hygroscopicity assessment was performed on hydrochloride form a, mesylate form C, hydrobromide form C and free base form D by dynamic moisture sorption (DVS). The percentage of mass change of the sample as a function of humidity at constant temperature of 25℃was collected from the test starting with a relative humidity of 0% (0% RH) or room humidity. DVS evaluation results are summarized in table 23, with the XRPD results before and after DVS testing being shown in fig. 39-45.

Table 23 summary of the results of the hygroscopicity assessment

Sample of	Moisture adsorption (25 ℃/80% RH)	Whether the crystal form changes after DVS test
			Hydrochloride crystal form A	0.66％	Whether or not
Methanesulfonate salt form C	19.8％	Deliquescence occurs
			Hydrobromide crystalline form C	3.05％	Whether or not
Free base form D	0.16％	Whether or not

The results showed that the moisture adsorption of hydrochloride form a, mesylate form C, hydrobromide form C and free base form D at 25 ℃/80% rh was 0.66%, 19.8%, 3.05% and 0.16%, respectively. The hydrochloride crystal form A has slightly hygroscopicity, the hydrobromide crystal form C has hygroscopicity, and the free base crystal form D has no hygroscopicity. The mesylate crystal form C is deliquesced after the DVS test, and the hydrochloride crystal form A, the hydrobromide crystal form C and the free base crystal form D are unchanged before and after the DVS test through XRPD test.

Experimental example 3: PLM (PLM)

PLM characterization was performed on hydrochloride form a, mesylate form C, hydrobromide form C and free base form D, and the results are shown in fig. 46-49, with particle sizes of all four samples being less than 50 μm.

Experimental example 4: dynamic solubility

About 15mg of the corresponding sample was weighed into a 4mL centrifuge tube, 3mL of solvent was added, mixed at room temperature (25 rpm) for 1, 4 and 24 hours, about 1mL each was sampled, and after centrifugation (0.45 μm PTFE filter head), the liquid was tested for HPLC concentration and pH. The results of the solubility test are summarized in Table 24, with the solubility curves shown in FIGS. 50-51. The results show that the dynamic solubility results of the 3 salt-based crystal forms are similar, and the solubility in water is obviously improved compared with that of the free base.

Table 24 summary of dynamic solubility test results

S: solubility (mg/mL), calculated as the free base;

LOQ：0.60μg/mL。

experimental example 5: solid state stability

After placing the hydrochloride form a, mesylate form C, hydrobromide form C and free base form D samples at 25 ℃/60% rh and 40 ℃/75% rh, respectively, for 1 week, the physical and chemical stability of the samples was checked by XRPD and HPLC. The test data are presented in Table 25.XRPD results are shown in fig. 52-55. The results show that 4 samples are not obviously degraded after being placed for 1 week under the conditions of 25 ℃/60% RH and 40 ℃/75% RH, and the crystal forms are not changed, so that the hydrochloride crystal form A, the mesylate crystal form C and the hydrobromide crystal form C are proved to have excellent stability.

Table 25 summary of solid state stability evaluation

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Claims

1. Pharmaceutically acceptable acid addition salts of the compounds of formula I or hydrates or solvates thereof,

wherein the acid is hydrochloric acid, methanesulfonic acid or hydrobromic acid; and/or

The molar ratio of the compound of formula I to the acid in the acid addition salt is 1 (0.2-5), more preferably 1 (0.5-1.5), still more preferably 1 (0.8-1.2).

2. The polymorph of an acid addition salt or a hydrate or solvate thereof according to claim 1, wherein the acid is hydrochloric acid; and/or

The molar ratio of the compound of formula I to the hydrochloric acid in the acid addition salt is 1 (0.5-3).

3. The polymorph of an acid addition salt according to claim 2, characterized in that the polymorph of the acid addition salt is any one of the following:

1) The polymorph has form a, which is the hydrochloride amorphous form, the XRPD pattern of form a comprising peaks at the following 2Θ values: 15.3±0.2°, 18.5±0.2° and 24.7±0.2°;

preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 20.9±0.2°, 22.0±0.2° and 26.5±0.2°;

more preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 12.3±0.2°, 23.0±0.2° and 25.6±0.2°;

Further preferably, the XRPD pattern of form a is substantially in accordance with figure 1;

2) The polymorph has form B, which is the hydrochloride amorphous form, the XRPD pattern of which comprises peaks at the following 2θ values: 12.2±0.2°, 17.4±0.2° and 21.4±0.2°;

preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 10.7±0.2°, 13.7±0.2° and 23.0±0.2°;

more preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 15.2±0.2°, 22.2±0.2° and 25.5±0.2°;

further preferably, the XRPD pattern of form B is substantially in accordance with figure 5;

3) The polymorph has form D, which is a hydrochloride hydrate form, which corresponds to at least one of the following:

I. the XRPD pattern of form D comprises peaks at the following 2θ values: 12.5±0.2°, 20.8±0.2° and 25.2±0.2°;

preferably, the XRPD pattern of form D further comprises peaks at the following 2θ values: 13.0±0.2°, 10.7±0.2° and 21.2±0.2°;

more preferably, the XRPD pattern of form D further comprises peaks at the following 2θ values: 8.4±0.2°, 22.6±0.2° and 29.8±0.2°;

Further preferably, the XRPD pattern of form D is substantially in accordance with figure 7;

the molar ratio of water to the compound of formula I in the polymorph is (0.4-0.8): 1, preferably (0.5-0.7): 1, more preferably 0.6:1;

4) The polymorph has form F, which is the hydrochloride amorphous form, the XRPD pattern of form F comprising peaks at the following 2θ values: 21.2±0.2°, 25.1±0.2° and 25.5±0.2°;

preferably, the XRPD pattern of form F further comprises peaks at the following 2θ values: 12.5±0.2°, 13.1±0.2° and 21.5±0.2°;

more preferably, the XRPD pattern of form F further comprises peaks at the following 2θ values: 10.8±0.2°, 17.4±0.2° and 23.0±0.2°;

further preferably, the XRPD pattern of form F is substantially in accordance with figure 13;

5) The polymorph has a form E, which is a polymorph of a solvate of a hydrochloride salt, the solvent is 1, 4-dioxane, and the form E meets at least one of the following conditions:

I. the XRPD pattern of form E comprises peaks at the following 2θ values: 10.9±0.2°, 12.7±0.2° and 21.4±0.2°;

preferably, the XRPD pattern of form E further comprises peaks at the following 2θ values: 15.8±0.2°, 19.6±0.2° and 23.1±0.2°;

Further preferably, the XRPD pattern of form E is substantially in accordance with figure 14;

the molar ratio of 1, 4-dioxane to the compound of formula I in the polymorph is (0.6-1.0): 1, preferably (0.7-0.9): 1, more preferably 0.8:1.

4. The polymorph of an acid addition salt or a hydrate or solvate thereof according to claim 1, wherein the acid is methanesulfonic acid; and/or

The molar ratio of the compound of formula I to methanesulfonic acid in the acid addition salt is 1 (0.5-3).

5. The polymorph of an acid addition salt according to claim 4, wherein the polymorph of an acid addition salt is any one of the following:

1) The polymorph has form a, whose XRPD pattern comprises peaks at the following 2θ values: 12.7±0.2°, 14.7±0.2° and 15.6±0.2°;

preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 11.6±0.2°, 21.1±0.2° and 22.0±0.2°;

more preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 18.5±0.2°, 19.9±0.2° and 20.2±0.2°;

further preferably, the XRPD pattern of form a is substantially in accordance with figure 18;

2) The polymorph has form B, whose XRPD pattern comprises peaks at the following 2θ values: 9.8±0.2°, 10.7±0.2° and 11.4±0.2°;

Preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 12.6±0.2°, 21.3±0.2° and 25.7±0.2°;

more preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 13.1±0.2°, 14.8±0.2° and 17.8±0.2°;

further preferably, the XRPD pattern of form B is substantially in accordance with figure 21;

3) The polymorph has form C, whose XRPD pattern comprises peaks at the following 2θ values: 12.4±0.2°, 19.3±0.2° and 19.8±0.2°;

preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 12.8±0.2°, 18.0±0.2° and 26.2±0.2°;

more preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 8.7±0.2°, 9.5±0.2° and 24.9±0.2°;

6. The polymorph of an acid addition salt or a hydrate or solvate thereof according to claim 1, wherein the acid is hydrobromic acid; and/or

The molar ratio of the compound of formula I to hydrobromic acid in the acid addition salt is 1 (0.5-3).

7. The polymorph of an acid addition salt according to claim 6, wherein the polymorph of an acid addition salt is any one of the following:

1) The polymorph has form a, whose XRPD pattern comprises peaks at the following 2θ values: 12.0±0.2°, 17.7±0.2° and 20.9±0.2°;

preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 10.4±0.2°, 13.6±0.2° and 22.6±0.2°;

more preferably, the XRPD pattern of form a further comprises peaks at the following 2θ values: 15.5 + -0.2 DEG and 23.2 + -0.2 DEG;

further preferably, the XRPD pattern of form a is substantially in accordance with figure 28;

2) The polymorph has form B, whose XRPD pattern comprises peaks at the following 2θ values: 22.3±0.2°, 23.9±0.2° and 30.5±0.2°;

preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 15.1±0.2°, 20.1±0.2° and 24.4±0.2°;

more preferably, the XRPD pattern of form B further comprises peaks at the following 2θ values: 11.6±0.2°, 21.8±0.2° and 29.8±0.2°;

further preferably, the XRPD pattern of form B is substantially in accordance with figure 29;

3) The polymorph has form C, whose XRPD pattern comprises peaks at the following 2θ values: 12.6±0.2°, 20.9±0.2° and 25.6±0.2°;

Preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 13.1±0.2°, 19.8±0.2° and 25.2±0.2°;

more preferably, the XRPD pattern of form C further comprises peaks at the following 2θ values: 10.6±0.2°, 17.6±0.2° and 29.4±0.2°;

8. The acid addition salt or a hydrate or solvate thereof according to claim 1 or the process for producing a polymorph of the acid addition salt or a hydrate or solvate thereof according to any one of claims 2 to 7, which is selected from the group consisting of an antisolvent addition method, a slow volatilization method, a slow cooling method, a suspension stirring method, a cyclic temperature increase and decrease method, a gas-solid permeation method, a gas-liquid diffusion method, a polymer induction method, a milling method, and a reactive crystallization method.

9. A pharmaceutical composition comprising the acid addition salt of claim 1 or a hydrate or solvate thereof or the polymorph of the acid addition salt of any one of claims 2-7 or a hydrate or solvate thereof;

preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising the polymorph of an acid addition salt or a hydrate or solvate thereof according to claim 1 or an acid addition salt or a hydrate or solvate thereof according to any one of claims 2-7 and one or more therapeutically active co-agents;

11. Use of an acid addition salt or a hydrate or solvate thereof according to claim 1, a polymorph of an acid addition salt or a hydrate or solvate thereof according to any one of claims 2-7, or a pharmaceutical composition according to claim 9 or 10, in the manufacture of a medicament for the prevention, alleviation and/or treatment of a disorder or condition associated with androgen receptor activity;

preferably, the androgen receptor activity associated disease or disorder is selected from the group consisting of prostate cancer, benign prostatic hyperplasia, acne, hirsutism, excessive sebum, and androgenic alopecia.