WO2024260348A1 - Crystal of dihydropteridinone compound and preparation method therefor - Google Patents

Abstract

Provided are a crystal of a dihydropteridinone compound as represented by formula (I) or a salt or eutectic thereof, and a method for preparing the crystal of the dihydropteridinone compound or the salt or eutectic thereof. In addition, the present disclosure also relates to the use of a pharmaceutical composition comprising the crystal of the dihydropteridinone compound or the salt or eutectic thereof in the preparation of a drug for preventing or treating related pharmacological conditions.

Description

Crystallization of dihydropteridinone compounds and preparation method thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority and benefits of Chinese Patent Application No. 202310730540.4 filed with the State Intellectual Property Office of China on June 19, 2023, and the contents disclosed in the application are incorporated herein by reference in their entirety.

Technical Field

The present disclosure belongs to the field of medical technology, and relates to a dihydropteridinone compound or a salt or co-crystal thereof, a method for preparing the dihydropteridinone compound or a salt or co-crystal thereof, a pharmaceutical composition comprising the dihydropteridinone compound or a salt or co-crystal thereof, and uses of the dihydropteridinone compound or a salt or co-crystal thereof or a pharmaceutical composition thereof.

Background Art

Ubiquitination is a reversible process involving a family of deubiquitinating enzymes (DUBs) that regulate a variety of cellular processes by deubiquitinating substrates. DUBs are encoded by approximately 100 human genes and are classified into six families, the largest of which is the ubiquitin-specific proteases (USPs) with more than 50 members.

USP1 is a cysteine isopeptidase of the USP subfamily of DUBs. The full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593, and Asp751. USP1 plays a role in DNA damage repair. USP1 is relatively inactive on its own and only acquires full enzymatic activity when it binds to the cofactor UAF1 to form a complex required for deubiquitinase activity. The USP1/UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia group complementary group D2), two proteins that play important roles in the trans-translational synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. Both pathways are required for the repair of DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC). The USPl/UAF1 complex also deubiquitinates FANCI (Fanconi anemia complementation group I). The importance of these findings was further confirmed by experiments showing that mice lacking USP1 are highly sensitive to DNA damage. Interestingly, the expression of USP1 is significantly increased in many cancers. Blocking USP1 to inhibit DNA repair can induce apoptosis in multiple myeloma cells and also enhance the sensitivity of lung cancer cells to cisplatin. These suggest that USP1 is a promising target for chemotherapy of certain cancers.

WO2022214053A1 discloses a compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (referred to as "compound of formula (I)"). Studies have found that the compound of formula (I) has good inhibitory activity against USP1.

Patent WO2022214053A1 discloses a compound of formula (I). It has become a very urgent task to research and develop a suitable crystal form to improve the stability and solubility of the compound of formula (I).

Summary of the invention

In one aspect, the present disclosure provides a crystal of a compound of formula (I):

In an optional embodiment, the crystal of the compound of formula (I) is selected from Form I, and the Form I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with diffraction peaks at 18.495±0.20°, 19.924±0.20°, and 22.000±0.20°.

In an optional embodiment, the crystalline form I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 13.288±0.20°, 13.680±0.20°, 16.935±0.20°, 18.495±0.20°, 19.924±0.20°, 22.000±0.20°, 22.613±0.20°, and 23.371±0.20°.

In an optional embodiment, the crystalline form I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 11.947±0.20°, 13.288±0.20°, 13.680±0.20°, 14.476±0.20°, 16.935±0.20°, 18.495±0.20°, 19.924±0.20°, 20.939±0.20°, 22.000±0.20°, 22.613±0.20°, 23.371±0.20°, 23.620±0.20°, 24.322±0.20°, and 25.232±0.20°.

In an optional embodiment, the crystalline form I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG1 .

In an optional embodiment, the crystal of the compound of formula (I) is selected from Form II, and the Form II has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with diffraction peaks at 7.029±0.20°, 22.059±0.20°, and 22.997±0.20°.

In an optional embodiment, the crystalline form II has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 7.029±0.20°, 16.418±0.20°, 17.020±0.20°, 20.132±0.20°, 22.059±0.20°, 22.997±0.20°, and 23.806±0.20°.

In an optional embodiment, the crystalline form II has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 7.029±0.20°, 11.503±0.20°, 15.015±0.20°, 16.418±0.20°, 17.020±0.20°, 19.547±0.20°, 20.132±0.20°, 22.059±0.20°, 22.997±0.20°, 23.806±0.20°, and 27.353±0.20°.

In an optional embodiment, the crystalline form II has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as substantially as shown in FIG. 2 .

In an optional embodiment, the TGA chart of Form II is substantially as shown in FIG3 .

In an alternative embodiment, the Form II has a DSC spectrum with an endothermic peak at 159.22±5.0°C.

In an optional embodiment, the DSC spectrum of the crystal form II is substantially as shown in FIG4 .

In one aspect, the present disclosure also provides a salt or co-crystal formed by a compound of formula (I) and an acid,

The acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid.

In an optional embodiment, the molar ratio of the compound of formula (I) to the acid molecule in the salt or co-crystal of the compound of formula (I) is 1:1 to 1:0.5, preferably 1:1 or 1:0.5.

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a fumarate or co-crystal of the compound of formula (I), wherein The molar ratio of the compound (I) to fumaric acid is 1:1 to 1:0.5, preferably 1:1 or 1:0.5.

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a fumarate or co-crystal of the compound of formula (I), and the fumarate or co-crystal is in a crystalline form, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:1 to 1:0.5, preferably 1:1 or 1:0.5.

In an optional embodiment, the salt or cocrystal of the compound of formula (I) is a hemifumarate or cocrystal of the compound of formula (I), which is Form A, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5, and the Form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 4.409±0.20°, 9.695±0.20°, 20.134±0.20°, and 22.131±0.20°.

In an optional embodiment, the crystalline form A has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 4.409±0.20°, 9.695±0.20°, 12.059±0.20°, 18.019±0.20°, 20.134±0.20°, 21.544±0.20°, and 22.131±0.20°.

In an optional embodiment, the crystalline form A has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 4.409±0.20°, 9.695±0.20°, 12.059±0.20°, 14.216±0.20°, 16.416±0.20°, 16.890±0.20°, 18.019±0.20°, 20.134±0.20°, 21.544±0.20°, 22.131±0.20°, 23.794±0.20°, and 26.493±0.20°.

In an optional embodiment, the crystalline form A has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as substantially as shown in FIG. 5 .

In an alternative embodiment, the crystalline form A has a DSC spectrum with endothermic peaks at 184.77±5.0°C, 197.15±5.0°C and 207.38±5.0°C.

In an optional embodiment, the DSC spectrum of the crystalline form A is substantially as shown in FIG6 .

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a hemi-fumarate salt or co-crystal of the compound of formula (I), which is Form B, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5, and the Form B has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 9.687±0.20°, 17.919±0.20°, and 22.347±0.20°.

In an optional embodiment, the crystalline form B has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 9.687±0.20°, 13.530±0.20°, 15.452±0.20°, 17.919±0.20°, 19.654±0.20°, and 22.347±0.20°.

In an optional embodiment, the crystalline form B has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 9.687±0.2°, 12.626±0.20°, 13.530±0.20°, 15.452±0.20°, 17.919±0.20°, 19.413±0.20°, 19.654±0.20°, 20.099±0.20°, 20.481±0.20°, 21.483±0.20°, 21.849±0.20°, 22.347±0.20°, 22.561±0.20°, 24.108±0.20°, and 28.449±0.20°.

In an optional embodiment, the crystalline form B has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 9.687±0.2°, 12.626±0.20°, 13.530±0.20°, 15.452±0.20°, 15.886±0.20°, 16.477±0.20°, 17.919±0.20°, 19.413±0.20° There are diffraction peaks at 19.654±0.20°, 20.099±0.20°, 20.481±0.20°, 21.483±0.20°, 21.849±0.20°, 22.347±0.20°, 22.561±0.20°, 23.762±0.20°, 24.108±0.20°, and 28.449±0.20°.

In an optional embodiment, the crystalline form B has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as substantially as shown in FIG. 7 .

In an alternative embodiment, the TGA chart of Form B is substantially as shown in FIG8 .

In an alternative embodiment, the crystalline form B has a DSC spectrum with an endothermic peak at 190.72±5.0°C.

In an optional embodiment, the DSC spectrum of the crystalline form B is substantially as shown in FIG. 9 .

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a fumarate salt or co-crystal of the compound of formula (I), which is Form F, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:1, and the Form F has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 11.124±0.20°, 22.484±0.20°, and 26.488±0.20°.

In an optional embodiment, the crystalline form F has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 11.124±0.20°, 15.890±0.20°, 21.250±0.20°, 22.484±0.20°, 23.432±0.20°, 24.341±0.20°, and 26.488±0.20°.

In an optional embodiment, the crystalline form F has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 11.124±0.20°, 15.890±0.20°, 17.194±0.20°, 17.834±0.20°, 20.004±0.20°, 21.250±0.20°, 21.810±0.20°, 22.484±0.20°, 23.432±0.20°, 24.341±0.20°, 26.488±0.20°, and 28.270±0.20°.

In an optional embodiment, the crystalline form F has an X-ray powder diffraction pattern represented by a diffraction angle 2θ. 10.527±0.20°, 11.124±0.20°, 12.759±0.20°, 13.438±0.20°, 13.853±0.20°, 15.890±0.20°, 16.7 12±0.20°, 17.194±0.20°, 17.528±0.20°, 17.834±0.20°, 18.480±0.20°, 20.004±0.20°, 21.250±0. There are diffraction peaks at 20°, 21.810±0.20°, 22.484±0.20°, 23.432±0.20°, 24.341±0.20°, 25.771±0.20°, 26.156±0.20°, 26.488±0.20°, 28.270±0.20°, 30.004±0.20°, 31.712±0.20°, 32.200±0.20°, and 33.845±0.20°.

In an optional embodiment, the crystalline form F has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as substantially as shown in FIG. 16 or FIG. 17 .

In an alternative embodiment, the TGA graph of Form F is substantially as shown in FIG. 18 .

In an alternative embodiment, the crystalline form F has a DSC spectrum with an endothermic peak at 220.26±5.0°C.

In an optional embodiment, the DSC spectrum of the crystalline form F is substantially as shown in Figure 19.

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a gentisate or co-crystal of the compound of formula (I), and the gentisate or co-crystal is in a crystalline form, wherein the molar ratio of the compound of formula (I) to gentisic acid is 1:1.

In an optional embodiment, the salt or cocrystal of the compound of formula (I) is a gentisate or cocrystal of the compound of formula (I), which is Form D, wherein the molar ratio of the compound of formula (I) to gentisic acid is 1:1, and the Form D has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 11.081±0.20°, 22.268±0.20°, and 26.418±0.20°.

In an optional embodiment, the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 11.081±0.20°, 16.885±0.20°, 19.638±0.20°, 22.268±0.20°, 23.217±0.20°, 24.261±0.20°, 25.901±0.20°, and 26.418±0.20°.

In an optional embodiment, the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 11.081±0.20°, 12.464±0.20°, 13.847±0.20°, 15.743±0.20°, 16.885±0.20°, 18.430±0.20°, 19.638±0.20°, 21.0 There are diffraction peaks at 20±0.20°, 21.700±0.20°, 22.268±0.20°, 23.217±0.20°, 24.261±0.20°, 25.901±0.20°, 26.418±0.20°, 26.593±0.20°, 28.233±0.20°, and 33.826±0.20°.

In an optional embodiment, the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 11.081±0.20°, 12.464±0.20°, 13.847±0.20°, 15.743±0.20°, 16.532±0.20°, 16.885±0.20°, 17.424±0.20°, 18.267±0.20°, 18.430±0.20°, 19.6 There are diffraction peaks at 38±0.20°, 21.020±0.20°, 21.700±0.20°, 22.268±0.20°, 23.217±0.20°, 24.261±0.20°, 25.901±0.20°, 26.418±0.20°, 26.593±0.20°, 28.233±0.20°, 31.369±0.20°, and 33.826±0.20°.

In an optional embodiment, the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG. 10 .

In an alternative embodiment, the TGA chart of Form D is substantially as shown in FIG. 11 .

In an alternative embodiment, the crystalline form D has a DSC spectrum with an endothermic peak at 231.29±5.0°C.

In an optional embodiment, the DSC spectrum of the crystalline form D is substantially as shown in FIG. 12 .

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a camphorate or co-crystal of the compound of formula (I), and the camphorate or co-crystal is in a crystalline form, wherein the molar ratio of the compound of formula (I) to camphoric acid is 1:1.

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a camphorate or co-crystal of the compound of formula (I), which is Form E, wherein the molar ratio of the compound of formula (I) to camphoric acid is 1:1, and the Form E has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 9.367±0.20°, 16.622±0.20°, 17.748±0.20°, and 19.070±0.20°.

In an optional embodiment, the crystalline form E has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 9.367±0.20°, 13.775±0.20°, 16.622±0.20°, 17.748±0.20°, 18.421±0.20°, 19.070±0.20°, and 23.983±0.20°.

In an optional embodiment, the crystalline form E has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 9.196±0.20°, 9.367±0.20°, 13.775±0.20°, 16.622±0.20°, 17.748±0.20°, 18.421±0.20°, 19.070±0.20°, 19.285±0.20°, 19.474±0.20°, 19.676±0.20°, 22.331±0.20°, 23.983±0.20°, 25.766±0.20°, and 28.031±0.20°.

In an optional embodiment, the crystalline form E has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 9.196±0.20°, 9.367±0.20°, 10.688±0.20°, 13.775±0.20°, 14.477±0.20°, 15.381±0.20°, 16.203±0.20°, 16.622±0.20°, 17.071±0.20°, 17.263±0.20°, 17.748±0.20°, 18.421±0.20°, 19.070±0.20 °, 19.285±0.20°, 19.474±0.20°, 19.676±0.20°, 20.956±0.20°, 21.233±0.20°, 22.331±0. There are diffraction peaks at 20°, 22.787±0.20°, 23.327±0.20°, 23.682±0.20°, 23.983±0.20°, 24.434±0.20°, 25.766±0.20°, 26.312±0.20°, 26.892±0.20°, 28.031±0.20°, 33.343±0.20°, and 33.926±0.20°.

In an optional embodiment, the crystalline form E has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as substantially as shown in FIG. 13 .

In an optional embodiment, the TGA chart of Form E is substantially as shown in Figure 14.

In an alternative embodiment, the crystalline form E has a DSC spectrum with an endothermic peak at 234.06±5.0°C.

In an optional embodiment, the DSC spectrum of the crystalline form E is substantially as shown in FIG. 15 .

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a methanesulfonate salt or co-crystal of the compound of formula (I), and the methanesulfonate salt or co-crystal is in a crystalline form, wherein the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1.

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a methanesulfonate or co-crystal of the compound of formula (I), which is Form G, wherein the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1, and the Form G has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 18.105±0.20°, 22.366±0.20°, and 24.239±0.20°.

In an optional embodiment, the crystalline form G has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 10.608±0.20°, 16.196±0.20°, 16.871±0.20°, 18.105±0.20°, 18.873±0.20°, 22.366±0.20°, 23.949±0.20°, and 24.239±0.20°.

In an optional embodiment, the crystalline form G has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as substantially shown in FIG. 20 .

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is the hydrochloride salt or co-crystal of the compound of formula (I), and the hydrochloride salt or co-crystal is in a crystalline form, wherein the molar ratio of the compound of formula (I) to hydrochloric acid is 1:1.

In an optional embodiment, the salt or co-crystal of the compound of formula (I) is a hydrochloride or co-crystal of the compound of formula (I), which is Form H, wherein the molar ratio of the compound of formula (I) to hydrochloric acid is 1:1, and the Form H has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with diffraction peaks at 6.723±0.20°, 18.390±0.20°, and 22.860±0.20°.

In an optional embodiment, the crystalline form H has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 10.608±0.20°, 6.723±0.20°, 10.383±0.20°, 18.390±0.20°, 20.696±0.20°, 22.860±0.20°, 26.081±0.20°, and 27.815±0.20°.

In an optional embodiment, the crystalline form H has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as substantially as shown in FIG. 21 .

On the other hand, the present disclosure also provides a method for preparing the aforementioned crystalline form I, comprising: adding the compound of formula (I) to isopropyl ether, and slurrying at room temperature for 8-15 hours to prepare crystalline form I.

On the other hand, the present disclosure also provides a method for preparing the aforementioned crystal form II, comprising: dissolving the compound of formula (I) in an ethanol aqueous solution, stirring, heating, dissolving, cooling to precipitate a solid; repeatedly heating, dissolving, cooling to precipitate a solid 2-3 times to prepare the crystal form II.

In another aspect, the present disclosure also provides a method for preparing a salt or co-crystal of the compound of the aforementioned formula (I), comprising:

(a) adding the compound of formula (I) into solvent (i) and dissolving it at room temperature or by heating,

(b) adding acid, stirring and crystallizing,

The acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid.

In an optional embodiment, in the method for preparing the crystal of the salt or co-crystal of the compound of formula (I), the solvent (i) is selected from any one of acetonitrile, methanol, ethanol, ethyl acetate or a mixed solvent thereof.

In an optional embodiment, in the method for preparing the crystallization of the salt or co-crystal of the compound of formula (I), the volume (ml) of the solvent (i) is 1 to 50 times, preferably 5 to 20 times, and more preferably 10 to 20 times the weight (g) of the compound.

The present disclosure also provides a method for preparing a hemi-fumarate or co-crystal form A of a compound of formula (I), comprising (a) adding the compound of formula (I) into methanol and dissolving it at room temperature or by heating, and (b) adding fumaric acid and stirring to crystallize; wherein the molar ratio of fumaric acid to the compound of formula (I) is 0.5 to 0.6:1.

The present disclosure also provides a method for preparing a hemi-fumarate salt or co-crystal form B of a compound of formula (I), comprising adding a hemi-fumarate salt form A of the compound of formula (I) to acetonitrile, slurrying at room temperature, and crystallizing.

The present disclosure also provides a method for preparing a fumarate salt or cocrystal form F of a compound of formula (I), comprising adding a hemifumarate salt or cocrystal form B of the compound of formula (I) to ethyl acetate, adding fumaric acid, heating to reflux, filtering, cooling, and stirring to crystallize.

The present disclosure also provides another method for preparing a fumarate salt or cocrystal form F of a compound of formula (I), comprising adding fumaric acid to ethyl acetate, heating to dissolve, adding the compound of formula (I), dissolving, cooling, removing part of the solvent, cooling, and stirring to crystallize.

In an optional embodiment, in the method for preparing a fumarate salt of the compound of formula (I) or a cocrystal form F, the molar ratio of fumaric acid to the compound of formula (I) is 0.9 to 1.2:1.

In an optional embodiment, in the method for preparing a fumarate salt of the compound of formula (I) or cocrystal form F, the molar ratio of fumaric acid to the compound of formula (I) is 1:1.

On the other hand, the present disclosure provides a pharmaceutical composition, which comprises the crystalline form I or crystalline form II of the compound of formula (I) described in the present disclosure, or the crystal of the salt or co-crystal formed by the compound of formula (I) and an acid (the acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid), and pharmaceutically acceptable excipients.

On the other hand, the present disclosure provides a method for treating a disease or condition mediated by USP1 in a mammal, comprising administering a therapeutically effective amount of crystalline Form I or Form II of the compound of formula (I) described in the present disclosure, or a crystal of a salt or co-crystal formed by the compound of formula (I) and an acid (the acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid), or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

On the other hand, the present disclosure provides use of Form I or Form II of the compound of formula (I), or a salt or co-crystal formed by the compound of formula (I) and an acid (the acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid) in the preparation of a medicament for preventing or treating a disease or condition mediated by USP1.

On the other hand, the present disclosure provides use of Form I or Form II of the compound of formula (I), or a salt or co-crystal formed by the compound of formula (I) and an acid (the acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid) in preventing or treating diseases or conditions mediated by USP1.

On the other hand, the present disclosure provides a crystalline form I or crystalline form II of the compound of formula (I) described in the present disclosure, or a crystal of a salt or co-crystal formed by the compound of formula (I) and an acid (the acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid), or a pharmaceutical composition thereof for preventing or treating a disease or condition mediated by USP1.

In an optional embodiment, the crystal of the salt or co-crystal formed by the compound of formula (I) and the acid is selected from the hemifumarate or co-crystal form A of the compound of formula (I), the hemifumarate or co-crystal form B of the compound of formula (I), the gentisate or co-crystal form D of the compound of formula (I), the camphorate or co-crystal form E of the compound of formula (I) and the fumarate or co-crystal form F of the compound of formula (I). In an optional embodiment, the crystal of the salt or co-crystal formed by the compound of formula (I) and the acid is the hemifumarate or co-crystal form A of the compound of formula (I), the hemifumarate or co-crystal form B of the compound of formula (I) or the fumarate or co-crystal form F of the compound of formula (I).

The diseases or conditions mediated by USP1 described in the present disclosure include, but are not limited to, tumors.

In alternative embodiments, the tumor is, for example, a solid tumor, an adenocarcinoma, or a hematological cancer, such as breast cancer.

Beneficial effects:

The crystal forms I and II of the compound of formula (I) described in the present invention (preferably the crystal form II of the compound of formula (I)) and the crystals of the salts or co-crystals of the compound of formula (I) (including the hemifumarate or co-crystal form A of the compound of formula (I), the hemifumarate or co-crystal form B of the compound of formula (I), the gentisate or co-crystal form D of the compound of formula (I), the camphorate or co-crystal form E of the compound of formula (I) and the fumarate or co-crystal form F of the compound of formula (I), preferably the fumarate or co-crystal of the compound of formula (I)) have one or more of the following advantages: good chemical stability, good physical stability, high solubility, low hygroscopicity, high crystallinity, high bioavailability, better pharmacokinetics, high safety, and are suitable for preparing the desired pharmaceutical composition.

Unless otherwise specified, the terms used in this disclosure have the following meanings. The definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a commercial term appears in this document, When referring to a product name, it is intended to refer to the corresponding product or its active ingredient.

Unless otherwise indicated, the terms "comprise", "comprise" or "comprises" and variations thereof, such as comprises or comprising, shall be construed in an open, non-exclusive sense, ie, "including but not limited to".

Reference to an "alternative embodiment" or "embodiment" in this disclosure refers to at least one embodiment including the specific referenced elements, structures, or features associated with the embodiment described. Therefore, the phrases "alternative embodiment" or "embodiment" appearing in different places in this disclosure do not necessarily all refer to the same embodiment. In addition, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

The term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that (i) treats a particular disease, condition, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or (iii) delays the onset of one or more symptoms of a particular disease, condition as described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) inhibiting a disease or disease state, i.e. arresting its development;

(ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes:

Preventing a disease or disease state from occurring in a subject (eg, a mammal) is particularly useful when such subject is susceptible to having the disease state but has not yet been diagnosed as having the disease state.

As used herein, examples of the term "mammal" include, but are not limited to, any member of the class Mammalian: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure or its pharmaceutically acceptable salt or cocrystal or solvate with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts or cocrystals thereof, or solvates thereof, or pharmaceutical compositions comprising the same, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure or their pharmaceutically acceptable salts or solvates to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or dragee cores. Suitable excipients include But not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

The therapeutically effective amount of the crystalline form of the compound of formula (I)/the pharmaceutically acceptable salt or co-crystal of the compound of formula (I) contained in the pharmaceutical composition of the present disclosure is selected from 0.001 mg/kg body weight to 1000 mg/kg body weight, for example 0.01 mg/kg body weight to 500 mg/kg body weight, in the form of single or divided doses.

The room temperature described in the present disclosure refers to 20±5.0°C.

The range “m˜n” described in the present disclosure represents an abbreviation of any combination of real numbers between m and n, wherein m and n are both real numbers.

The “X-ray powder diffraction pattern” described in the present disclosure is obtained by measuring using Cu Kα radiation.

The "X-ray powder diffraction pattern" or "XRPD pattern" described in the present disclosure refers to the Bragg formula 2d sinθ=nλ (wherein, d is the crystal plane spacing, θ is the diffraction angle, λ is the wavelength of the incident X-ray, the diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1). When the X-ray is incident on an atomic plane with a lattice plane spacing of a crystal or a partial crystal sample at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle), the Bragg equation is satisfied, thereby measuring this set of X-ray powder diffraction patterns.

For the same type of crystal form of the same compound, the peak positions of their XRPD patterns are similar overall, and the relative intensity errors may be large. It should also be noted that in the identification of mixtures, some diffraction lines may be missing due to factors such as decreased content. At this time, it is not necessary to rely on all the diffraction peaks observed in high-purity samples, and even one diffraction peak may be characteristic for a given crystal.

The "2θ or 2θ angle" described in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree.

For those skilled in the art, due to factors such as crystal defects and measurement errors, the molar ratio of the disclosed compound to the acid/base molecule and the solvent molecule in the solvate often has a certain degree of error. Generally speaking, ±10% is within the reasonable error range. There is a certain degree of error variation depending on the context where it is used, and the error variation does not exceed ±10%, preferably ±5%.

Those skilled in the art recognize that the measured data of the XRPD peak position and/or intensity for a given crystalline form of the same compound will vary within the error range. The 2θ values in the present disclosure cover an appropriate error range, which is usually represented by "±". For example, the 2θ values represented by a specific angle value of ±0.20° in the present disclosure represent that the specific angle value has an error range of ±0.20°, that is, 5.92±0.20°2θ means that 2θ is in the range of 6.12 to 5.72. Depending on the sample preparation technology, the calibration technology applied to the instrument, human operating bias, etc., those skilled in the art recognize that the appropriate error range for the XRPD diffraction angle may be ±0.20°, ±0.15°, ±0.10°, ±0.05° or less, and the peak intensity allows a certain variability. The terms "substantially the same" or "substantially as shown" or "substantially as shown" when used to describe an XRPD pattern refer to a pattern comprising diffraction peaks having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% of the diffraction angles within a standard deviation of ±0.20° 2θ.

As those skilled in the art recognize that the measured data of the DSC spectra for a given crystalline form of the same compound will vary within the error tolerance. The single peak value (expressed in degrees Celsius) allows for an appropriate error range. Typically, the error range is represented by "±". For the same type of crystal form of the same compound, in continuous analysis, the thermal transition temperature and melting point errors are typically within ± 5.0 ° C. For example, the peak value of "140.96 ± 5.0" is represented in the range of 145.96 to 135.96. Depending on the sample preparation technique, the calibration technique applied to the instrument, human operating bias, etc., those skilled in the art recognize that the appropriate error range for the single peak value may be ± 5.0, ± 4.0, ± 3.0, ± 2.0 or less.

In order to provide a more concise description, some quantitative data in this article do not use the term "about". It should be understood that, whether the term "about" is used explicitly or not, each numerical value given here includes not only the actual given value (given value), but also means to include an approximate value of such given value reasonably inferred by a person of ordinary skill in the art, including equivalents and approximate values of such given value due to experimental and/or measurement conditions. The approximate value is preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2% or ±1% based on the given value.

The compounds of formula (I) or their salt crystalline forms disclosed herein may also be isotopically labeled. The disclosure also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that may be incorporated into the compounds of the disclosure include hydrogen, Isotopes of carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, respectively.

Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.

Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein deuterium substitution may be partial or full, partial deuterium substitution meaning that at least one hydrogen is replaced by deuterium.

The test conditions of the instruments used in this public experiment are:

1. X-ray powder diffraction

Instrument model: Bruker D8 Focus

X-ray source: Cu Kα

Kα1 1.54060; Kα2 1.54439; Kα2/Kα1 intensity ratio: 0.50

Wavelength 1.54060

Slit ( ^o ): 2.5

Scanning mode: θ/2θ, scanning range: 3-40 ^o (2θ angle)

Dwell time (seconds): 0.12

Scan step ( ^o 2θ): 0.01

Scanning flow rate: 5 ^o /min

Voltage: 40kV

Current: 40mA

2. Differential Scanning Calorimetry (DSC)

Instrument model: Discovery DSC2500

Purge gas: Nitrogen

Sample pan: Aluminum pan, non-sealed cover

Method: Linear temperature ramp

Heating rate: 10℃/min

Temperature range: 30℃～300℃

3. Thermogravimetric analysis (TGA) instrument

Instrument model: Discovery TA 55

Purge gas: Nitrogen

Sample pan: platinum, open

Method: Linear temperature ramp

Heating rate: Starting from the initial temperature of 30°C, the temperature is increased at a rate of 10°C per minute to 300°C

Temperature range: 30℃～300℃

The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

XRPD pattern of the crystalline form I of the compound of formula (I) as shown in FIG1 ;

FIG2 shows an XRPD pattern of the crystalline form II of the compound of formula (I);

FIG3 is a TGA diagram of the crystalline form II of the compound of formula (I);

FIG4 is a DSC diagram of the crystalline form II of the compound of formula (I);

FIG5 is an XRPD pattern of the hemifumarate or cocrystal Form A of the compound of formula (I);

FIG6 is a DSC spectrum of the hemi-fumarate or co-crystal Form A of the compound of formula (I);

FIG. 7 shows an XRPD pattern of the hemifumarate or cocrystal Form B of the compound of formula (I);

FIG8 is a TGA diagram of the hemi-fumarate salt or co-crystal Form B of the compound of formula (I);

FIG9 is a DSC graph of the hemi-fumarate salt or co-crystal Form B of the compound of formula (I);

FIG10 is an XRPD pattern of the gentisate salt or cocrystal Form D of the compound of formula (I);

FIG11 is a TGA chart of the gentisate salt or cocrystal form D of the compound of formula (I);

FIG12 is a DSC graph of the gentisate salt or cocrystal form D of the compound of formula (I);

FIG. 13 shows an XRPD pattern of the camphorate salt or co-crystal Form E of the compound of formula (I);

FIG14 is a TGA chart of the camphorate salt or co-crystal Form E of the compound of formula (I);

FIG15 is a DSC graph of the camphorate salt or co-crystal Form E of the compound of formula (I);

FIG. 16 shows the XRPD pattern of the fumarate salt or co-crystal Form F of the compound of formula (I);

FIG. 17 shows another XRPD pattern of the fumarate salt or cocrystal Form F of the compound of formula (I);

FIG18 is a TGA chart of the fumarate salt or co-crystal Form F of the compound of formula (I);

FIG19 is a DSC graph of the fumarate salt or co-crystal Form F of the compound of formula (I);

FIG20 shows an XRPD pattern of the mesylate salt or co-crystal Form G of the compound of formula (I);

FIG. 21 shows the XRPD pattern of the hydrochloride salt or cocrystal Form H of the compound of formula (I).

DETAILED DESCRIPTION

The present disclosure is explained in more detail below in conjunction with embodiments or test examples. The embodiments or test examples in the present disclosure are only used to illustrate the technical solutions of the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

The structures of the compounds were determined by nuclear magnetic resonance (NMR). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The measurement solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ) or the like, and the internal standard is tetramethylsilane (TMS).

The reagents used in the present disclosure can be obtained through commercial channels. All solvents used in the present disclosure are commercially available and used without further purification.

Unless otherwise specified, the ratio of mixed solvents is the volume ratio. For example, "5-95% acetonitrile/water" means that in the gradient elution process, the volume ratio of acetonitrile to water in the mixed eluent is 5:95-95:5.

Unless otherwise specified, % refers to mass % by weight.

The compounds were named manually or by software, and commercially available compounds used the supplier's catalog names.

Example 1 Preparation of the compound of formula (I)

Add 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (7.5 mg, 14 μmol), cesium carbonate (9.1 mg, 28 μmol), and then add N,N-dimethylformamide (0.50 mL) to the reaction bottle. Cool the mixture to 0°C, add iodomethane (2.0 mg, 14 μmol, 0.87 μL) dropwise, and react for 30 min. 0.2 mL of water was added to the resulting mixture, and the resulting mixture was purified by preparative chromatography (Waters Xbridge C18, 5-95% acetonitrile/water mobile phase) to obtain a white solid compound of formula (I) (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one).

m/z(ESI):551[M+H] ⁺

1H NMR(400MHz,Chloroform-d)δ8.62(s,1H),8.14(s,1H),7.93(s,1H),7.67(d,J＝8.2Hz,2H),7.48(d,J＝ 8.2H z,2H),4.83(s,2H),4.23(s,2H),3.85(s,3H),3.76(s,3H),3.30(s,3H),1.79(m,1H),1.00(m ,2H),0.84(m,2H).

Example 2 Compound of Formula (I) Crystalline Form I

50 mg of the compound of formula (I) prepared in Example 1 was placed in a 5 mL centrifuge tube, 1 mL of isopropyl ether was added, and the mixture was slurried at room temperature for 12 h. The filter cake was vacuum dried at room temperature to obtain the crystalline form I of the compound of formula (I).

The XRPD spectrum of the crystalline form I of the compound of formula (I) is shown in FIG1 , and its XRPD diffraction peak parameters are shown in Table 1 below.

Table 1 XRPD diffraction peak parameters of the crystalline form I of the compound of formula (I)

Example 3 Crystalline Form II of the Compound of Formula (I)

Take 3g of Form I of the compound of formula (I) and put it in a 50mL three-necked flask, add 18mL of 50% ethanol aqueous solution, stir at room temperature, if it is not dissolved, heat it to 75°C, slowly cool it to 18°C after it is dissolved, and solid precipitates. Continue to heat it to 75°C, slowly cool it to 20°C after it is dissolved, and a large amount of solid precipitates. Stir for 20 minutes and continue to heat it to 75°C, slowly cool it to 20°C after it is dissolved, and more solid precipitates. Filter it with suction, rinse it with 50% ethanol water, and dry the filter cake in vacuo at 45°C to obtain Form II of the compound of formula (I).

The XRPD spectrum of the crystalline form II of the compound of formula (I) is shown in FIG2 , the TGA spectrum is shown in FIG3 , and the DSC spectrum is shown in FIG4 . The endothermic peak is near 159.22° C. The XRPD diffraction peak parameters are shown in Table 2 below.

Table 2 XRPD diffraction peak parameters of the crystalline form II of the compound of formula (I)

Example 4 Hemifumarate or co-crystal form A of the compound of formula (I) (i.e. the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5)

0.46 g of Form II of the compound of formula (I) was placed in a reaction bottle, 5 mL of methanol was added, and the mixture was stirred at room temperature to dissolve. 0.058 g of fumaric acid was added. After a large amount of white solid was precipitated, the temperature was lowered to 0-5°C under nitrogen protection, and the mixture was stirred for crystallization for one hour. The filter cake was rinsed with 0-5°C methanol, and the filter cake was vacuum dried at 55°C to obtain the hemifumarate or cocrystal Form A of the compound of formula (I).

¹ H NMR (400MHz, DMSO-d ₆ )δ13.15(s,1H),8.61(s,1H),8.13(s,1H),7.93(d,J＝1.5Hz,1H),7.66(d,J＝8 .0Hz,2H),7.47(d,J＝8.0Hz,2H),6.62(s,1H),4.82(s,2H),4.22(s,2H),3.84 (s,3H),3.75(s,3H),3.29(s,3H),1.78(dq,J＝8.1,4.1,3.6Hz,1H),0.99(p,J＝3.7Hz,2H),0.83( dq,J＝10.1,3.5Hz,2H).

The XRPD spectrum of the hemifumarate or cocrystal form A of the compound of formula (I) is shown in Figure 5, and the XRPD diffraction peak parameters are shown in Table 3 below. The DSC spectrum is shown in Figure 6, and the endothermic peaks are near 184.77°C, near 197.15°C and near 207.38°C.

Table 3 XRPD diffraction peak parameters of hemifumarate or cocrystal form A of compound of formula (I)

Example 5 Hemifumarate or co-crystal form B of the compound of formula (I) (i.e., the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5)

Take 2.0 g of the hemifumarate or cocrystal form A of the compound of formula (I) and place it in a 50 mL single-mouth bottle, add 20 mL of acetonitrile, slurry at room temperature for 24 hours, filter, and vacuum dry the filter cake at room temperature to obtain the hemifumarate or cocrystal form B of the compound of formula (I).

¹ H NMR (400MHz, DMSO-d ₆ )δ13.12(s,1H),8.61(s,1H),8.14(s,1H),7.92(d,J＝1.4Hz,1H),7.68–7.65(m,2H),7.48(d,J ＝8.0Hz,2H),6.62(s,1H),4.83(s,2H), 4.22(s,2H),3.85(s,3H),3.76(s,3H),3.30(s,3H),1.79(tt,J＝8.3,4.6Hz,1H),1.00(m,J＝3.6Hz ,2H),0.83(dq,J=10.2,3.4Hz,2H).

The XRPD spectrum of the hemifumarate or cocrystal form B of the compound of formula (I) is shown in Figure 7, the TGA spectrum is shown in Figure 8, and the DSC spectrum is shown in Figure 9. The DSC peak is around 190.72°C, and the XRPD diffraction peak parameters are shown in Table 4 below.

Table 4 XRPD diffraction peak parameters of hemifumarate or cocrystal form B of compound of formula (I)

Example 6 Gentisate or cocrystal form D of the compound of formula (I)

Take 100 mg of the crystal form II of the compound of formula (I) and place it in a 5 mL centrifuge tube, add 2 mL of ethanol, stir at room temperature until it dissolves, add 28.3 mg of gentisic acid, stir until more solids precipitate, filter, and vacuum dry the filter cake at room temperature to obtain the gentisate of the compound of formula (I) or the cocrystal form D.

¹ H NMR (400 MHz, DMSO-d ₆ )δ9.15(s,1H),8.62(s,1H),8.15(s,1H),7.94(q,J＝1.3Hz,1H),7.69–7.66(m, 2H),7.50–7.47(m,2H),7.15(d,J＝3.1Hz,1H),6.96(dd,J＝8.9,3.1Hz,1H),6.78 (d,J＝8.9Hz,1H),4.84(s,2H),4.23(s,2H),3.86(s,3H),3.77(s,3H),1.79(m, J＝8.1,4.1Hz,1H),1.23(s,1H),1.08–0.98(m,3H),0.85(dt,J＝8.2,3.3Hz,2H).

The XRPD spectrum of the gentisate or cocrystal form D of the compound of formula (I) is shown in Figure 10, the TGA spectrum is shown in Figure 11, and the DSC spectrum is shown in Figure 12. The DSC peak is around 231.29°C, and the XRPD diffraction peak parameters are shown in Table 5 below.

Table 5 XRPD diffraction peak parameters of gentisate or cocrystal form D of compound of formula (I)

Example 7 Camphorate or cocrystal form E of compound of formula (I)

100 mg of Form II of the compound of formula (I) was placed in a 5 mL centrifuge tube, 1 mL of acetonitrile was added, and the mixture was stirred at room temperature until dissolved. 37.1 mg of camphoric acid was added, and the mixture was stirred until a large amount of solid was precipitated. The mixture was filtered, and the filter cake was dried under vacuum at room temperature to obtain camphorate or cocrystal Form E of the compound of formula (I).

¹ H NMR (400MHz, DMSO-d ₆ )δ12.14(s,2H),8.62(s,1H),8.14(s,1H),7.94(d,J＝1.3Hz,1H),7.69–7.66(m,2H),7.48(d,J = 8.2Hz,2H),4.83(s,2H),4.23(s,2H),3.85(s,3H),3.76(s,3H),3.30(s,3H),2.75(d,J＝9.4Hz, 1H),2.37–2.32(m,1H),2.03–1.91(m,2H),1.81–1.77(m,1H),1.74–1.68(m,1H),1.38–1.33(m, 1H),1.19(s,3H),1.13(s,3H),1.00(t,J＝3.8Hz,2H),0.84(dd,J＝8.1,3.2Hz,2H),0.76(s,3H).

The XRPD spectrum of the camphorate salt or cocrystal form E of the compound of formula (I) is shown in Figure 13, the TGA spectrum is shown in Figure 14, and the DSC spectrum is shown in Figure 15. The DSC peak is around 234.06°C, and the XRPD diffraction peak parameters are shown in Table 6 below.

Table 6 XRPD diffraction peak parameters of camphorate salt or co-crystal form E of compound of formula (I)

Example 8 Fumarate salt of the compound of formula (I) or co-crystal form F (i.e. the molar ratio of the compound of formula (I) to fumaric acid is 1:1)

Preparation method 1: Add 1.80 g of hemifumarate or cocrystal form B of the compound of formula (I), 0.172 g of fumaric acid, and 36 mL of ethyl acetate to a reaction bottle, stir and heat to reflux, filter while hot after reflux, slowly cool the filtrate, stir and crystallize overnight, filter after a large amount of solid precipitates, and vacuum dry the filter cake at 45°C to obtain 1.25 g of fumarate or cocrystal form F of the compound of formula (I) in solid form.

Preparation method 2: Add 2.108 g of fumaric acid and 200 mL of ethyl acetate to a reaction bottle, protect with nitrogen, stir and heat to 60-65°C, add 10.0 g of the compound of formula (I) prepared in Example 1 after the solid is dissolved, stop heating after the solid is dissolved, slowly cool to 30°C and stir overnight, continue to cool to 20°C, distill under reduced pressure to remove ethyl acetate, slowly cool to 0-10°C, stir for 2h and then filter, rinse the filter cake with 20 ml of ethyl acetate and vacuum dry at 50°C to obtain 8.87 g of fumarate or cocrystal form F of the compound of formula (I) in solid form.

¹ H NMR (400MHz, DMSO-d ₆ )δ13.13(s,2H),8.62(s,1H),8.14(s,1H),7.93(d,J＝1.4Hz,1H),7.69–7.66(m,2H),7.50–7.47(m ,2H),6.63(s,2H),4.83(s ,2H),4.23(s,2H),3.86(s,3H),3.76(s,3H),3.30(s,3H),1.82–1.77(m,1H),1.00(dq,J＝6.1,3.5 Hz,2H),0.86–0.82(m,2H).

The XRPD spectrum of the fumarate salt or co-crystal form F of the compound of formula (I) prepared by method 1 is shown in Figure 16, the TGA spectrum is shown in Figure 18, and the DSC spectrum is shown in Figure 19. The DSC peak is around 220.26°C, and the XRPD diffraction peak parameters are shown in Table 7 below. The XRPD spectrum of the fumarate salt or co-crystal form F of the compound of formula (I) prepared by method 2 is shown in Figure 17, Its XRPD diffraction peak parameters are shown in Table 8 below.

Table 7 XRPD diffraction peak parameters of the fumarate salt or co-crystal form F of the compound of formula (I)

Table 8 XRPD diffraction peak parameters of the fumarate salt or co-crystal form F of the compound of formula (I)

Example 9 Methanesulfonate or co-crystal form G of the compound of formula (I)

Take 26 g of Form II of the compound of formula (I) in a 500 mL single-necked bottle, add 260 mL of ethyl acetate, stir to dissolve at room temperature, slowly add 4.54 g of methanesulfonic acid, stir until more solid precipitates, filter, and vacuum dry the filter cake at 45 ° C to obtain 10.3 g of a white solid, which is the methanesulfonate or cocrystal Form G of the compound of formula (I).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.73(s,1H),8.25(s,1H),7.94(d,J＝1.4Hz,1H),7.71–7.65(m,2H),7.51(d,J＝8.2Hz,2H), 4.98(s,2H),4.42( s,2H),3.92(s,3H),3.30(s,3H),2.31(s,3H),1.98–1.85(m,1H),1.05(dq,J＝6.5,3.6Hz,2H),0.89 –0.82(m,2H).

The XRPD spectrum of the mesylate salt or co-crystal form G of the compound of formula (I) is shown in Figure 20, and its XRPD diffraction peak parameters are shown in Table 9 below.

Table 9 XRPD diffraction peak parameters of the mesylate salt or co-crystal form G of the compound of formula (I)

Example 10 Hydrochloride or cocrystal form H of the compound of formula (I)

Take 3g of the crystal form II of the compound of formula (I) and add it to a three-necked flask, add 30mL of ethyl acetate, cool to -5°C under nitrogen protection, slowly drop 2.6mL 2mol/L hydrogen chloride ethyl acetate, filter after a large amount of solid precipitates, wash the filter cake with ethyl acetate, and then slurry the filter cake with 15mL of ethyl acetate for one hour, filter, and vacuum dry the filter cake at 45°C. Take 0.80g of the filter cake, add 8mL of anhydrous ethanol, heat to 62°C under nitrogen protection to dissolve, stop heating, slowly cool, filter after a large amount of solid precipitates, rinse with anhydrous ethanol, and vacuum dry the filter cake at 60°C to obtain the hydrochloride of the compound of formula (I) or the cocrystal crystal form H.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.71(s,1H),8.23(s,1H),7.94(d,J＝1.4Hz,1H),7.68(d,J＝8.1Hz,2H),7.50(d,J＝8.0Hz, 2H),4.96(s,2H),4.40(s,2H ),3.90(s,3H),3.75(s,3H),3.30(s,3H),1.87(m,J＝8.0,4.1Hz,1H),1.04(p,J＝3.5Hz,2H),0.84 (dq,J=10.5,3.6Hz,2H).

The XRPD spectrum of the hydrochloride salt or co-crystal form H of the compound of formula (I) is shown in Figure 21, and its XRPD diffraction peak parameters are shown in Table 10 below.

Table 10 XRPD diffraction peak parameters of the hydrochloride salt or co-crystal form H of the compound of formula (I)

Experimental Example 1: Chemical Stability Data

Experimental method: The samples of Examples 1, 2, 4 to 10 were placed in a 2 mL screw-top brown sample bottle and left open. The stability of the samples was investigated under high temperature 40°C, high temperature 60°C, high humidity (40°C, 75% RH), high temperature and high humidity (60°C, 92.5% RH) conditions (see the placement conditions in Table 11 for details, for example, 60°C + 92.5% RH-3d means placing under high temperature and high humidity (60°C, 92.5% RH) conditions for 3 days). The results are shown in Table 11. The above results show that the stability of the compound of formula (I) crystal form I, the compound of formula (I) hemifumarate or cocrystal crystal form A and crystal form B, the compound of formula (I) gentisate or cocrystal crystal form D, the compound of formula (I) camphorate or cocrystal crystal form E, and the compound of formula (I) fumarate or cocrystal crystal form F is good.

Table 11 Chemical stability test results

Experimental Example 2: Physical Stability

The samples of Examples 2 to 8 were placed in a 2 mL screw-top brown sample bottle and left open. They were placed under high humidity (40°C, 75% RH) conditions for 1 month (1M), and the morphological changes of the samples were observed under an electron microscope. The results are shown in Table 12. After being placed under high humidity conditions for 1 month, the crystal habit of the crystal form I of the compound of formula (I) shrank, the agglomerates broke, and the powder state changed. The powder of the crystal form II of the compound of formula (I) did not change, and the physical stability was good. The crystal form II prepared in Example 3 had a higher degree of crystallinity, while the crystal form I prepared in Example 2 had a lower degree of crystallinity. The powder states of the hemifumarate or cocrystal form A and form B of the compound of formula (I), the gentisate or cocrystal form D of the compound of formula (I), the camphorate or cocrystal form E of the compound of formula (I), and the fumarate or cocrystal form F of the compound of formula (I) did not change, and the physical stability was good.

Table 12 Physical stability test results

Experimental Example 3: Solubility Experiment

The thermodynamic solubility of the compounds of the present disclosure was determined using the following test method.

1. Dissolution medium configuration

1. FeSSIF (simulated full intestinal fluid): Weigh 4.04g sodium hydroxide, 8.65g glacial acetic acid and 11.87g sodium chloride, add 900mL water to dissolve, adjust pH to 5.0 with 1N hydrochloric acid solution or 1N sodium hydroxide solution, add water to 1000mL to obtain buffer solution. Measure 50mL buffer solution and add 1.12g FeSSIF powder, stir to dissolve, then add buffer solution to 100mL and stir evenly.

2. Test steps

The thermodynamic solubility of the solids obtained in Examples 1, 2, 3, 4, 5, 6, 7, 8, and 9 of the present disclosure in the dissolution medium (FeSSIF) was investigated. 1000 μL of the dissolution medium was measured and placed in a 1 mL transparent glass tube. An appropriate amount of sample was weighed to saturate the solution and dispersed by shaking. The sample was placed on a roller mixer and shaken in the dissolution medium for a certain period of time (the sampling time was 1h/2h/4h (24h) respectively). An appropriate amount of sample was taken and filtered through a microporous filter membrane (Jin Teng Nylon 66, 0.45 μm). The content was determined using a high performance liquid chromatograph (Aglient 1200) using the external standard method, and the thermodynamic solubility (mg/mL) of the compound in the medium was calculated.

The solubility results are shown in Table 13.

Table 13 Solubility test results

Experimental Example 4: Moisture absorption test

Experimental method: The solids obtained in Examples 2, 4, 5, 6, 7, 8 and 10 above were placed in a constant humidity sealed container and placed at 25°C and relative humidity of 92.5%±5% for 14 days. The sampling time is detailed in Table 14. The weights of the example compounds before and after the test were accurately weighed, and the weight changes of the example compounds compared with 0 days were calculated to examine the hygroscopic and deliquescent properties of the example compounds. The experimental results are shown in Table 14.

Table 14 Hygroscopicity test results

Claims (17)

Crystals of the compound of formula (I):
The crystal of the compound of formula (I) according to claim 1, wherein the crystal is selected from Form I, and the Form I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 18.495±0.20°, 19.924±0.20°, and 22.000±0.20°; Alternatively, the crystalline form I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 13.288±0.20°, 13.680±0.20°, 16.935±0.20°, 18.495±0.20°, 19.924±0.20°, 22.000±0.20°, 22.613±0.20°, and 23.371±0.20°; Alternatively, the crystalline form I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 11.947±0.20°, 13.288±0.20°, 13.680±0.20°, 14.476±0.20°, 16.935±0.20°, 18.495±0.20°, 19.924±0.20°, 20.939±0.20°, 22.000±0.20°, 22.613±0.20°, 23.371±0.20°, 23.620±0.20°, 24.322±0.20°, and 25.232±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystalline form I represented by a diffraction angle 2θ is substantially as shown in FIG1 . The crystal of the compound of formula (I) according to claim 1, wherein the crystal is selected from Form II, and the Form II has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 7.029±0.20°, 22.059±0.20°, and 22.997±0.20°; Alternatively, the crystalline form II has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with diffraction peaks at 7.029±0.20°, 16.418±0.20°, 17.020±0.20°, 20.132±0.20°, 22.059±0.20°, 22.997±0.20°, and 23.806±0.20°; Alternatively, the crystalline form II has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has diffraction peaks at 7.029±0.20°, 11.503±0.20°, 15.015±0.20°, 16.418±0.20°, 17.020±0.20°, 19.547±0.20°, 20.132±0.20°, 22.059±0.20°, 22.997±0.20°, 23.806±0.20°, and 27.353±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystalline form II represented by a diffraction angle 2θ is substantially as shown in FIG. 2 . The crystal of the compound of formula (I) according to claim 3, wherein the crystalline form II has a DSC spectrum with an endothermic peak at 159.22±5.0°C; or, the DSC spectrum of the crystalline form II is substantially as shown in Figure 4; And/or the TGA diagram of the crystalline form II is substantially as shown in Figure 3. A salt or co-crystal formed by a compound of formula (I) and an acid,
The acid is selected from methanesulfonic acid, hydrochloric acid, fumaric acid, gentisic acid or camphoric acid; preferably fumaric acid, gentisic acid or camphoric acid, more preferably fumaric acid. The salt or co-crystal of the compound of formula (I) according to claim 5, wherein the molar ratio of the compound of formula (I) to the acid molecule is 1:1 to 1:0.5, preferably 1:1 or 1:0.5. The salt or co-crystal of the compound of formula (I) according to claim 5 or 6, wherein the salt or co-crystal of the compound of formula (I) is a fumarate or co-crystal of the compound of formula (I), and the molar ratio of the compound of formula (I) to fumaric acid is 1:1 to 1:0.5, preferably 1:1 or 1:0.5. The salt or co-crystal of the compound of formula (I) according to any one of claims 5 to 7, wherein the salt or co-crystal of the compound of formula (I) is a hemifumarate or co-crystal of the compound of formula (I), which is Form A, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5, and the Form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 4.409±0.20°, 9.695±0.20°, 20.134±0.20°, and 22.131±0.20°; or, the Form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 4.409±0.20°, 9.695±0.20°, 12.059±0.20°, 18.019±0.20°, 20.134±0.20°. 0.20°, 21.544±0.20°, and 22.131±0.20°; or, the crystalline form A has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 4.409±0.20°, 9.695±0.20°, 12.059±0.20°, 14.216±0.20°, 16.416±0.20°, 1 There are diffraction peaks at 6.890±0.20°, 18.019±0.20°, 20.134±0.20°, 21.544±0.20°, 22.131±0.20°, 23.794±0.20°, and 26.493±0.20°; or, the X-ray powder diffraction pattern of the crystalline form A represented by the diffraction angle 2θ is substantially as shown in Figure 5. The salt or co-crystal of the compound of formula (I) according to claim 8, wherein the crystalline form A has a DSC spectrum with endothermic peaks at 184.77±5.0°C, 197.15±5.0°C and 207.38±5.0°C; or, the DSC spectrum of the crystalline form A is substantially as shown in Figure 6. The salt or co-crystal of the compound of formula (I) according to any one of claims 5 to 7, wherein the salt or co-crystal of the compound of formula (I) is a hemi-fumarate or co-crystal of the compound of formula (I), which is Form B, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5, and the Form B has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 9.687±0.20°, 17.919±0.20°, and 22.347±0.20°; or, the Form B has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 9.687±0. 20°, 13.530±0.20°, 15.452±0.20°, 17.919±0.20°, 19.654±0.20°, and 22.347±0.20°; or, the crystalline form B has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 9.687±0.2°, 12.626±0.20°, 13.530±0.20°, 15.452±0.20°, 17.919±0.20°, 19.413±0.20°, 19.654±0.20°, 20.099±0. 20°, 20.481±0.20°, 21.483±0.20°, 21.849±0.20°, 22.347±0.20°, 22.561±0.20°, 24.108±0.20°, and 28.449±0.20°; or, the crystalline form B has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 9.687±0.2°, 12.626±0.20°, 13.530±0.20°, 15.452±0.20°, 15.886±0.20°, 16.477±0. 7. The crystal form B has diffraction peaks at 20°, 17.919±0.20°, 19.413±0.20°, 19.654±0.20°, 20.099±0.20°, 20.481±0.20°, 21.483±0.20°, 21.849±0.20°, 22.347±0.20°, 22.561±0.20°, 23.762±0.20°, 24.108±0.20°, and 28.449±0.20°; or, the X-ray powder diffraction pattern of the crystal form B represented by the diffraction angle 2θ is substantially as shown in Figure 7. The salt or co-crystal of the compound of formula (I) according to claim 10, wherein the crystalline form B has a DSC spectrum with an endothermic peak at 190.72±5.0°C; or, the DSC spectrum of the crystalline form B is substantially as shown in Figure 9; and/or the TGA diagram of the crystalline form B is substantially as shown in Figure 8. The salt or co-crystal of the compound of formula (I) according to any one of claims 5 to 7, wherein the salt or co-crystal of the compound of formula (I) is a fumarate or co-crystal of the compound of formula (I), which is Form F, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:1, and the Form F has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 11.124±0.20°, 22.484±0.20°, and 26.488±0.20°; or, the Form F has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 11.124±0.20°, 15.890±0.20°, 21.250±0.20°, 22.484±0.20°, 23.432±0.20°, 24.341±0.20°, and 26.488±0.20° have diffraction peaks; or, the crystalline form F, an X-ray powder diffraction pattern represented by a diffraction angle 2θ, has diffraction peaks at 11.124±0.20°, 15.890±0.20°, 17.194±0.20°, 17.834±0.20°, 20.004±0.20°, The crystal form F has diffraction peaks at 21.250±0.20°, 21.810±0.20°, 22.484±0.20°, 23.432±0.20°, 24.341±0.20°, 26.488±0.20°, and 28.270±0.20°; the X-ray powder diffraction pattern of the crystal form F expressed by the diffraction angle 2θ is at 10.527±0.20°, 11.124±0.20°, 12.759±0.20°, 13.438±0.20°, 13.853±0.20°, 15. 890±0.20°, 16.712±0.20°, 17.194±0.20°, 17.528±0.20°, 17.834±0.20°, 18.480±0.20°, 20.004±0.20°, 21.250±0 .20°, 21.810±0.20°, 22.484±0.20°, 23.432±0.20°, 24.341±0.20°, 25.771±0.20°, 26.156±0.20°, 26.488±0.20°, There are diffraction peaks at 28.270±0.20°, 30.004±0.20°, 31.712±0.20°, 32.200±0.20°, and 33.845±0.20°; or, the X-ray powder diffraction pattern of the crystal form F represented by the diffraction angle 2θ is basically as shown in Figure 16 or Figure 17. The salt or co-crystal of the compound of formula (I) according to claim 12, wherein the crystalline form F has a DSC spectrum with an endothermic peak at 220.26±5.0°C; or, the DSC spectrum of the crystalline form F is substantially as shown in Figure 19; and/or the TGA diagram of the crystalline form F is substantially as shown in Figure 18. The salt or co-crystal of the compound of formula (I) according to claim 5 or 6, wherein the salt or co-crystal of the compound of formula (I) is a gentisate or co-crystal of the compound of formula (I), which is a crystalline form D, wherein the molar ratio of the compound of formula (I) to gentisic acid is 1:1, and the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 11.081±0.20°, 22.268±0.20°, and 26.418±0.20°; or, the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 11.081±0.20°, 16.885±0.20°, 19.638±0.2 0°, 22.268±0.20°, 23.217±0.20°, 24.261±0.20°, 25.901±0.20°, and 26.418±0.20°; or, the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 11.081±0.20°, 12.464±0.20°, 13.847±0.20°, 15.743±0.20°, 16.885±0.20°, 18.430±0.20°, 19.638±0.20°, 21.020±0.20°, 21.700±0.20°, 22.26 8±0.20°, 23.217±0.20°, 24.261±0.20°, 25.901±0.20°, 26.418±0.20°, 26.593±0.20°, 28.233±0.20°, and 33.826±0.20° have diffraction peaks; or, the crystalline form D has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 11.081±0.20°, 12.464±0.20°, 13.847±0.20°, 15.743±0.20°, 16.532±0.20°, 16.885±0.20°, 17.424±0.20°, There are diffraction peaks at 18.267±0.20°, 18.430±0.20°, 19.638±0.20°, 21.020±0.20°, 21.700±0.20°, 22.268±0.20°, 23.217±0.20°, 24.261±0.20°, 25.901±0.20°, 26.418±0.20°, 26.593±0.20°, 28.233±0.20°, 31.369±0.20°, and 33.826±0.20°; or, the X-ray powder diffraction pattern of the crystalline form D represented by the diffraction angle 2θ is substantially as shown in Figure 10; Optionally, the crystalline form D has a DSC spectrum with an endothermic peak at 231.29±5.0°C; or, the DSC spectrum of the crystalline form D is substantially as shown in FIG. 12 ; and/or the TGA graph of the crystalline form D is substantially as shown in FIG. 11 . The salt or co-crystal of the compound of formula (I) according to any one of claims 5 or 6, wherein the salt or co-crystal of the compound of formula (I) is a camphorate or co-crystal of the compound of formula (I), which is Form E, wherein the molar ratio of the compound of formula (I) to camphoric acid is 1:1, and the Form E has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 9.367±0.20°, 16.622±0.20°, 17.748±0.20°, and 19.070±0.20°; or, the Form E has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and has diffraction peaks at 9.367±0.20°, 13.775±0.20°, 16.622±0.20°, 17 .748±0.20°, 18.421±0.20°, 19.070±0.20°, and 23.983±0.20°; or, the crystalline form E has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 9.196±0.20°, 9.367±0.20°, 13.775±0.20°, 16.622±0.20°, 17.748±0.20°, 18.421±0.20°, 19.070±0.20°, 19.285±0.20°, 19.474±0.20°, 19.676±0.20°, 22.331±0.20°, 23.983±0.20°, 25.76 6±0.20°, 28.031±0.20°; or, the crystalline form E has an X-ray powder diffraction pattern represented by a diffraction angle 2θ at 9.196±0.20°, 9.367±0.20°, 10.688±0.20°, 13.775±0.20°, 14.477±0.20°, 15.381±0.20°, 16.203±0.20°, 16.622±0.20°, 17.071±0.20°, 17.263±0.20°, 17.748±0.20°, 18.421±0.20°, 19.070±0.20°, 19.285±0.20°, 19.474±0.20° 14.434±0.20°, 15.766±0.20°, 26.312±0.20°, 26.892±0.20°, 28.031±0.20°, 33.343±0.20°, and 33.926±0.20°; or, the X-ray powder diffraction pattern of the crystalline form E represented by the diffraction angle 2θ is substantially as shown in Figure 13; Optionally, the crystalline form E has a DSC spectrum with an endothermic peak at 234.06±5.0°C; or, the DSC spectrum of the crystalline form E is substantially as shown in FIG. 15 ; and/or the TGA graph of the crystalline form E is substantially as shown in FIG. 14 . A pharmaceutical composition, wherein the pharmaceutical composition comprises a crystal of a compound of formula (I) according to any one of claims 1 to 4 or a salt or co-crystal of a compound of formula (I) according to any one of claims 5 to 15, and a pharmaceutically acceptable excipient. Use of a crystal of a compound of formula (I) according to any one of claims 1 to 4, a salt or co-crystal of a compound of formula (I) according to any one of claims 5 to 15, or a pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing or treating a disease or condition mediated by USP1.