Crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile

Abstract

The present invention relates to crystalline forms of 2-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride, pharmaceutically acceptable compositions containing these crystalline forms, and methods of using these crystalline forms.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 63 / 484,602, filed February 13, 2023, and U.S. Provisional Application No. 63 / 516,668, filed July 31, 2023, the disclosures of each of which are incorporated herein by reference in their entirety. [Technical Field]

[0002] FIELD OF THE INVENTION The present invention relates to the hydrochloride salt of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile and specific crystalline forms thereof, methods for preparing the crystalline forms, and pharmaceutical compositions containing the crystalline forms. The crystalline forms are useful for treating and / or preventing diseases and / or conditions associated with cell proliferation, such as cancer. In particular, the crystalline forms exert therapeutic effects as MTA-cooperative inhibitors of protein arginine N-methyltransferase 5 (PRMT5). [Background technology]

[0003] BACKGROUND OF THE INVENTION Protein arginine N-methyltransferase (PRMT5) is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the omega-nitrogen of the guanidino group of L-arginine residues in proteins (omega-monomethylation) and a second methyl group transfer to the other omega-nitrogen to generate symmetric dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylosomal protein 50), which is required for substrate recognition and orientation and for PRMT5-dependent SDMA modification of histone 2A and histone 4 methyltransferase activity (see, e.g., Ho et al. (2013) PLOS ONE 8(8):10.1371 / annotation / e6b5348e-9052-44ab-8f06-90d01dc88fc2).

[0004] Homozygous deletions of p16 / CDKN2a are common in cancer, and these mutations are commonly associated with co-deletions of neighboring genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of all human cancers harbor homozygous deletions of the MTAP gene (see, e.g., Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):13754-13760. doi:10.1021 / jacs.7b05803. Epub 2017 Sep 20).

[0005] Cells lacking MTAP activity have elevated concentrations of the MTAP substrate methylthioadenosine (MTA), a potent inhibitor of PRMT5. Inhibiting PRMT5 activity reduces its methylation activity and sensitizes cell proliferation to PRMT5 depletion or loss of activity. Thus, loss of MTAP activity reduces the methylation activity of PRMT5 and renders cells selectively dependent on PRMT5 activity.

[0006] Therefore, MTA-cooperative inhibition of PRMT5 activity in MTAP-deficient cancers may have therapeutic benefits for a wide range of cancers. The compounds of the present invention provide therapeutic benefit as MTA-cooperative inhibitors of PRMT5 that negatively regulate the activity of MTA-bound PRMT5 in cells (particularly MTAP-deficient cells), or for treating various forms of MTAP-associated cancers.

[0007] In particular, 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile has been shown to be a potent and selective inhibitor of PRMT5 and to be pharmacologically active. In the present application, a crystalline hydrochloride salt of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile has been found to be suitable for use in pharmaceutical compositions.

[0008] (Summary of the Invention) In one aspect, the present disclosure provides a crystalline form of the hydrochloride salt of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (hereinafter Compound 1), shown below. [ka]

[0009] In another aspect, the present disclosure also provides a particular crystalline form of Compound 1 (hereinafter Form A of the hydrochloric acid (HCl) salt). The present disclosure further provides a method for making Form A of the HCl salt. The present disclosure further provides a pharmaceutical composition comprising Form A of the HCl salt and a pharmaceutically acceptable carrier.

[0010] In another aspect, the present disclosure also provides a particular crystalline form of Compound 1 (hereinafter Form B of the hydrochloric acid (HCl) salt). The present disclosure further provides a method for making Form B of the HCl salt. The present disclosure further provides a pharmaceutical composition comprising Form B of the HCl salt and a pharmaceutically acceptable carrier.

[0011] In another aspect, the present disclosure also provides a particular crystalline form of Compound 1 (hereinafter Form E of the hydrochloric acid (HCl) salt). The present disclosure further provides a method for making Form E of the HCl salt. The present disclosure further provides a pharmaceutical composition comprising Form E of the HCl salt and a pharmaceutically acceptable carrier.

[0012] In another embodiment, the present disclosure also provides a particular crystalline form of Compound 1, hereinafter Form F of the hydrochloric acid (HCl) salt. The present disclosure further provides a method of making Form F of the HCl salt.

[0013] The present disclosure further provides a pharmaceutical composition comprising Form F of the HCl salt and a pharmaceutically acceptable carrier.

[0014] In another aspect, the present disclosure also provides a particular crystalline form of Compound 1 (hereinafter, Form G of the hydrochloric acid (HCl) salt). The present disclosure further provides a method for making Form G of the HCl salt. The present disclosure further provides a pharmaceutical composition comprising Form G of the HCl salt and a pharmaceutically acceptable carrier.

[0015] The present disclosure further provides a method for treating cancer, comprising administering to a subject in need thereof a crystalline form of Compound 1 or a pharmaceutical composition comprising a crystalline form of Compound 1 disclosed herein. [Brief explanation of the drawings]

[0016] [Figure 1A] FIG. 1A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay for crystalline Form A of the HCl salt of Compound 1. [Figure 1B]FIG. 1B is an X-ray powder diffraction (XRPD) pattern for crystalline Form A of the HCl salt of Compound 1. [Figure 1C] FIG. 1C is a polarized light microscope (PLM) image of crystals of Form A of the HCl salt of Compound 1. [Figure 1D] FIG. 1D is a dynamic vapor sorption (DVS) isotherm plot for crystalline Form A of the HCl salt of Compound 1. [Figure 2A] FIG. 2A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay for crystalline Form B of the HCl salt of Compound 1. [Figure 2B] FIG. 2B is an X-ray powder diffraction (XRPD) pattern for crystalline Form B of the HCl salt of Compound 1. [Figure 2C] FIG. 2C is a polarized light microscope (PLM) image of crystals of Form B of the HCl salt of Compound 1. [Figure 2D] FIG. 2D is a dynamic vapor sorption (DVS) isotherm plot for crystalline Form B of the HCl salt of Compound 1. [Figure 3A] FIG. 3A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay for crystalline Form E of the HCl salt of Compound 1. [Figure 3B] FIG. 3B is an X-ray powder diffraction (XRPD) pattern for crystalline Form E of the HCl salt of Compound 1. [Figure 3C] FIG. 3C is a dynamic vapor sorption (DVS) isotherm plot for crystalline Form E of the HCl salt of Compound 1. [Figure 3D] FIG. 3D is a proton nuclear magnetic resonance ( 1 H-NMR) spectrum for a crystal of Form E of the HCl salt of Compound 1. [Figure 4A] FIG. 4A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay for crystals of Form F of the HCl salt of Compound 1. [Figure 4B] FIG. 4B is an X-ray powder diffraction (XRPD) pattern for crystalline Form F of the HCl salt of Compound 1. [Figure 4C]FIG. 4C is a proton nuclear magnetic resonance ( 1 H-NMR) spectrum for a crystal of Form F of the HCl salt of Compound 1. [Figure 5A] FIG. 5A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay for crystals of Form G of the HCl salt of Compound 1. [Figure 5B] FIG. 5B is an X-ray powder diffraction (XRPD) pattern for crystalline Form G of the HCl salt of Compound 1. [Figure 5C] FIG. 5C is a proton nuclear magnetic resonance ( 1 H-NMR) spectrum of Form G of the HCl salt of Compound 1. [Figure 6A] FIG. 6A is an X-ray powder diffraction (XRPD) pattern of the amorphous HCl salt of Compound 1. [Figure 6B] FIG. 6B is a polarized light microscope (PLM) image of the amorphous HCl salt of Compound 1. [Figure 6C] FIG. 6C is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay of the amorphous HCl salt of Compound 1. [Figure 6D] FIG. 6D is a proton nuclear magnetic resonance ( 1 H-NMR) spectrum of the amorphous HCl salt of Compound 1. [Figure 6E] FIG. 6E is a high-performance liquid chromatography (HPLC) spectrum of the amorphous HCl salt of Compound 1. [Figure 7A] FIG. 7A is a graph of the area under the plasma concentration curve of Form A of the HCl salt of Compound 1 and Form B of the HCl salt of Compound 1 administered to a mammal. [Figure 7B] FIG. 7B is a graph of the area under the plasma concentration curve of Form B of the HCl salt of Compound 1 administered to mammals. [Figure 8] FIG. 8 is a graph of total impurity content of Form B of the HCl salt of Compound 1 versus excipients. [Figure 9A] FIG. 9A is a graph of porosity versus compaction pressure for Form B of the HCl salt of Compound 1. [Figure 9B] FIG. 9B is a graph of tensile strength versus compressive pressure for Form B of the HCl salt of Compound 1. [Figure 9C] FIG. 9C is a graph of tensile strength versus porosity for Form B of the HCl salt of Compound 1. [Figure 10] FIG. 10 is a powder X-ray diffraction (XRPD) pattern of Form B of the HCl salt of Compound 1 before and after high compression. [Figure 11A] FIG. 11A is a graph of the intrinsic dissolution rate of Form B of the HCl salt of Compound 1. [Figure 11B] FIG. 11B is a graph of the dissolution of Form B of the HCl salt of Compound 1 in capsules in biorelevant media. Detailed Description of the Invention

[0017] As mentioned above, the present invention provides a specific crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0018] In some embodiments, the present invention also provides Form A of the HCl salt, a particular crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0019] In some embodiments, the present invention also provides Form B of the HCl salt, a specific crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0020] In some embodiments, the present invention also provides Form E of the HCl salt, a specific crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0021] In some embodiments, the present invention also provides Form F of the HCl salt, a particular crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0022] In some embodiments, the present invention also provides Form G of the HCl salt, a specific crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0023] Crystalline forms as described herein can be identified by numerous methods known to those skilled in the art, such as thermal analysis [e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)], powder X-ray diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM), polarizing microscopy) and spectroscopy [e.g., infrared, Raman, solid-state nuclear magnetic resonance and proton nuclear magnetic resonance ( 1 The purity of the crystalline forms provided herein can be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC) and mass spectrometry (MS).

[0024] HCl salt form A In one embodiment, the disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride, i.e., Form A of the HCl salt. In various embodiments, Form A of the HCl salt has a differential scanning calorimetry (DSC) thermogram (e.g., including multiple endothermic peaks). In some embodiments, Form A of the HCl salt has an endothermic DSC peak temperature of about 118°C (e.g., within about 118°C ± 2%). In some embodiments, Form A of the HCl salt has an endothermic DSC peak temperature of about 118°C ± 1% or within 118°C ± 0.5%. In some embodiments, Form A of the HCl salt has an endothermic DSC peak temperature of about 211°C (e.g., within about 211°C ± 2%). In some embodiments, Form A of the HCl salt has an endothermic DSC peak temperature within 211° C. ± 1% or within 211° C. ± 0.5%. In various embodiments, Form A of the HCl salt has a DSC thermogram with peak temperatures at about 118° C. (e.g., within about 118° C. ± 2%, within about 118° C. ± 1%, or within about 118° C. ± 0.5%) and about 211° C. (e.g., within about 211° C. ± 2%, within about 211° C. ± 1%, or within about 211° C. ± 0.5%). For example, in some embodiments, Form A of the HCl salt has a DSC thermogram substantially as shown in FIG. 2A.

[0025] In various embodiments, Form A of the HCl salt has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Form A of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 6.8°±0.2°. In some embodiments, Form A of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 7.4°±0.2°. In some embodiments, Form A of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 13.9°±0.2°. In some embodiments, Form A of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 23.9°±0.2°. In some embodiments, Form A of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 26.2°±0.2°. In some embodiments, Form A of the HCl salt has an XRPD pattern comprising peaks at 2θ angles of 6.8°±0.2°, 7.4°±0.2°, 13.9°±0.2°, 23.9°±0.2°, and 26.2°±0.2°. For example, in some embodiments, Form A of the HCl salt has an XRPD pattern substantially as shown in Figure 2B. In some embodiments described herein, Form A of the HCl salt is a trihydrate.

[0026] In some embodiments described herein, Form A of the HCl salt has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 9.7% when heated from about 25° C. to about 150° C. For example, in some embodiments, Form A of the HCl salt has a TGA plot substantially as shown in FIG.

[0027] In some embodiments described herein, Form A of the HCl salt has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. In some embodiments, Form A of the HCl salt has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0028] HCl salt form B Another embodiment described herein, this disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride, i.e., Form B of the HCl salt. In various embodiments, Form B of the HCl salt has a differential scanning calorimetry (DSC) thermogram (e.g., including multiple endothermic peaks). In some embodiments, Form B of the HCl salt has an endothermic DSC peak temperature of about 97°C (e.g., within about 97°C ± 2%). In some embodiments, Form B of the HCl salt has an endothermic DSC peak temperature within 97°C ± 1% or within 97°C ± 0.5%. In some embodiments, Form B of the HCl salt has an endothermic DSC peak temperature of about 245°C (e.g., within 245°C ± 2%). In some embodiments, Form B of the HCl salt has an endothermic DSC peak temperature within 245° C. ±1% or within 245° C. ±0.5%. In various embodiments, Form B of the HCl salt has a DSC thermogram with peak temperatures at about 97° C. (e.g., within about 97° C. ±2%, within about 97° C. ±1%, or within about 97° C. ±0.5%) and about 245° C. (e.g., within about 245° C. ±2%, within about 245° C. ±1%, or within about 245° C. ±0.5%). For example, in some embodiments, Form B of the HCl salt has a DSC thermogram substantially as shown in FIG. 2A.

[0029] In various embodiments, Form B of the HCl salt has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Form B of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 12.2°±0.2°. In some embodiments, Form B of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 14.3°±0.2°. In some embodiments, Form B of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 18.9°±0.2°. In some embodiments, Form B of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 23.2°±0.2°. In some embodiments, Form B of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 26.0°±0.2°. In some embodiments, Form B of the HCl salt has an XRPD pattern comprising peaks at 2θ angles of 12.2°±0.2°, 14.3°±0.2°, 18.9°±0.2°, 23.2°±0.2°, and 26.0°±0.2°. For example, in some embodiments, Form B of the HCl salt has an XRPD pattern substantially as shown in Figure 2B. In some embodiments described herein, Form B of the HCl salt is a monohydrate.

[0030] In some embodiments described herein, Form B of the HCl salt has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 3.6% when heated from about 25° C. to about 150° C. For example, in some embodiments, Form B of the HCl salt has a TGA plot substantially as shown in FIG. 2A.

[0031] In some embodiments described herein, Form B of the HCl salt has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. In some embodiments, Form B of the HCl salt has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0032] HCl salt form E Another embodiment described herein, this disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride, i.e., Form E of the HCl salt. In various embodiments, Form E of the HCl salt has a differential scanning calorimetry (DSC) thermogram (e.g., including multiple endothermic peaks). In some embodiments, Form E of the HCl salt has an endothermic DSC peak temperature of about 239°C (e.g., within about 239°C ± 2%). In some embodiments, Form E of the HCl salt has an endothermic DSC peak temperature within 239°C ± 1% or within 239°C ± 0.5%. For example, in some embodiments, Form E of the HCl salt has a DSC thermogram substantially as shown in FIG. 3A.

[0033] In various embodiments, Form E of the HCl salt has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Form E of the HCl salt has an XRPD pattern including a peak at 9.7°±0.2° 2θ. In some embodiments, Form E of the HCl salt has an XRPD pattern including a peak at 12.1°±0.2° 2θ. In some embodiments, Form E of the HCl salt has an XRPD pattern including a peak at 14.3°±0.2° 2θ. In some embodiments, Form E of the HCl salt has an XRPD pattern including a peak at 22.3°±0.2° 2θ. In some embodiments, Form E of the HCl salt has an XRPD pattern including a peak at 22.8°±0.2° 2θ. In some embodiments, Form E of the HCl salt has an XRPD pattern including a peak at 24.5°±0.2° 2θ. In some embodiments, Form E of the HCl salt has an XRPD pattern comprising peaks at 2θ angles of 9.7°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 22.3°±0.2°, 22.8°±0.2°, and 24.5°±0.2°. For example, in some embodiments, Form E of the HCl salt has an XRPD pattern substantially as shown in Figure 3B. In some embodiments described herein, Form E of the HCl salt is anhydrous.

[0034] In some embodiments described herein, Form E of the HCl salt has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 1.0% when heated from about 25° C. to about 150° C. For example, in some embodiments, Form E of the HCl salt has a TGA plot substantially as shown in FIG.

[0035] In some embodiments described herein, Form E of the HCl salt has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. In some embodiments, Form E of the HCl salt has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0036] HCl salt form F Another embodiment described herein, this disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride, i.e., Form F of the HCl salt. In various embodiments, Form F of the HCl salt has a differential scanning calorimetry (DSC) thermogram (e.g., including multiple endothermic peaks). In some embodiments, Form F of the HCl salt has an endothermic DSC peak temperature of about 15°C (e.g., within about 15°C ± 2%). In some embodiments, Form F of the HCl salt has an endothermic DSC peak temperature within 15°C ± 1% or within 15°C ± 0.5%. In some embodiments, Form F of the HCl salt has an endothermic DSC peak temperature of about 97°C (e.g., within about 97°C ± 2%). In some embodiments, Form F of the HCl salt has an endothermic DSC peak temperature within 97°C ± 1% or within 97°C ± 0.5%. In some embodiments, Form F of the HCl salt has an endothermic DSC peak temperature of about 162°C (e.g., within 162°C ± 2%). In some embodiments, Form F of the HCl salt has an endothermic DSC peak temperature within 162°C ± 1% or within 162°C ± 0.5%. In various embodiments, Form F of the HCl salt has peak temperatures in a DSC thermogram of about 15°C (e.g., within about 15°C ± 2%, within about 15°C ± 1%, or within about 15°C ± 0.5%), about 97°C (e.g., within 97°C ± 2%, within 97°C ± 1%, or within 97°C ± 0.5%), and about 162°C (e.g., within 162°C ± 2%, within 162°C ± 1%, or within 162°C ± 0.5%). For example, in some embodiments, Form F of the HCl salt has a DSC thermogram substantially as shown in Figure 4A.

[0037] In various embodiments, Form F of the HCl salt has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Form F of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 4.3°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 6.3°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 7.9°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 18.8°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 20.3°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 23.7°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 26.7°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern comprising peaks at 2θ angles of 4.3°±0.2°, 6.3°±0.2°, 7.9°±0.2°, 18.8°±0.2°, 20.3°±0.2°, 23.7°±0.2°, and 26.7°±0.2°. For example, in some embodiments, Form F of the HCl salt has an XRPD pattern substantially as shown in Figure 4B. In some embodiments described herein, Form F of the HCl salt is an n-methyl-2-pyrrolidone (NMP) solvate.

[0038] In some embodiments described herein, Form F of the HCl salt has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 9.5% when heated from about 25° C. to about 150° C. For example, in some embodiments, Form F of the HCl salt has a TGA plot substantially as shown in FIG.

[0039] In some embodiments described herein, Form F of the HCl salt has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. In some embodiments, Form F of the HCl salt has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0040] HCl salt form G Another embodiment of the disclosure described herein provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride, i.e., Form G of the HCl salt. In various embodiments, Form G of the HCl salt has a differential scanning calorimetry (DSC) thermogram (e.g., including multiple endothermic peaks). In some embodiments, Form G of the HCl salt has an endothermic DSC peak temperature of about 62°C (e.g., within about 62°C ± 2%). In some embodiments, Form G of the HCl salt has an endothermic DSC peak temperature within 62°C ± 1% or within 62°C ± 0.5%. For example, in some embodiments, Form F of the HCl salt has a DSC thermogram substantially as shown in FIG. 5A.

[0041] In various embodiments, Form G of the HCl salt has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Form G of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 6.3°±0.2°. In some embodiments, Form G of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 18.8°±0.2°. In some embodiments, Form G of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 20.3°±0.2°. In some embodiments, Form G of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 22.3°±0.2°. In some embodiments, Form G of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 23.8°±0.2°. In some embodiments, Form G of the HCl salt has an XRPD pattern including a peak at a 2θ angle of 26.7°±0.2°. In some embodiments, Form F of the HCl salt has an XRPD pattern comprising peaks at 2θ angles of 6.3°±0.2°, 18.8°±0.2°, 20.3°±0.2°, 22.3°±0.2°, 23.8°±0.2°, and 26.7°±0.2°. For example, in some embodiments, Form G of the HCl salt has an XRPD pattern substantially as shown in Figure 5B. In some embodiments described herein, Form G of the HCl salt is an n-methyl-2-pyrrolidone (NMP) solvate.

[0042] In some embodiments described herein, Form G of the HCl salt has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 5.5% when heated from about 25° C. to about 150° C. For example, in some embodiments, Form G of the HCl salt has a TGA plot substantially as shown in FIG.

[0043] In some embodiments described herein, Form G of the HCl salt has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. In some embodiments, Form G of the HCl salt has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

[0044] Method for preparing the crystalline form of the HCl salt of Compound 1 In another aspect, the disclosure provides methods of preparing crystalline forms of the HCl salt of Compound 1 (e.g., HCl salt Form A, HCl salt Form B, HCl salt Form E, HCl salt Form F, and HCl salt Form G). The crystalline forms of HCl salt Form A, HCl salt Form B, HCl salt Form E, HCl salt Form F, and HCl salt Form G can be prepared by various methods, as discussed in the Examples below. For example, the crystalline forms described herein may be prepared by a slurry method, an antisolvent addition method, a solid vapor diffusion method, a liquid vapor diffusion method, a slow evaporation method at room temperature, a slow cooling method, or a polymer-induced crystallization method.

[0045] In various embodiments, the slurry method can be carried out at various temperatures and with various solvents.For example, in some embodiments, the slurry method is carried out at room temperature or at an elevated temperature (for example, 50°C).To prepare crystalline form using the slurry method, the amorphous HCl salt of Compound 1 is suspended in a solvent at a temperature (for example, room temperature or at an elevated temperature) and stirred to obtain a solid.

[0046] In various embodiments, antisolvent addition can be carried out at various temperatures and with various solvents.For example, in some embodiments, antisolvent addition is carried out at room temperature.To prepare crystals by antisolvent addition, the amorphous HCl salt of Compound 1 is dissolved in a solvent to obtain a saturated solution, and an antisolvent is added, for example, up to 20 times in volume, to obtain a solid.

[0047] In various embodiments, solid vapor diffusion can be carried out at various temperatures and with various solvents.For example, in some embodiments, solid vapor diffusion is carried out at room temperature.To prepare a crystalline form by solid vapor diffusion, the amorphous HCl salt of Compound 1 is placed in a first vial and placed in a second vial containing a solvent.There is no physical contact between the solid HCl salt of Compound 1 in the first vial and the solvent in the second vial.The solid is then characterized after 14 days.

[0048] In various embodiments, liquid vapor diffusion method can be carried out at various temperatures and with various solvents.For example, in some embodiments, liquid vapor diffusion method is carried out at room temperature.To prepare crystals by liquid vapor diffusion method, the amorphous HCl salt of compound 1 is dissolved in a solvent to obtain a saturated solution in a first vial, and then the first vial is placed in a second vial that contains an anti-solvent to obtain a solid.

[0049] In various embodiments, the slow evaporation method can be carried out at various temperatures and using various solvents. For example, in some embodiments, the slow evaporation method is carried out at room temperature or at an elevated temperature (e.g., 50°C). To prepare a crystalline form by the slow evaporation method, the amorphous HCl salt of Compound 1 is dissolved in a solvent to obtain a saturated solution. The vial is then covered with paraffin film with multiple holes (e.g., 3-5 holes) and evaporated to obtain a solid.

[0050] In various embodiments, the slow cooling process can be carried out at various temperatures and using various solvents. For example, in some embodiments, the slow cooling process is carried out at a high temperature (e.g., 55°C). To prepare the crystalline form by the slow cooling process, the amorphous HCl salt of Compound 1 is dissolved in a solvent to obtain a saturated solution at, for example, 40-70°C, 45-70°C, 50-70°C, 40-65°C, 45-65°C, 50-65°C, 40-60°C, 45-60°C, or 50-60°C. In some embodiments, to prepare the crystalline form by the slow cooling process, the free base of Compound 1 is dissolved in a solvent to obtain a saturated solution at, for example, about 55°C. The solution is then slowly cooled to room temperature to obtain a solid.

[0051] In various embodiments, polymer-induced crystallization can be carried out at various temperatures and with various solvents.For example, in some embodiments, polymer-induced crystallization is carried out at room temperature.To produce crystals by polymer-induced crystallization, the amorphous HCl salt of compound 1 is dissolved in a solvent to form a saturated solution.Then, polymer is added to the saturated solution to induce heterogeneous nucleation and obtain a solid.

[0052] In some embodiments, a slurry method or a solid vapor diffusion method can be used to obtain HCl salt Form A. When a slurry method is used, the solvent can be water. When a solid vapor diffusion method is used, the solvent can be water.

[0053] In some embodiments, a slurry method or a solid vapor diffusion method can be used to obtain Form B of the HCl salt. When using the slurry method, the solvent can be selected from acetonitrile (ACN) or isopropyl alcohol / water. When using the solid vapor diffusion method, the solvent can be ACN.

[0054] In some embodiments, to provide Form E of the HCl salt, a slurry method, an anti-solvent addition method, a solid vapor diffusion method, a liquid vapor diffusion method, a slow evaporation method at room temperature, a slow cooling method, or a polymer-induced crystallization method can be used. When using the slurry method, the solvent can be selected from methanol (MeOH), n-propyl alcohol (NPA), dichloromethane (DCM), ethanol (EtOH), ACN, tetrahydrofuran (THF) / n-heptane, IPA / toluene, and MeOH / water. When using the anti-solvent addition method, the solvent can be MeOH, and the anti-solvent can be selected from methyl tert-butyl ether (MTBE), ACN, and heptane. When using solid vapor diffusion, the solvent can be EtOH. When using liquid vapor diffusion, the solvent can be MeOH, and the anti-solvent can be selected from cyclopentyl methyl ether (CPME), ACN, and isopropyl acetate (IPAc). When using the slow evaporation method, the solvent can be selected from MeOH, IPA, and 1-butanol (1-BuOH). When using the slow cooling method, the solvent can be selected from MeOH and EtOH. When using polymer-induced crystallization, the solvent can be MeOH and the polymer can be polyvinylpyrrolidone (PVP).

[0055] In some embodiments, liquid vapor diffusion can be used to obtain the HCl salt Form F. When liquid vapor diffusion is used, the solvent can be n-methylpyrrolidone (NMP) and the anti-solvent can be selected from heptane or MTBE.

[0056] In some embodiments, solid vapor diffusion can be used to obtain the HCl salt Form F. When liquid vapor diffusion is used, the solvent can be NMP.

[0057] Pharmaceutical Composition In another aspect, the present disclosure provides a pharmaceutical product comprising a crystalline form of Compound 1 (e.g., Form A of the HCl salt, Form B of the HCl salt, Form E of the HCl salt, Form F of the HCl salt, and Form G of the HCl salt) and a suitable carrier, excipient, or diluent. The exact nature of the carrier, excipient, or diluent will vary depending on the desired use of the composition and may be suitable or acceptable for a range of uses, from veterinary to human. The composition may optionally include one or more additional compounds. In certain embodiments, the composition may include one or more antibiotics. In another aspect, the present disclosure provides a pharmaceutical composition comprising Form A of the HCl salt and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising Form B of the HCl salt and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising Form E of the HCl salt and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising Form F of the HCl salt and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising Form G of the HCl salt and a pharmaceutically acceptable carrier.

[0058] When used to treat or prevent the above-described diseases, Compound 1 described herein can be administered alone, as a mixture of one or more compounds, or as a mixture or combination with other drugs useful for treating the above-described diseases and / or symptoms associated with the above-described diseases. The compound can also be administered in combination with or in admixture with drugs useful for treating other disorders or diseases, such as steroids, membrane stabilizers, 5LO inhibitors, leukotriene synthesis inhibitors and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, β-agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines. Compound 1 can be administered in the crystalline form described herein or as a pharmaceutical composition comprising the crystalline form described herein.

[0059] Pharmaceutical compositions containing various crystalline forms of Compound 1 can be prepared by conventional mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. The compositions may be formulated by conventional methods using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants to facilitate processing of the compound into pharmaceutically usable preparations.

[0060] Pharmaceutical compositions can be in a form suitable for virtually any mode of administration (e.g., topical, ophthalmic, oral, buccal, systemic, nasal, injectable, transdermal, rectal, vaginal, etc.) or by administration by inhalation or insufflation.

[0061] For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. Systemic formulations include formulations designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as formulations designed for transdermal, transmucosal oral, or pulmonary administration.

[0062] Useful injection preparations include sterile suspensions, solutions, or emulsions of the active compound in aqueous or oily vehicles. The compositions may also contain compounding agents such as suspending agents, stabilizing agents, and / or dispersing agents. The injection preparations may be in unit dosage forms, such as ampoules or multi-dose containers, and may contain additional preservatives. Alternatively, the injection preparations may be provided in powder form, for dissolving in a suitable vehicle (including, but not limited to, sterile pyrogen-free water, buffer, glucose solution, etc.) before use. For this purpose, the active compound can be dried using techniques known in the art, such as lyophilization, and then dissolved before use.

[0063] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0064] For oral administration, the pharmaceutical compositions may be in the form of lozenges, tablets, or capsules prepared by conventional techniques with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art, such as with sugars, films, or enteric coatings.

[0065] Liquid preparations for oral administration may be in the form of, for example, elixirs, solutions, syrups, or suspensions, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats and oils); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, Cremophor®, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners, as desired.

[0066] As is well known, the preparation for oral administration can be appropriately formulated to control the release of compound.For sublingual administration, composition can be in the form of tablets or lozenges that are formulated in a conventional manner.For rectal and vaginal administration, compound can be formulated as a solution (enema) suppository or ointment that contains conventional suppository base such as cocoa butter or other glycerides.

[0067] For nasal administration or administration by inhalation or insufflation, the compounds can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. Capsules and cartridges (e.g., capsules and cartridges made of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0068] When administered to the eye, the compounds may be formulated as solutions, emulsions, suspensions, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art.

[0069] For long-term delivery, the compound can be formulated as a depot preparation and administered by implantation or intramuscular injection.The compound(s) can be formulated with suitable polymer or hydrophobic material (for example, emulsion in acceptable oil) or ion exchange resin, or as a poorly soluble derivative (for example, as a poorly soluble salt).Alternatively, for transdermal absorption, a transdermal administration system can be used, which is manufactured as an adhesive disk or patch that releases the compound in a sustained release.For this reason, a penetration enhancer can be used to promote the percutaneous penetration of the compound.

[0070] Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver compounds. Organic solvents such as dimethyl sulfoxide (DMSO) can also be used, but are usually more toxic.

[0071] The pharmaceutical compositions may optionally be placed in a pack or dispenser device that can contain one or more unit dosage forms containing the compound. The pack can be, for example, a metal or plastic foil, such as a blister pack. The pack or dispenser may be accompanied by instructions for administration.

[0072] How to use The crystalline forms or compositions thereof described herein are generally used in an amount effective to achieve the intended result (e.g., an amount effective to treat or prevent the particular disease being treated). Therapeutic benefit refers to eradication or alleviation of the underlying disease being treated and / or eradication or alleviation of one or more symptoms associated with the underlying disease, such that the patient reports an improvement in mood or condition. Therapeutic benefit also generally includes halting or slowing the progression of the disease, regardless of whether improvement is achieved.

[0073] In yet another aspect, the present invention provides a method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired in vitro with an effective amount of a crystalline form of Compound 1, as described herein, or a pharmaceutical composition comprising an effective amount of a crystalline form of Compound 1, as described herein. In one embodiment, the cell is an MTAP-deficient cell.

[0074] The compositions and methods provided herein are believed to be particularly useful for inhibiting PRMT5 activity in cells in vivo. In one embodiment, cells in which inhibition of PRMT5 activity is desired are contacted in vivo with a therapeutically effective amount of a crystalline form of Compound 1 described herein or a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound 1 described herein. In one embodiment, the cells are MTAP-deficient cells. In one embodiment, negatively regulating PRMT5 activity occurs in the presence of bound MTA.

[0075] In particular, for cells lacking MTAP activity, negative regulation of PRMT5 activity can be used to inhibit PRMT5 activity and block cell proliferation. According to a specific treatment regimen, cells can be contacted with a single or multiple doses to negatively regulate the target PRMT5 activity. The degree of PRMT5 inhibition can be monitored in vitro against the intracellular enzyme in the presence and absence of MTA using well-known methods, including the method described in Example B below, to evaluate the effectiveness of the treatment and dosage.

[0076] In another aspect, there is provided a method of treating cancer, comprising administering to a patient suffering from cancer a therapeutically effective amount of a crystalline form of Compound 1 described herein or a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound 1 described herein. In one embodiment, the cancer is an MTAP-associated cancer.

[0077] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors (e.g., prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc.). More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds can be used to treat the following: cardiac system: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; pulmonary system: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolopulmonary) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; digestive system Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, lipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth muscle tumors); genitourinary system: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma tumor, hepatic hemangioma; biliary tract: gallbladder cancer, duodenal papilla, bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), benign chondroma, chondroblastoma, chondrodysplastic fibroma, osteoid osteoma, and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary [ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma], vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma) tumor, melanoma), granulosa cell tumor, vagina [(clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)], fallopian tube (cancer); blood system: blood [myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome], Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL);

[0078] In one embodiment, the cancer is an MTAP-associated cancer selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0079] In other embodiments, the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma, and thyroid carcinoma.

[0080] In other embodiments, the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, and uterine cancer.

[0081] The concentration and route of administration to a patient will vary depending on the cancer being treated. The crystalline forms of Compound 1 described herein or pharmaceutical compositions comprising the crystalline forms of Compound 1 described herein may also be co-administered with other anti-neoplastic compounds (e.g., chemotherapy) or used as a pre- or post-surgical adjuvant in combination with other treatments, such as radiation or surgical intervention. [Example]

[0082] The following examples are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0083] Example 1: Characterization of the amorphous HCl salt of Compound 1 Compound 1 can be prepared as a gum according to the procedures disclosed in International Publication No. WO2021050915. See Example 16-8.

[0084] The amorphous salt of compound 1 (2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile) obtained as a white solid was characterized by XRPD, PLM, DSC, TGA, and NMR. 1 The compounds were characterized by H-NMR and HPLC, and the results are summarized in Table 1 and shown in Figures 6A-6E. [Table 1]

[0085] Example 2: Formation of Form A of the HCl Salt of Compound 1 The amorphous HCl salt of compound 1 (30 mg) was suspended in water (2 mL) at room temperature. The solid in the slurry was characterized by XRPD, PLM, DSC, TGA, and DVS after 14 days. The resulting crystals were off-white solids. The characterization results are summarized in Table 2 and are shown in Figures 1A-1D. [Table 2]

[0086] Alternative methods for preparing crystalline forms of Compound 1 were also evaluated to obtain Form A of the HCl salt. Four alternative methods were found to yield Form A of the HCl salt: slurrying at 50° C., solid vapor diffusion, slow evaporation, and slow cooling.

[0087] For the 50° C. slurry experiment, the amorphous HCl salt of Compound 1 (approximately 30 mg) was suspended in water (2 mL) in a 4 mL vial and stirred at 50° C. After 6 days, the solid in the slurry was characterized by XRPD and identified as Form A of the HCl salt.

[0088] In solid vapor diffusion experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was placed in a 4 mL vial, which was then placed in a 20 mL glass vial containing water. The solid was characterized by XRPD after 14 days and identified as Form A of the HCl salt.

[0089] In slow evaporation experiments, evaporation occurred at room temperature. The amorphous HCl salt of compound 1 (approximately 30 mg) was dissolved in water in a 4 mL vial to obtain a saturated solution. The vial was covered with paraffin film with 3-5 holes and left at room temperature for evaporation. The resulting solid was characterized by XRPD and identified as Form A of the HCl salt.

[0090] In the slow-cooling experiment, the amorphous HCl salt of Compound 1 (approximately 30 mg) was dissolved in water to obtain a saturated solution in a 4 mL vial using a hot plate at 55° C. The solution was slowly cooled to room temperature using the following gradient: 55° C. for 3 hours, 40° C. for 4 hours, 25° C. for 4 hours, 15° C. for 5 hours, and 10° C. for 5 hours. The resulting solid was characterized by XRPD and identified as Form A of the HCl salt.

[0091] Table 3 shows the XRD pattern for the crystalline form of Form A of the HCl salt of Compound 1 shown in Figure 1B. [Table 3-1] [Table 3-2]

[0092] The hygroscopicity of Form A of the HCl salt was also evaluated by performing dynamic vapor sorption experiments. Figure 1D shows the DVS isotherm of Form A of the HCl salt, which showed a water absorption of approximately 1.43% between 10% and 90% relative humidity at 25 °C. No morphological changes were observed in the samples after DVS evaluation.

[0093] Example 3: Formation of Form B of the HCl Salt of Compound 1 The amorphous HCl salt of compound 1 (30 mg) was suspended in acetonitrile (2 mL) at room temperature. The solid in the slurry was characterized by XRPD, PLM, DSC, TGA, and DVS after 14 days. The resulting crystals were off-white solids. The characterization results are summarized in Table 4 and are shown in Figures 2A-2D. [Table 4]

[0094] Alternative methods for preparing crystalline forms of Compound 1 were also evaluated to obtain Form B of the HCl salt. Two additional methods were found to provide Form B of the HCl salt: a room temperature slurry method and a solid vapor diffusion method.

[0095] For room temperature slurry experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was suspended in IPA / HO solution (1.5 mL) in a 4 mL vial and stirred at room temperature. Four IPA / HO solutions were used: 20%, 40%, 60%, and 80% IPA. The solid in the slurry was characterized by XRPD after 6 days and identified as Form B of the HCl salt.

[0096] In solid vapor diffusion experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was placed in a 4 mL vial and placed in a 20 mL glass vial containing acetonitrile. The solid was characterized by XRPD after 14 days and identified as Form B of the HCl salt.

[0097] Table 5 shows the XRD pattern for the crystalline form of Form B of the HCl salt of Compound 1 shown in Figure 2B. [Table 5] TIFF2026504701000008.tif10776

[0098] The hygroscopicity of Form B of the HCl salt was also evaluated by performing dynamic vapor sorption experiments. Figure 2D shows the DVS isotherm of Form B of the HCl salt, which showed a water absorption of approximately 1.3% between 10% and 90% relative humidity at 25 °C. No morphological changes were observed in the samples after DVS evaluation.

[0099] Example 4: Formation of Form E of the HCl Salt of Compound 1 Various methods for preparing crystalline forms of Compound 1 were evaluated to obtain Form E of the HCl salt. Eight methods were found to yield Form E of the HCl salt: slurry at room temperature, slurry at 50°C, antisolvent addition, solid vapor diffusion, liquid vapor diffusion, slow evaporation at room temperature, slow cooling, and polymer-induced crystallization.

[0100] For room temperature slurry experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was suspended in 1.5-2.0 mL of different solvents in 4 mL vials and stirred at room temperature. After 14 days, the solids in the slurry were analyzed by XRPD. Table 6 discloses the parameters resulting in Form E of the HCl salt for room temperature slurry experiments. [Table 6]

[0101] For the 50° C. slurry experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was suspended and stirred in various solvents in 4 mL vials at 50° C. After 6 days, the solids in the slurries were analyzed by XRPD. Table 7 discloses the parameters resulting in Form E of the HCl salt for the 50° C. slurry experiments. [Table 7]

[0102] In anti-solvent addition experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was dissolved in various solvents to obtain saturated solutions, and up to 20 volumes of anti-solvent were added. The resulting solids were characterized by XRPD. Table 8 discloses the parameters resulting in Form E of the HCl salt for the anti-solvent addition experiments. [Table 8]

[0103] In solid vapor diffusion experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was placed in a 4 mL vial and placed in a 20 mL glass vial containing various solvents. After 14 days, the solid was characterized by XRPD. Table 9 discloses the parameters resulting in Form E of the HCl salt for the solid vapor diffusion experiments. [Table 9]

[0104] For liquid vapor diffusion experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was dissolved in various solvents in 4 mL vials to obtain saturated solutions, which were then placed in 20 mL vials containing antisolvents. After 12 days, the resulting solids were characterized by XRPD. Table 10 discloses the parameters resulting in Form E of the HCl salt for liquid vapor diffusion experiments. [Table 10]

[0105] For slow evaporation experiments, evaporation was carried out at room temperature or 50°C. The amorphous HCl salt of compound 1 (approximately 30 mg) was dissolved in various solvents in 4 mL vials to obtain saturated solutions. The vials were covered with paraffin film with 3-5 holes and placed at room temperature or 50°C to allow evaporation. The resulting solids were characterized by XRPD. Table 11 discloses the parameters resulting in Form E of the HCl salt for the slow evaporation experiments. [Table 11]

[0106] In the slow-cooling experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was dissolved in various solvents in a 4 mL vial at 55° C. using a hot plate to obtain a saturated solution. The solution was slowly cooled to room temperature using the following temperature gradient: 55° C. for 3 hours, 40° C. for 4 hours, 25° C. for 4 hours, 15° C. for 5 hours, and 10° C. for 5 hours. The resulting solid was characterized by XRPD. Table 12 discloses the parameters resulting in Form E of the HCl salt for the slow-cooling experiments. [Table 12]

[0107] In polymer-induced crystallization experiments, the amorphous HCl salt of Compound 1 (approximately 30 mg) was dissolved in various solvents to create saturated solutions. Either polyvinylpyrrolidone (PVP), polyethylene glycol (PEO), polyvinyl alcohol (PVA), or hydroxypropylmethylcellulose (HPMC) was added to the saturated solution to induce heterogeneous nucleation. After 12 days, the resulting solid was characterized by XRPD. Table 13 discloses the parameters resulting in Form E of the HCl salt from the polymer-induced crystallization experiments. [Table 13]

[0108] Form E of the HCl salt can be determined by various methods, e.g., XRPD, DSC, TGA, DVS, and 1 The results of the characterization are summarized in Table 14 and shown in Figures 3A-3D. [Table 14]

[0109] Table 15 shows the XRD pattern for the crystalline form of Form E of the HCl salt of Compound 1 shown in Figure 4A. [Table 15]

[0110] The hygroscopicity of Form E of the HCl salt was also evaluated by performing dynamic vapor sorption experiments. Figure 3C shows the DVS isotherm of Form E of the HCl salt, which showed a water absorption of approximately 2.56% between 0% and 80% relative humidity at 25 °C. No morphological changes were observed in the samples after DVS evaluation.

[0111] Example 5: Formation of Form F of the HCl Salt of Compound 1 Form F of the HCl salt of Compound 1 was formed by liquid vapor diffusion. The amorphous HCl salt of Compound 1 (30 mg) was dissolved in NMP to obtain a saturated solution in a 4 mL vial, which was placed in a 20 mL glass vial containing anti-solvents (heptane and MTBE). After 12 days, the resulting solid was analyzed by XRPD, DSC, TGA, and NMR. 1 The crystals were characterized by H-NMR. The resulting crystals were off-white solids. The characterization results are summarized in Table 16, and the results are shown in Figures 4A-4C. [Table 16]

[0112] Table 17 shows the XRD pattern for the crystalline form of Form F of the HCl salt of Compound 1 shown in Figure 5A. [Table 17-1] [Table 17-2]

[0113] Example 6: Formation of Form G of the HCl Salt of Compound 1 Form G of the HCl salt of Compound 1 was prepared by solid vapor diffusion. Amorphous HCl salt of Compound 1 (30 mg) was placed in a 4 mL vial and placed in a 20 mL glass vial containing NMP. After 14 days, the resulting solid was analyzed by XRPD, DSC, TGA, and 1 The crystals were characterized by H-NMR. The resulting crystals were off-white solids. The characterization results are summarized in Table 18, and the results are shown in Figures 5A-5C. [Table 18]

[0114] Table 19 shows the XRD pattern for the crystalline form of Form G of the HCl salt of Compound 1 shown in Figure 6A. [Table 19-1] [Table 19-2]

[0115] Example 7: Competitive Slurry Experiments Table 20 summarizes the results of competitive slurry experiments under various conditions to explore the relative stability of HCl salt Form A, HCl salt Form B, and HCl salt Form E. Experiments CS-1 to CS-6 were run at various water activities (α w Experiments were performed at room temperature using a mixture of HCl salt Form E (30 mg), HCl salt Form A (5 mg), and HCl salt Form B (5 mg) suspended in a solution with HCl salt. Experiment CS-7 was performed at room temperature using only HCl salt Form E suspended in pure water. Experiment CS-8 was performed at 60 °C using HCl salt Form A and HCl salt Form B in pure water. Experiment CS-9 was performed at room temperature using amorphous HCl salt in EtOH / water solution (40:60 v / v). Analogous Form A was observed under certain conditions during competitive slurry experiments. Analogous Form A was confirmed to be racemic by chiral HPLC analysis. [Table 20]

[0116] Example 8: Preclinical bioavailability The pharmacokinetics of different crystalline forms of Compound 1 were investigated after oral administration of Compound 1 free base Form A, HCl salt Form A, and HCl salt Form B to male beagle dogs at a dose of 100 mg / dog (approximately 10 mg / kg). After potency correction, the active ingredient was filled into empty HPMC capsules and administered with 40 mL of water to dogs pretreated with pentagastrin or famotidine. Pentagastrin stimulates gastric acid secretion, while famotidine neutralizes gastric acid. Therefore, pretreatment with pentagastrin and famotidine was performed to simulate the effect of gastric pH on bioavailability and reduce variability in gastric pH among dogs.

[0117] Plasma samples were collected at predetermined intervals and analyzed for Compound 1 concentration. max , T max , AUC 0-t and AUC 0-inf The plasma concentration versus time data were analyzed by non-compartmental methods using the Win Nonlin software program to estimate PK parameters such as: The results are shown in Figures 7A and 7B.

[0118] The results indicate that HCl salt Form A is less stable than HCl salt Form B, and that the HCl salt exhibits common ion effects in the gastric medium, which may have contributed to the high variability in pentagastrin-treated dogs. Furthermore, free base Form A exhibits exposures comparable to the HCl salt when normalized for particle size. Furthermore, significant differences in bioavailability were observed between pentagastrin-treated and famotidine-treated dogs for both HCl salt forms tested, suggesting that both forms may be affected by food.

[0119] Example 9: Excipient Compatibility The compatibility of both Compound 1 free base Form A and HCl salt Form B with several excipients commonly used in oral solid dosage (OSD) formulation development was evaluated. Sample mixtures were prepared by mixing the active ingredient and excipients (filler: compound to excipient ratio 1:10, all other excipients: 1:1) using a mortar and pestle, accurately weighing the resulting mixture, and transferring it to a sample vial. The excipients used were: colloidal silicon dioxide 200, croscarmellose sodium, crosprovidone XL-10, dibasic calcium phosphate (an), hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, mannitol 100SD, MCC PH102, Opadry® II, povidone K-30, pregelatinized starch 1500, sodium starch glycolate, and sodium stearyl fumarate. The sample vials were left unsealed at 40°C / 75% RH for 8 weeks and then analyzed for impurity levels using HPLC. The total impurity content results for these samples are shown in Figure 8 and are compared to Compound 1 free base Form A and HCl salt Form B without any excipients.

[0120] From Figure 8, it can be seen that both Form A of the free base and Form B of the HCl salt of Compound 1 exhibit good compatibility with excipients. Furthermore, Form A of the free base was more sensitive to colloidal silicon dioxide and lactose monohydrate than Form B of the HCl salt. Although the risk of chemical stability is slightly higher for Form A of the free base and Form B of the HCl salt, this can be successfully addressed by considering the choice of excipients.

[0121] Example 10: Ease of Manufacturing and Physical Stability The compressibility (i.e., porosity vs. compression pressure), tabletability (i.e., tensile strength vs. compression pressure), and compatibility (i.e., tensile strength vs. porosity) of Form B of the HCl salt of Compound 1 were measured. The results of these tests are shown in Figures 9A-9C. Furthermore, the phase stability of Form B of the HCl salt of Compound 1 at a compression pressure of 300 MPa was investigated by XRD. The XRD pattern was compared with that of the uncompressed compound. Powder X-ray diffraction patterns were obtained using a wide-angle X-ray diffractometer (X'Pert Pro; PANalytical Inc., West Borough, MA) using Cu Kα radiation. The voltage used was 45 kV, and the current was 40 mA. Each measurement was performed over the 2θ range of 5 to 35°, with a step size of 0.0167° and a dwell time of 0.4 seconds. These results are shown in Figure 10.

[0122] Form B of the HCl salt exhibited good compressibility, tabletability and compatibility, although a decrease in crystallinity was observed upon compression at high pressures.

[0123] Example 11: Intrinsic Dissolution Rate (IDR) and Capsule Drug Solubility in Fasted Simulated Gastric Fluid (FaSSGF) and Fasted Simulated Intestinal Fluid (FaSSIF) The intrinsic dissolution rate (IDR) was determined by measuring the amount of dissolved compound in buffer solution (Form A of the free base and Form B of the HCl salt) and then constructing a linear curve of dissolved compound versus time. The IDR rate was calculated by plotting the slope of the line as a function of the surface area of ​​the tablet (0.5 cm). 2 The dissolution rate was calculated by dividing the dissolution rate by the average dissolution rate (IRR) of the free base of Compound 1 by the average dissolution rate (IRR). Form A of the free base and Form B of the HCl salt of Compound 1 were each compressed into 0.8 cm diameter tablets at 14 MPa. Capsules of Form B of the HCl salt were stirred at 50 rpm at 37°C in pH 1.2 and pH 6.8 buffer solutions using a USP Type II dissolution apparatus with a sinker, and capsules of Form A of the free base were also stirred in a pH 6.8 buffer solution under the same conditions. 0.6 mL of liquid was withdrawn at each time point using a syringe and filtered. The concentration of the filtrate was analyzed by HPLC. The IDR results are shown in Figure 11A, and the dissolution of the capsules is shown in Figure 11B.

[0124] The dissolution of HCl salt Form B was slow due to the common ion effect, while the free base Form A showed more rapid dissolution in gastric media. In intestinal media, HCl salt Form B dissolves slightly faster than free base Form A, but after 30 minutes, as the pH shifts from gastric to intestinal pH, it was determined that free base Form A is able to maintain a supersaturated state in intestinal fluids.

[0125] List of Items of Implementation Embodiment 1. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 118°C ± 2%. Embodiment 2. The crystalline form of embodiment 1, having an endothermic DSC peak temperature within 118°C ± 1%. Embodiment 3. The crystalline form of embodiment 1, wherein the endothermic DSC peak temperature is within 118°C ± 0.5%. Embodiment 4. The crystalline form of embodiment 1, wherein the crystalline form has an endothermic DSC peak temperature within 211°C ± 2%. Embodiment 5. The crystalline form of embodiment 4, having an endothermic DSC peak temperature within 211°C ± 1%. Embodiment 6. The crystalline form of embodiment 4, having an endothermic DSC peak temperature within 211°C ± 0.5%. Embodiment 7. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.8°±0.2°. Embodiment 8. The crystalline form of embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 7.4°±0.2°. Embodiment 9. The crystalline form of embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 13.9°±0.2°. Embodiment 10. The crystalline form of embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.9°±0.2°. Embodiment 11. The crystalline form of embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.2°±0.2°. Embodiment 12. The crystalline form of embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.8°±0.2°, 7.4°±0.2°, 13.9°±0.2°, 23.9°±0.2°, and 26.2°±0.2°. Embodiment 13. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 1B. Embodiment 14. The crystalline form of any one of embodiments 1 to 13, wherein the crystalline form is a trihydrate. Embodiment 15. The crystalline form of any one of embodiments 1-14, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of about 9.7% when heated from about 25°C to about 150°C. Embodiment 16. The crystalline form of any one of embodiments 1-15, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 17. The crystalline form of any one of embodiments 1-16, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 18. A pharmaceutical composition comprising the crystalline form of any one of embodiments 1-17 and a pharmaceutically acceptable carrier. Embodiment 19. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 97°C ± 2%. Embodiment 20. The crystalline form of embodiment 19, having an endothermic DSC peak temperature within 97°C ± 1%. Embodiment 21. The crystalline form of embodiment 19, having an endothermic DSC peak temperature within 97°C ± 0.5%. Embodiment 22. The crystalline form of embodiment 19, wherein the crystalline form has an endothermic DSC peak temperature within 245°C ± 2%. Embodiment 23. The crystalline form of embodiment 19, having an endothermic DSC peak temperature within 245°C ± 1%. Embodiment 24. The crystalline form of embodiment 19, having an endothermic DSC peak temperature within 245°C ± 0.5%. Embodiment 25. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 12.2°±0.2°. Embodiment 26. The crystalline form of embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 14.3°±0.2°. Embodiment 27. The crystalline form of embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 18.9°±0.2°. Embodiment 28. The crystalline form of embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.2°±0.2°. Embodiment 29. The crystalline form of embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.0°±0.2°. Embodiment 30. The crystalline form of embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 12.2°±0.2°, 14.3°±0.2°, 18.9°±0.2°, 23.2°±0.2°, and 26.0°±0.2°. Embodiment 31. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 2B. Embodiment 32. The crystalline form of any one of embodiments 19 to 31, wherein the crystalline form is a monohydrate. Embodiment 33. The crystalline form of any one of embodiments 19-32, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of 3.6% when heated from about 25°C to about 150°C. Embodiment 34. The crystalline form of any one of embodiments 19-33, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 35. The crystalline form of any one of embodiments 19-34, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 36. A pharmaceutical composition comprising the crystalline form of any one of embodiments 19 to 35 and a pharmaceutically acceptable carrier. Embodiment 37. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 239°C ± 2%. Embodiment 38. The crystalline form of embodiment 37, having an endothermic DSC peak temperature within 239°C ± 1%. Embodiment 39. The crystalline form of embodiment 37, having an endothermic DSC peak temperature within 239°C ± 0.5%. Embodiment 40. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 9.7°±0.2°. Embodiment 41. The crystalline form of embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 12.1°±0.2°. Embodiment 42. The crystalline form of embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 14.3°±0.2°. Embodiment 43. The crystalline form of embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 22.3°±0.2°. Embodiment 44. The crystalline form of embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 22.8°±0.2°. Embodiment 45. The crystalline form of embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 24.5°±0.2°. Embodiment 46. The crystalline form of embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 9.7°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 22.3°±0.2°, 22.8°±0.2°, and 24.5°±0.2°. Embodiment 47. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 3B. Embodiment 48. The crystalline form of any one of embodiments 37 to 47, wherein the crystalline form is anhydrous. Embodiment 49. The crystalline form of any one of embodiments 37-48, wherein the crystalline form has a thermogravimetric analysis (TGA) plot comprising a mass loss of about 1.0% when heated from about 25°C to about 150°C. Embodiment 50. The crystalline form of any one of embodiments 37-49, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 51. The crystalline form of any one of embodiments 37-50, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 52. A pharmaceutical composition comprising the crystalline form of any one of embodiments 37-51 and a pharmaceutically acceptable carrier. Embodiment 53. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 15°C ± 2%. Embodiment 54. The crystalline form of embodiment 53, having an endothermic DSC peak temperature within 15°C ± 1%. Embodiment 55. The crystalline form of embodiment 53, having an endothermic DSC peak temperature within 15°C ± 0.5%. Embodiment 56. The crystalline form of embodiment 53, wherein the crystalline form has an endothermic DSC peak temperature within 97°C ± 2%. Embodiment 57. The crystalline form of embodiment 56, having an endothermic DSC peak temperature within 97°C ± 1%. Embodiment 58. The crystalline form of embodiment 56, having an endothermic DSC peak temperature within 97°C ± 0.5%. Embodiment 59. The crystalline form of embodiment 53, wherein the crystalline form has an endothermic DSC peak temperature within 162°C ± 2%. Embodiment 60. The crystalline form of embodiment 59, having an endothermic DSC peak temperature within 162°C ± 1%. Embodiment 61. The crystalline form of embodiment 59, having an endothermic DSC peak temperature within 162°C ± 0.5%. Embodiment 62. The crystalline form of embodiment 53, wherein the crystalline form has endothermic DSC peak temperatures within 15°C ± 2%, within 97°C ± 2%, and within 162°C ± 2%. Embodiment 63. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 43°±0.2°. Embodiment 64. The crystalline form of embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.3°±0.2°. Embodiment 65. The crystalline form of embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 7.9°±0.2°. Embodiment 66. The crystalline form of embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 18.8°±0.2°. Embodiment 67. The crystalline form of embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 20.3°±0.2°. Embodiment 68. The crystalline form of embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.7°±0.2°. Embodiment 69. The crystalline form of embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.7°±0.2°. Embodiment 70. The crystalline form of embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 4.3°±0.2°, 6.3°±0.2°, 7.9°±0.2°, 18.8°±0.2°, 20.3°±0.2°, 23.7°±0.2°, and 26.7°±0.2°. Embodiment 71. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 4B. Embodiment 72. The crystalline form of any one of embodiments 53-71, wherein the crystalline form is an n-methyl-2-pyrrolidone (NMP) solvate. Embodiment 73. The crystalline form of any one of embodiments 53-72, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of about 9.5% when heated from about 25°C to about 150°C. Embodiment 74. The crystalline form of any one of embodiments 53-73, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 75. The crystalline form of any one of embodiments 53-74, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 76. A pharmaceutical composition comprising the crystalline form of any one of embodiments 53 to 75 and a pharmaceutically acceptable carrier. Embodiment 77. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 62°C ± 2%. Embodiment 78. The crystalline form of embodiment 77, having an endothermic DSC peak temperature within 62°C ± 1%. Embodiment 79. The crystalline form of embodiment 77, having an endothermic DSC peak temperature within 62°C ± 0.5%. Embodiment 80. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.3°±0.2°. Embodiment 81. The crystalline form of embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 18.8°±0.2°. Embodiment 82. The crystalline form of embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 20.3°±0.2°. Embodiment 83. The crystalline form of embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 22.3°±0.2°. Embodiment 84. The crystalline form of embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.8°±0.2°. Embodiment 85. The crystalline form of embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.7°±0.2°. Embodiment 86. The crystalline form of embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.3°±0.2°, 18.8°±0.2°, 20.3°±0.2°, 22.3°±0.2°, 23.8°±0.2°, and 26.7°±0.2°. Embodiment 87. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 5B. Embodiment 88. The crystalline form of any one of embodiments 77-87, wherein the crystalline form is an n-methyl-2-pyrrolidone (NMP) solvate. Embodiment 89. The crystalline form of any one of embodiments 77-88, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of about 5.5% when heated from about 25°C to about 150°C. Embodiment 90. The crystalline form of any one of embodiments 77-89, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 91. The crystalline form of any one of embodiments 77-90, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride. Embodiment 92. A pharmaceutical composition comprising the crystalline form of any one of embodiments 77-91 and a pharmaceutically acceptable carrier. Embodiment 93. A method for treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the crystalline form of any one of embodiments 1-17, 19-35, 37-51, 53-75, or 77-91, or the crystalline form of any one of embodiments 18, 36, 52, 76, or 92. Embodiment 94. The method of embodiment 93, wherein the cancer is an MTAP-associated cancer. Embodiment 95. The method of embodiment 93, wherein the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma, and thyroid carcinoma. Embodiment 96. The method of embodiment 93, wherein the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer and uterine cancer.

[0126] While the invention has been described in relation to particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is generally intended to cover such modifications, uses, or adaptations of the invention as fall within the scope of the appended claims, in accordance with the principles of the invention, including departures from the present disclosure as may be applicable to the essential features hereinabove described, which are within known or customary practice in the art to which this invention pertains.

Claims

1. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 118°C ± 2%.

2. 2. The crystalline form of claim 1, having an endothermic DSC peak temperature within 118°C ± 1%.

3. 2. The crystalline form of claim 1, having an endothermic DSC peak temperature within 118°C ± 0.5%.

4. 10. The crystalline form of claim 1, wherein the crystalline form exhibits an endothermic DSC peak temperature within 211°C ± 2%.

5. 5. The crystalline form of claim 4, having an endothermic DSC peak temperature within 211°C ± 1%.

6. 5. The crystalline form of claim 4, having an endothermic DSC peak temperature within 211°C ± 0.5%.

7. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ angle of 6.8°±0.2°.

8. 8. The crystalline form of claim 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 7.4°±0.2°.

9. 8. The crystalline form of claim 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 13.9°±0.2°.

10. 8. The crystalline form of claim 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.9°±0.2°.

11. 8. The crystalline form of claim 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.2°±0.2°.

12. 8. The crystalline form of claim 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.8°±0.2°, 7.4°±0.2°, 13.9°±0.2°, 23.9°±0.2°, and 26.2°±0.2°.

13. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a powder X-ray diffraction pattern substantially as shown in FIG. 1B.

14. 14. The crystalline form of any of claims 1 to 13, wherein the crystalline form is a trihydrate.

15. 15. The crystalline form of any one of claims 1-14, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 9.7% when heated from about 25°C to about 150°C.

16. 16. The crystalline form of any of claims 1-15, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

17. 17. The crystalline form of any one of claims 1 to 16, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

18. 18. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 97°C ± 2%.

20. 20. The crystalline form of claim 19, having an endothermic DSC peak temperature within 97°C ± 1%.

21. 20. The crystalline form of claim 19, having an endothermic DSC peak temperature within 97°C ± 0.5%.

22. 20. The crystalline form of claim 19, wherein the crystalline form has an endothermic DSC peak temperature within 245°C ± 2%.

23. 20. The crystalline form of claim 19, having an endothermic DSC peak temperature within 245°C ± 1%.

24. 20. The crystalline form of claim 19, having an endothermic DSC peak temperature within 245°C ± 0.5%.

25. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern containing peaks at 2θ angles of 12.2°±0.2°.

26. 26. The crystalline form of claim 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 14.3°±0.2°.

27. 26. The crystalline form of claim 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 18.9°±0.2°.

28. 26. The crystalline form of claim 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.2°±0.2°.

29. 26. The crystalline form of claim 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.0°±0.2°.

30. 26. The crystalline form of claim 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 12.2°±0.2°, 14.3°±0.2°, 18.9°±0.2°, 23.2°±0.2°, and 26.0°±0.2°.

31. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a powder X-ray diffraction pattern substantially as shown in FIG. 2B.

32. 32. The crystalline form of any one of claims 19 to 31, wherein the crystalline form is a monohydrate.

33. 33. The crystalline form of any one of claims 19-32, wherein the crystalline form has a thermogravimetric analysis (TGA) plot comprising a mass loss of 3.6% when heated from about 25°C to about 150°C.

34. 34. The crystalline form of any one of claims 19 to 33, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

35. 35. The crystalline form of any one of claims 19 to 34, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

36. 36. A pharmaceutical composition comprising the crystalline form of any one of claims 19 to 35 and a pharmaceutically acceptable carrier.

37. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 239°C ± 2%.

38. 38. The crystalline form of claim 37, having an endothermic DSC peak temperature within 239°C ± 1%.

39. 38. The crystalline form of claim 37, having an endothermic DSC peak temperature within 239°C ± 0.5%.

40. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ angle of 9.7°±0.2°.

41. 41. The crystalline form of claim 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 12.1°±0.2°.

42. 41. The crystalline form of claim 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 14.3°±0.2°.

43. 41. The crystalline form of claim 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 22.3°±0.2°.

44. 41. The crystalline form of claim 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 22.8°±0.2°.

45. 41. The crystalline form of claim 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 24.5°±0.2°.

46. 41. The crystalline form of claim 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 9.7°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 22.3°±0.2°, 22.8°±0.2°, and 24.5°±0.2°.

47. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a powder X-ray diffraction pattern substantially as shown in FIG. 3B.

48. 48. The crystalline form of any one of claims 37 to 47, wherein the crystalline form is anhydrous.

49. 49. The crystalline form of any one of claims 37-48, wherein the crystalline form has a thermogravimetric analysis (TGA) plot comprising about 1.0% mass loss when heated from about 25°C to about 150°C.

50. 50. The crystalline form of any one of claims 37-49, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

51. 51. The crystalline form of any one of claims 37-50, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

52. 52. A pharmaceutical composition comprising the crystalline form of any one of claims 37 to 51 and a pharmaceutically acceptable carrier.

53. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 15°C ± 2%.

54. 54. The crystalline form of claim 53, having an endothermic DSC peak temperature within 15°C ± 1%.

55. 54. The crystalline form of claim 53, having an endothermic DSC peak temperature within 15°C ± 0.5%.

56. 54. The crystalline form of claim 53, wherein the crystalline form has an endothermic DSC peak temperature within 97°C ± 2%.

57. 57. The crystalline form of claim 56, having an endothermic DSC peak temperature within 97°C ± 1%.

58. 57. The crystalline form of claim 56, having an endothermic DSC peak temperature within 97°C ± 0.5%.

59. 54. The crystalline form of claim 53, wherein the crystalline form has an endothermic DSC peak temperature within 162°C ± 2%.

60. 60. The crystalline form of claim 59, having an endothermic DSC peak temperature within 162°C ± 1%.

61. 60. The crystalline form of claim 59, having an endothermic DSC peak temperature within 162°C ± 0.5%.

62. 54. The crystalline form of claim 53, wherein the crystalline form has endothermic DSC peak temperatures within 15°C ± 2%, within 97°C ± 2%, and within 162°C ± 2%.

63. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ angle of 4.3°±0.2°.

64. 64. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.3°±0.2°.

65. 64. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 7.9°±0.2°.

66. 64. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 18.8°±0.2°.

67. 64. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 20.3°±0.2°.

68. 64. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.7°±0.2°.

69. 64. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.7°±0.2°.

70. 64. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 4.3°±0.2°, 6.3°±0.2°, 7.9°±0.2°, 18.8°±0.2°, 20.3°±0.2°, 23.7°±0.2°, and 26.7°±0.2°.

71. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a powder X-ray diffraction pattern substantially as shown in FIG. 4B.

72. 72. The crystalline form of any one of claims 53 to 71, wherein the crystalline form is an n-methyl-2-pyrrolidone (NMP) solvate.

73. 73. The crystalline form of any one of claims 53-72, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 9.5% when heated from about 25°C to about 150°C.

74. 74. The crystalline form of any one of claims 53-73, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

75. 75. The crystalline form of any one of claims 53-74, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

76. 76. A pharmaceutical composition comprising the crystalline form of any one of claims 53 to 75 and a pharmaceutically acceptable carrier.

77. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a differential scanning calorimetry (DSC) endothermic peak temperature within 62°C ± 2%.

78. 78. The crystalline form of claim 77, having an endothermic DSC peak temperature within 62°C ± 1%.

79. 78. The crystalline form of claim 77, having an endothermic DSC peak temperature within 62°C ± 0.5%.

80. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ angle of 6.3°±0.2°.

81. 81. The crystalline form of claim 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 18.8°±0.2°.

82. 81. The crystalline form of claim 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 20.3°±0.2°.

83. 81. The crystalline form of claim 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 22.3°±0.2°.

84. 81. The crystalline form of claim 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 23.8°±0.2°.

85. 81. The crystalline form of claim 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 26.7°±0.2°.

86. 81. The crystalline form of claim 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.3°±0.2°, 18.8°±0.2°, 20.3°±0.2°, 22.3°±0.2°, 23.8°±0.2°, and 26.7°±0.2°.

87. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride having a powder X-ray diffraction pattern substantially as shown in FIG. 5B.

88. 88. The crystalline form of any one of claims 77 to 87, wherein the crystalline form is an n-methyl-2-pyrrolidone (NMP) solvate.

89. 89. The crystalline form of any one of claims 77-88, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 5.5% when heated from about 25°C to about 150°C.

90. 90. The crystalline form of any one of claims 77-89, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

91. 91. The crystalline form of any one of claims 77-90, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride.

92. 92. A pharmaceutical composition comprising the crystalline form of any one of claims 77 to 91 and a pharmaceutically acceptable carrier.

93. 10. A method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the crystalline form of any one of claims 1-17, 19-35, 37-51, 53-75 or 77-91, or the crystalline form of any one of claims 18, 36, 52, 76 or 92.

94. 94. The method of claim 93, wherein the cancer is an MTAP-associated cancer.

95. 94. The method of claim 93, wherein the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma, and thyroid carcinoma.

96. 94. The method of claim 93, wherein the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer and uterine cancer.

Images