Crystalline forms 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-(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 comprising these crystalline forms, and methods of using these crystalline forms.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 484,602, filed February 13, 2023, and U.S. Provisional Application No. 63 / 516,668, filed July 13, 2023, the contents of each of which are hereby incorporated by reference in their entirety. Field of the Invention

[0003] 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-cyclopropyloxy-3-fluorobenzonitrile and a specific crystalline form thereof, a method for preparing the crystalline form, and a pharmaceutical composition comprising the crystalline form. The crystalline form can be used to treat and / or prevent diseases and / or conditions associated with cell proliferation, such as cancer. In particular, the crystalline form provides therapeutic benefits as an MTA-co-inhibitor of protein arginine N-methyltransferase 5 (PRMT5). Background of the Invention

[0005] 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 ω-nitrogen of the guanidino functional group of protein L-arginine residues (ω-monomethylation) and the transfer of a second methyl group to another ω-nitrogen, thereby generating symmetric dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylbody protein 50), which is required for substrate recognition and orientation, and is also required for the PRMT5-catalyzed histone 2A and histone 4 methyltransferase activities (e.g., see Ho et al., (2013) PLOS ONE 8(8):10.1371 / annotation / e6b5348e-9052-44ab-8f06-90d01dc88fc2).

[0006] Homozygous deletions of p16 / CDKN2a are common in cancer, and these mutations often involve co-deletions of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of all human cancers have homozygous deletions of the MTAP gene (e.g., see Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):13754-13760. doi:10.1021 / jacs.7b05803. Epub 2017 Sep 20).

[0007] Cells lacking MTAP activity have elevated levels of the MTAP substrate, methylthioadenosine (MTA), a potent inhibitor of PRMT5. Inhibition of PRMT5 activity leads to reduced methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Thus, loss of MTAP activity reduces the methylation activity of PRMT5, rendering cells selectively dependent on PRMT5 activity.

[0008] Therefore, MTA-cooperative inhibition of PRMT5 activity in MTAP-deficient cancers may provide therapeutic benefits for a wide range of cancers. The compounds of the present invention provide such therapeutic benefits as MTA-cooperative inhibitors of PRMT5, which negatively regulate the activity of MTA-bound PRMT5 in cells, particularly MTAP-deficient cells, or are useful for treating various forms of MTAP-associated cancers.

[0009] Specifically, 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile is a potent and selective inhibitor of PRMT5 and has been found to be pharmacologically active. Herein, the crystalline hydrochloride salt of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile has been found to be suitable for use in pharmaceutical compositions. SUMMARY OF THE INVENTION

[0011] 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-cyclopropyloxy-3-fluorobenzonitrile (hereinafter referred to as Compound 1) as shown below.

[0012]

[0013] In another aspect, the present disclosure also provides a specific crystalline form of Compound 1, hereinafter referred to as hydrochloride (HCl) Salt Form A. The present disclosure further provides a method for preparing HCl Salt Form A. The present disclosure further provides a pharmaceutical composition comprising HCl Salt Form A and a pharmaceutically acceptable carrier.

[0014] In another aspect, the present disclosure also provides a specific crystalline form of Compound 1, hereinafter referred to as hydrochloride (HCl) Salt Form B. The present disclosure further provides a method for preparing HCl Salt Form B. The present disclosure further provides a pharmaceutical composition comprising HCl Salt Form B and a pharmaceutically acceptable carrier.

[0015] In another aspect, the present disclosure also provides a specific crystalline form of Compound 1, hereinafter referred to as hydrochloride (HCl) Salt Form E. The present disclosure further provides a method for preparing HCl Salt Form E. The present disclosure further provides a pharmaceutical composition comprising HCl Salt Form E and a pharmaceutically acceptable carrier.

[0016] In another aspect, the present disclosure also provides a specific crystalline form of Compound 1, hereinafter referred to as hydrochloride (HCl) Salt Form F. The present disclosure further provides a method for preparing HCl Salt Form F. The present disclosure further provides a pharmaceutical composition comprising HCl Salt Form F and a pharmaceutically acceptable carrier.

[0017] In another aspect, the present disclosure also provides a specific crystalline form of Compound 1, hereinafter referred to as hydrochloride (HCl) Salt Form G. The present disclosure further provides a method for preparing HCl Salt Form G. The present disclosure further provides a pharmaceutical composition comprising HCl Salt Form G and a pharmaceutically acceptable carrier.

[0018] The present disclosure further provides methods of treating cancer, comprising administering a crystalline form of Compound 1 as disclosed herein, or a pharmaceutical composition comprising a crystalline form of Compound 1, to a subject in need of such treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1A is an overlay of the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of Compound 1 HCl Form A crystals.

[0021] Figure 1B It is the X-ray powder diffraction (XRPD) pattern of HCl Form A crystals of Compound 1.

[0022] Figure 1C is a polarized light microscopy (PLM) image of Compound 1 HCl Form A crystals.

[0023] Figure 1D is a dynamic vapor sorption (DVS) isotherm plot of Compound 1 HCl Form A crystals.

[0024] Figure 2A is an overlay of the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of Compound 1 HCl Form B crystals.

[0025] Figure 2B It is the X-ray powder diffraction (XRPD) pattern of Compound 1 HCl Form B crystals.

[0026] Figure 2C is a polarized light microscopy (PLM) image of Compound 1 HCl Form B crystals.

[0027] Figure 2D is a dynamic vapor sorption (DVS) isotherm plot of Compound 1 HCl Form B crystals.

[0028] Figure 3A is an overlay of the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of Compound 1 HCl Form E crystals.

[0029] Figure 3B It is the X-ray powder diffraction (XRPD) pattern of HCl Form E crystals of Compound 1.

[0030] Figure 3C is a dynamic vapor sorption (DVS) isotherm plot of HCl Form E crystals of Compound 1.

[0031] Figure 3D The proton NMR of the HCl form E crystal of compound 1 is ( 1 H-NMR) spectrum.

[0032] Figure 4A is an overlay of the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of Compound 1 HCl Form F crystals.

[0033] Figure 4B The X-ray powder diffraction (XRPD) pattern of Compound 1 HCl Form F crystals.

[0034] Figure 4C The proton NMR of the HCl form F crystal of compound 1 is ( 1 H-NMR) spectrum.

[0035] Figure 5A is an overlay of the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of Compound 1 HCl Form G crystals.

[0036] Figure 5B It is the X-ray powder diffraction (XRPD) pattern of HCl Form G crystals of Compound 1.

[0037] Figure 5C The proton NMR of the HCl form G crystal of compound 1 is ( 1 H-NMR) spectrum.

[0038] Figure 6A is the X-ray powder diffraction (XRPD) pattern of the amorphous HCl salt of Compound 1.

[0039] Figure 6B is a polarized light microscopy (PLM) image of the amorphous HCl salt of Compound 1.

[0040] Figure 6Cis an overlay of the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of the amorphous HCl salt of Compound 1.

[0041] Figure 6D is the proton NMR of the amorphous HCl salt of compound 1 ( 1 H-NMR) spectrum.

[0042] Figure 6E is the high pressure liquid chromatography (HPLC) spectrum of the amorphous HCl salt of Compound 1.

[0043] Figure 7A is a graph of the area under the curve for plasma concentrations of Compound 1 HCl Form A and Compound 1 HCl Form B administered to mammals.

[0044] Figure 7B is a graph of the area under the curve for plasma concentrations of Compound 1 HCl Form B administered to mammals.

[0045] Figure 8 is a graph of the total impurity content of Compound 1 HCl Form B versus excipients.

[0046] Figure 9A is a graph of the porosity of Compound 1 HCl Form B versus compression pressure.

[0047] Figure 9B is a graph of tensile strength versus compression pressure for Compound 1 HCl Form B.

[0048] Figure 9C Plot of tensile strength versus porosity for Compound 1 HCl Form B.

[0049] Figure 10 The X-ray powder diffraction (XRPD) patterns of Compound 1 HCl Form B crystals before and after high-intensity compression.

[0050] Figure 11A is a graph of the intrinsic dissolution rate of Compound 1 HCl Form B.

[0051] Figure 11B is a graph of the dissolution of Compound 1 HCl Form B from capsules in biorelevant media. Detailed Description of the Invention

[0053] As described 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0054] In some embodiments, the present invention also provides HCl Salt Form A, 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0055] In some embodiments, the present invention also provides HCl Salt Form B, 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0056] In some embodiments, the present invention also provides HCl Salt Form E, 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0057] In some embodiments, the present invention also provides HCl Salt Form F, 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0058] In some embodiments, the present invention also provides HCl Salt Form G, 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0059] The crystalline forms described herein can be characterized using a number of methods known to those of ordinary skill in the art, including thermal analysis (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM), polarized light microscopy), and spectroscopic analysis (e.g., infrared, Raman, solid-state nuclear magnetic resonance, proton nuclear magnetic resonance ( 1 (HNMR)). Particle size and particle size distribution can be determined by conventional methods, such as laser scattering techniques. 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).

[0060] HCl Salt Form A

[0061] In one embodiment, the present 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride, i.e., HCl Salt Form A. In various embodiments, HCl Salt Form A has a differential scanning calorimetry (DCS) thermogram (e.g., including an endothermic peak). In some embodiments, HCl Salt Form A has an endothermic DSC peak temperature of about 118°C, e.g., within about ±2% of 118°C. In some embodiments, HCl Salt Form A has an endothermic DSC peak temperature of about 118°C, e.g., within about ±1% of 118°C or within ±0.5% of 118°C. In some embodiments, HCl Salt Form A has an endothermic DSC peak temperature of about 211°C, e.g., within about ±2% of 211°C. In some embodiments, HCl Salt Form A has an endothermic DSC peak temperature that is within ±1% of 211° C. or within ±0.5% of 211° C. In various embodiments, HCl Salt Form A has a DSC thermogram with a peak temperature at about 118° C. (e.g., within about ±2% of 118° C. or ±1% of 118° C. or ±0.5% of 118° C.) and about 211° C. (e.g., within about ±2% of 211° C. or ±1% of 211° C. or ±0.5% of 211° C.). For example, in some embodiments, HCl Salt Form A has a peak temperature substantially as Figure 2A DSC thermogram shown in .

[0062] In various embodiments, HCl salt form A has an X-ray powder diffraction (XRPD) pattern. In some embodiments, HCl salt form A has an XRPD pattern including a peak at 2θ angles of 6.8°±0.2°. In some embodiments, HCl salt form A has an XRPD pattern including a peak at 2θ angles of 7.4°±0.2°. In some embodiments, HCl salt form A has an XRPD pattern including a peak at 2θ angles of 13.9°±0.2°. In some embodiments, HCl salt form A has an XRPD pattern including a peak at 2θ angles of 23.9°±0.2°. In some embodiments, HCl salt form A has an XRPD pattern including a peak at 2θ angles of 26.2°±0.2°. In some embodiments, HCl Salt Form A 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, HCl Salt Form A has substantially Figure 2B The XRPD pattern is shown in . In some embodiments as described herein, HCl Salt Form A is a trihydrate.

[0063] In some embodiments as described herein, HCl Salt Form A has a thermogravimetric analysis (TGA) pattern comprising a mass loss of about 9.7% when heated from about 25° C. to about 150° C. For example, in some embodiments, HCl Salt Form A has substantially Figure 2A The TGA graph shown in .

[0064] In some embodiments as described herein, the purity of HCl Salt Form A is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride. In some embodiments, the purity of HCl Salt Form A is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0065] HCl Salt Form B

[0066] Another embodiment of the present disclosure as 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride, HCl Salt Form B. In various embodiments, HCl Salt Form B has a differential scanning calorimetry (DCS) thermogram (e.g., including an endothermic peak). In some embodiments, HCl Salt Form B has an endothermic DSC peak temperature of about 97°C, e.g., within about ±2% of 97°C. In some embodiments, HCl Salt Form B has an endothermic DSC peak temperature of within ±1% of 97°C or within ±0.5% of 97°C. In some embodiments, HCl Salt Form B has an endothermic DSC peak temperature of about 245°C, e.g., within about ±2% of 245°C. In some embodiments, HCl Salt Form B has an endothermic DSC peak temperature that is within ±1% of 245°C or within ±0.5% of 245°C. In various embodiments, HCl Salt Form B has a DSC thermogram with peak temperatures at about 97°C (e.g., within about ±2% of 97°C or ±1% of 97°C or ±0.5% of 97°C) and at about 245°C (e.g., within about ±2% of 245°C or ±1% of 245°C or ±0.5% of 245°C). For example, in some embodiments, HCl Salt Form B has a peak temperature that is substantially as Figure 2A DSC thermogram shown in .

[0067] In various embodiments, HCl salt form B has an X-ray powder diffraction (XRPD) pattern. In some embodiments, HCl salt form B has an XRPD pattern including a peak at 2θ angles of 12.2 ° ± 0.2 °. In some embodiments, HCl salt form B has an XRPD pattern including a peak at 2θ angles of 14.3 ° ± 0.2 °. In some embodiments, HCl salt form B has an XRPD pattern including a peak at 2θ angles of 18.9 ° ± 0.2 °. In some embodiments, HCl salt form B has an XRPD pattern including a peak at 2θ angles of 23.2 ° ± 0.2 °. In some embodiments, HCl salt form B has an XRPD pattern including a peak at 2θ angles of 26.0 ° ± 0.2 °. In some embodiments, HCl Salt Form B 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, HCl Salt Form B 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°. Figure 2B The XRPD pattern is shown in . In some embodiments as described herein, HCl Salt Form B is a monohydrate.

[0068] In some embodiments as described herein, HCl Salt Form B has a thermogravimetric analysis (TGA) profile comprising a mass loss of about 3.6% when heated from about 25° C. to about 150° C. For example, in some embodiments, HCl Salt Form B has substantially Figure 2A The TGA graph shown in .

[0069] In some embodiments as described herein, the purity of HCl Salt Form B is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride. In some embodiments, the purity of HCl Salt Form B is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0070] HCl salt form E

[0071] Another embodiment of the present disclosure as 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride, i.e., HCl Salt Form E. In various embodiments, HCl Salt Form E has a differential scanning calorimetry (DCS) thermogram (e.g., including an endothermic peak). In some embodiments, HCl Salt Form E has an endothermic DSC peak temperature of about 239°C, e.g., within about ±2% of 239°C. In some embodiments, HCl Salt Form E has an endothermic DSC peak temperature of within ±1% of 239°C or within ±0.5% of 239°C. For example, in some embodiments, HCl Salt Form E has substantially Figure 3A DSC thermogram shown in .

[0072] In various embodiments, HCl salt form E has an X-ray powder diffraction (XRPD) pattern. In some embodiments, HCl salt form E has an XRPD pattern including a peak at 2θ angles of 9.7°±0.2°. In some embodiments, HCl salt form E has an XRPD pattern including a peak at 2θ angles of 12.1°±0.2°. In some embodiments, HCl salt form E has an XRPD pattern including a peak at 2θ angles of 14.3°±0.2°. In some embodiments, HCl salt form E has an XRPD pattern including a peak at 2θ angles of 22.3°±0.2°. In some embodiments, HCl salt form E has an XRPD pattern including a peak at 2θ angles of 22.8°±0.2°. In some embodiments, HCl salt form E has an XRPD pattern including a peak at 2θ angles of 24.5°±0.2°. In some embodiments, HCl Salt Form E 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, HCl Salt Form E 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°. Figure 3B The XRPD pattern shown in . In some embodiments as described herein, HCl Salt Form E is an anhydrate.

[0073] In some embodiments as described herein, HCl Salt Form E has a thermogravimetric analysis (TGA) pattern comprising a mass loss of about 1.0% when heated from about 25° C. to about 150° C. For example, in some embodiments, HCl Salt Form E has substantially Figure 3A The TGA graph shown in .

[0074] In some embodiments as described herein, the purity of HCl Salt Form E is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride. In some embodiments, the purity of HCl Salt Form E is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0075] HCl Salt Form F

[0076] Another embodiment of the present disclosure as 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride, HCl Salt Form F. In various embodiments, HCl Salt Form F has a differential scanning calorimetry (DCS) thermogram (e.g., including an endothermic peak). In some embodiments, HCl Salt Form F has an endothermic DSC peak temperature of about 15°C, e.g., within about ±2% of 15°C. In some embodiments, HCl Salt Form F has an endothermic DSC peak temperature of about 97°C, e.g., within about ±2% of 97°C. In some embodiments, HCl Salt Form F has an endothermic DSC peak temperature within ±1% of 97° C. or within ±0.5% of 97° C. In some embodiments, HCl Salt Form F has an endothermic DSC peak temperature of about 162° C., e.g., within about ±2% of 162° C. In some embodiments, HCl Salt Form F has an endothermic DSC peak temperature within ±1% of 162° C. or within ±0.5% of 162° C. In various embodiments, HCl salt Form F has a DSC thermogram with peak temperatures at about 15°C (e.g., within about ±2% of 15°C, or ±1% of 15°C, or ±0.5% of 15°C), at about 97°C (e.g., within about ±2% of 97°C, or ±1% of 97°C, or ±0.5% of 97°C), and at about 162°C (e.g., within about ±2% of 162°C, or ±1% of 162°C, or ±0.5% of 162°C). For example, in some embodiments, HCl salt Form F has a peak temperature substantially as Figure 4A DSC thermogram shown in .

[0077] In various embodiments, HCl salt form F has an X-ray powder diffraction (XRPD) pattern. In some embodiments, HCl salt form F has an XRPD pattern including a peak at 2θ angles of 4.3°±0.2°. In some embodiments, HCl salt form F has an XRPD pattern including a peak at 2θ angles of 6.3°±0.2°. In some embodiments, HCl salt form F has an XRPD pattern including a peak at 2θ angles of 7.9°±0.2°. In some embodiments, HCl salt form F has an XRPD pattern including a peak at 2θ angles of 18.8°±0.2°. In some embodiments, HCl salt form F has an XRPD pattern including a peak at 2θ angles of 20.3°±0.2°. In some embodiments, HCl salt form F has an XRPD pattern including a peak at 2θ angles of 23.7°±0.2°. In some embodiments, HCl salt Form F has an XRPD pattern comprising a peak at 2θ angles of 26.7°±0.2°. In some embodiments, HCl salt Form F 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, HCl salt Form F has substantially Figure 4B The XRPD pattern is shown in . In some embodiments as described herein, HCl salt Form F is an n-methyl-2-pyrrolidone (NMP) solvate.

[0078] In some embodiments as described herein, HCl Salt Form F has a thermogravimetric analysis (TGA) pattern comprising a mass loss of about 9.5% when heated from about 25° C. to about 150° C. For example, in some embodiments, HCl Salt Form F has a TGA pattern substantially as shown in Figure 5B4A.

[0079] In some embodiments as described herein, the purity of HCl Salt Form F is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride. In some embodiments, the purity of HCl Salt Form F is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0080] HCl Salt Form G

[0081] Another embodiment of the present disclosure as 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride, i.e., HCl Salt Form G. In various embodiments, HCl Salt Form G has a differential scanning calorimetry (DCS) thermogram (e.g., including an endothermic peak). In some embodiments, HCl Salt Form G has an endothermic DSC peak temperature of about 62°C, e.g., within about ±2% of 62°C. In some embodiments, HCl Salt Form G has an endothermic DSC peak temperature of within ±1% of 62°C or within ±0.5% of 62°C. For example, in some embodiments, HCl Salt Form F has substantially Figure 5A DSC thermogram shown in .

[0082] In multiple embodiments, HCl salt form G has an X-ray powder diffraction (XRPD) pattern. In some embodiments, HCl salt form G has an XRPD pattern including a peak at 2θ angles of 6.3°±0.2°. In some embodiments, HCl salt form G has an XRPD pattern including a peak at 2θ angles of 18.8°±0.2°. In some embodiments, HCl salt form G has an XRPD pattern including a peak at 2θ angles of 20.3°±0.2°. In some embodiments, HCl salt form G has an XRPD pattern including a peak at 2θ angles of 22.3°±0.2°. In some embodiments, HCl salt form G has an XRPD pattern including a peak at 2θ angles of 23.8°±0.2°. In some embodiments, HCl salt form G has an XRPD pattern including a peak at 2θ angles of 26.7°±0.2°. In some embodiments, HCl salt form F 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, HCl salt form G has an XRPD pattern substantially as Figure 5B The XRPD pattern is shown in . In some embodiments as described herein, HCl salt Form G is an n-methyl-2-pyrrolidone (NMP) solvate.

[0083] In some embodiments as described herein, HCl Salt Form G has a thermogravimetric analysis (TGA) profile comprising a mass loss of about 5.5% when heated from about 25° C. to about 150° C. For example, in some embodiments, HCl Salt Form G has substantially Figure 5A The TGA graph shown in .

[0084] In some embodiments as described herein, the purity of HCl Salt Form G is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride. In some embodiments, the purity of HCl Salt Form G is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0085] Method for preparing a crystalline form of the HCl salt of Compound 1

[0086] In another aspect, the present disclosure provides methods for preparing crystalline forms of the HCl salt of Compound 1, such as HCl Salt Form A, HCl Salt Form B, HCl Salt Form E, HCl Salt Form F, and HCl Salt Form G. 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 a variety of methods as discussed in the Examples below. For example, the crystalline forms described herein can be prepared by a slurry process, antisolvent addition, solid vapor diffusion, liquid vapor diffusion, slow evaporation at room temperature, slow cooling, or polymer-induced crystallization.

[0087] In various embodiments, the slurry process can be performed at various temperatures and using various solvents. For example, in some embodiments, the slurry process is performed at room temperature or at an elevated temperature (e.g., 50° C.). To prepare a crystalline form using a slurry process, the amorphous HCl salt of Compound 1 is suspended in a solvent at a certain temperature (e.g., room temperature or elevated temperature) and stirred to provide a solid.

[0088] In various embodiments, the antisolvent addition method can be performed at various temperatures and using various solvents. For example, in some embodiments, the antisolvent addition method is performed at room temperature. To prepare a crystalline form using the antisolvent addition method, the amorphous HCl salt of Compound 1 is dissolved in a solvent to obtain a saturated solution, and an antisolvent is added in an amount of up to, for example, 20 times the volume to provide a solid.

[0089] In various embodiments, the solid vapor diffusion method can be performed at various temperatures and using various solvents. For example, in some embodiments, the solid vapor diffusion method is performed at room temperature. To prepare a crystalline form using the solid vapor diffusion method, the amorphous HCl salt of Compound 1 is provided in a first vial, which is placed in a second vial containing a solvent. There is no physical contact between the solid free base of Compound 1 in the first vial and the solvent in the second vial. The solid is then characterized after 14 days.

[0090] In various embodiments, the liquid vapor diffusion method can be performed at various temperatures and using various solvents. For example, in some embodiments, the liquid vapor diffusion method is performed at room temperature. To prepare a crystalline form using the 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, which is placed in a second vial containing an antisolvent to provide a solid.

[0091] 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 using 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 parafilm having a plurality of holes, e.g., 3-5 holes, and evaporated to provide a solid.

[0092] In a number of embodiments, the slow cooling method can be carried out at various temperatures and using various solvents. For example, in some embodiments, the slow cooling method is carried out at an increased temperature (e.g., 55°C). For preparing crystalline forms using the slow cooling method, the amorphous HCl salt of compound 1 is dissolved in a solvent to obtain a saturated solution, for example, in the range of 40-70°C, or 45-70°C, or 50-70°C, or 40-65°C, or 45-65°C, or 50-65°C, or 40-60°C, or 45-60°C, or 50-60°C. In some embodiments, for preparing crystalline forms using the slow cooling method, the free alkali of compound 1 is dissolved in a solvent to obtain a saturated solution, for example, at about 55°C. The solution is slowly cooled to room temperature to provide a solid.

[0093] In various embodiments, the polymer-induced crystallization method can be carried out at various temperatures and using various solvents. For example, in some embodiments, the polymer-induced crystallization is carried out at room temperature. To prepare a crystalline form using the polymer-induced crystallization method, the amorphous HCl salt of compound 1 is dissolved in a solvent to obtain a saturated solution. The polymer is then added to the saturated solution to induce heterogeneous nucleation and provide a solid.

[0094] In some embodiments, a slurry method or a solid vapor diffusion method can be used to provide HCl Salt Form A. When a slurry method is used, the solvent can be water. When solid vapor diffusion is used, the solvent can be water.

[0095] In some embodiments, a slurry method or a solid vapor diffusion method can be used to provide HCl Salt Form B. When a slurry method is used, the solvent can be selected from acetonitrile (ACN) or isopropanol / water. When a solid vapor diffusion method is used, the solvent can be ACN.

[0096] In some embodiments, in order to provide HCl salt form E, slurry process, anti-solvent addition, solid vapor diffusion, liquid vapor diffusion, room temperature slow evaporation, slow cooling and polymer induced crystallization method can be used.When using slurry process, solvent can be selected from methanol (MeOH), n-propyl alcohol (NPA), dichloromethane (DCM), ethanol (EtOH), ACN, tetrahydrofuran (THF) / normal heptane, IPA / toluene and MeOH / water.When using anti-solvent addition method, solvent can be MeOH, and anti-solvent can be selected from methyl tert-butyl ether (MTBE), ACN and heptane.When using solid vapor diffusion method, solvent can be EtOH.When using liquid vapor diffusion method, solvent can be MeOH, and anti-solvent can be selected from cyclopentyl methyl ether (CPME), ACN and isopropyl acetate (IPAc).When using slow evaporation method, solvent can be selected from MeOH, IPA and 1-butanol (1-BuOH).When using slow cooling method, solvent can be selected from MeOH and EtOH. When the polymer-induced crystallization method is used, the solvent may be MeOH and the polymer may be polyvinylpyrrolidone (PVP).

[0097] In some embodiments, liquid vapor diffusion can be used to provide HCl Salt Form F. When liquid vapor diffusion is used, the solvent can be n-methylpyrrolidone (NMP) and the antisolvent can be selected from heptance or MTBE.

[0098] In some embodiments, solid vapor diffusion can be used to provide HCl Salt Form F. When liquid vapor diffusion is used, the solvent can be NMP.

[0099] Pharmaceutical composition

[0100] In another aspect, the present disclosure provides a medicament comprising a crystalline form 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) and a suitable carrier, excipient, or diluent. The exact nature of the carrier, excipient, or diluent will depend on the desired use of the composition and may range from suitable or acceptable for veterinary use to suitable or acceptable for human use. The composition may optionally include one or more additional compounds. In certain embodiments, the composition may include one or more antibiotic compounds. In another aspect, the present disclosure provides a pharmaceutical composition comprising HCl salt form A and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising HCl salt form B and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising HCl salt form E and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising HCl salt form F and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a pharmaceutical composition comprising HCl salt form G and a pharmaceutically acceptable carrier.

[0101] When used to treat or prevent such diseases, Compound 1 as described herein can be administered alone, as a mixture of one or more compounds, or mixed or combined with other active agents used to treat such diseases and / or symptoms associated with such diseases. These compounds can also be mixed or combined with active agents used to treat other disorders or diseases (maladies), such as steroids, membrane stabilizers, 5LO inhibitors, leukotriene synthesis and receptor inhibitors, IgE isotype switching or IgE synthesis inhibitors, IgG isotype switching or IgG synthesis inhibitors, beta-agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, rituximab (retuxin), PD4 inhibitors, p38 inhibitors, PDE4 inhibitors and antihistamines, to name a few. Compound 1 can be administered in the form of a crystalline form described herein or as a pharmaceutical composition comprising a crystalline form described herein.

[0102] Pharmaceutical compositions comprising various crystalline forms of Compound 1 can be prepared by conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping or lyophilizing methods. The compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants that facilitate processing of the compound into preparations that can be used pharmaceutically.

[0103] The pharmaceutical compositions can be in a form suitable for nearly any mode of administration including, for example, topical, ophthalmic, oral, buccal, systemic, nasal, parenteral, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0104] For topical administration, the compound(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well known in the art. Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0105] Available injection preparations include sterile suspensions, solutions or emulsions of (one or more) active compounds in aqueous or oily vehicles. Compositions can also include formulating agents, such as suspending agents, stabilizers and / or dispersants. Preparations for injection can exist in unit dosage form, for example, in ampoules or in multidose containers, and can include added preservatives. Alternatively, injection preparations can be provided in powder form so as to be reconstructed using a suitable vehicle before use, including but not limited to sterile pyrogen-free water, buffer, glucose solution, etc. For this reason, (one or more) active compounds can be dried by any technology known in the art (e.g., lyophilized) and reconstructed before use.

[0106] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0107] For oral administration, the pharmaceutical composition can be in the form of, for example, lozenges, tablets, or capsules, prepared by conventional means using pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated with, for example, sugar, film, or enteric coatings by methods well known in the art.

[0108] Liquid preparations for oral administration can be in the form of, for example, elixirs, solutions, syrups or suspensions, or they can be present as dry products and be prepared with water or other suitable vehicles before use. Pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, cremophore™ or fractionated vegetable oils); and preservatives (e.g., methyl benzoate or propyl paraben or sorbic acid) can be used to prepare the liquid preparations by conventional means. The preparations can also contain buffer salts, preservatives, flavorings, coloring agents and sweeteners as needed.

[0109] As is well known, preparations for oral administration can be suitably formulated to provide controlled release of the compound. For buccal administration, the composition can take the form of tablets or lozenges formulated in a conventional manner. For rectal and vaginal administration routes, the compound(s) can be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0110] For nasal administration or administration by inhalation or insufflation, the compound(s) can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, a valve can be provided to deliver a metered amount to determine the dosage unit. Capsules and cartridges for use in an inhaler or insufflator (for example, capsules and cartridges composed of gelatin) can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0111] For ocular administration, the compound(s) 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.

[0112] For the delivery of extension, (one or more) compound can be formulated into a depot preparation for use by implantation or intramuscular injection. Suitable polymers or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins can be utilized, or as insoluble derivatives, for example, (one or more) compounds are prepared as insoluble salts. Alternatively, a transdermal delivery system for slowly releasing (one or more) compounds made into a sticky sheet or patch (adhesive patch) can be used for percutaneous absorption. For this reason, a penetration enhancer can be used to promote the transdermal penetration of (one or more) compounds.

[0113] Alternatively, other drug delivery systems can be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver (one or more) compounds. Certain organic solvents such as dimethyl sulfoxide (DMSO) can also be used, although usually at the expense of greater toxicity.

[0114] If desired, the pharmaceutical composition can be present in a package or dispenser device which can contain one or more unit dosage forms containing the compound(s). For example, the package can comprise metal or plastic film, such as a blister pack. The package or dispenser device can be accompanied by instructions for administration.

[0115] How to use

[0116] The compound(s) described herein, or compositions thereof, will generally be used in an amount effective to achieve the desired result (e.g., an amount effective to treat or prevent the specific disease being treated). A therapeutic benefit is defined as eradication or amelioration of the underlying disorder being treated and / or eradication or amelioration of one or more of the symptoms associated with the underlying disorder, such that the patient reports an improvement in feeling or condition, even though the patient may still be suffering from the underlying disorder. A therapeutic benefit also generally includes stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

[0117] In 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 with an effective amount of a crystalline form of compound 1 as described herein or a pharmaceutical composition containing a crystalline form of compound 1 as described herein in vitro. In one embodiment, the cell is an MTAP-deficient cell.

[0118] The compositions and methods provided herein are particularly contemplated to be useful for inhibiting PRMT5 activity in cells in vivo. In one embodiment, cells in which PRMT5 activity is desired to be inhibited are contacted in vivo with a therapeutically effective amount of a crystalline form of compound 1 as described herein or a pharmaceutical composition containing a crystalline form of compound 1 as described herein. In one embodiment, the cells are MTAP-deficient cells. In one embodiment, negative regulation of PRMT5 activity is performed in the presence of bound MTA.

[0119] By negatively regulating the activity of PRMT5, particularly in the case of cells lacking MTAP activity, the method is designed to inhibit PRMT5 activity to block cell proliferation. Depending on the specific treatment regimen, cells can be contacted in the form of a single dose or multiple doses to affect the desired PRMT5 negative regulation. In the presence and absence of MTA, the extent of PRMT5 inhibition of the enzyme can be monitored in vitro using well-known methods (including those described in Example B below) in cells to assess the effectiveness of treatment and dosage.

[0120] In another aspect, a method of treating cancer comprises administering to a patient suffering from cancer a therapeutically effective amount of a crystalline form of Compound 1 as described herein, or a pharmaceutical composition containing a crystalline form of Compound 1 as described herein. In one embodiment, the cancer is an MTAP-associated cancer.

[0121] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors, such as 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 astrocytic carcinoma, 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, and thyroid cancer and sarcomas. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors), Tumors, VIPomas), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma), =Liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteocartilaginous exostoses), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;Nervous System: Skull (osteomas, hemangiomas, granulomas, xanthoma, osteitis deformans), Meninges (meningiomas, meningeal sarcomas, gliomas), Brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), Spinal Neurofibromas, Meningiomas, Glioma, Sarcomas); Gynecological: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical dysplasia), Ovary (ovarian cancer (plasmatocystic cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosa-thecal cell tumors, Sertoli-Leydig cell tumors Tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphocytic 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, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0122] 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.

[0123] In other embodiments, the cancer is selected from ovarian plasma cystadenocarcinoma, squamous cell lung cancer, lung adenocarcinoma, mesothelioma; esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, cholangiocarcinoma; osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial cancer, and thyroid cancer.

[0124] In other embodiments, the cancer is selected from bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, and uterine cancer.

[0125] The concentration and route of administration to the patient will vary depending on the cancer being treated. The crystalline form of Compound 1 described herein or a pharmaceutical composition containing the crystalline form of Compound 1 described herein can also be co-administered with other anti-tumor compounds (e.g., chemotherapy) or used in combination with other therapeutic interventions (e.g., radiation or surgery) as a pre- or post-operative adjuvant. Example

[0126] The following examples are intended to illustrate further certain embodiments of the present invention, but are not intended to limit the scope of the present invention.

[0127] Example 1: Characterization of the Amorphous HCl Salt of Compound 1

[0128] Compound 1 can be prepared as a jelly according to the method disclosed in published international application number WO2021050915. See Example 16-8.

[0129] By XRPD, PLM, DSC, TGA, 1 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-cyclopropyloxy-3-fluorobenzonitrile) provided as a white solid was characterized by H-NMR and HPLC. The results are summarized in Table 1 and shown in FIG. Figures 6A-6E middle.

[0130] Table 1.

[0131]

[0132]

[0133] Example 2: Formation of HCl Form A of Compound 1

[0134] The amorphous HCl salt of compound 1 (30 mg) was suspended in 2 mL of water at room temperature. After 14 days, the solid in the slurry was characterized by XRPD, PLM, DSC, TGA, and DVS. The resulting crystals were off-white solids. The characterization results are summarized in Table 2 and shown in Table 2. Figures 1A-1D middle.

[0135] Table 2.

[0136]

[0137] Other methods of preparing crystalline forms of Compound 1 were also evaluated to provide HCl Salt Form A. Four additional methods were found to provide HCl Salt Form A: slurry method at 50°C, solid vapor diffusion, slow evaporation, and slow cooling.

[0138] For the 50° C. slurry experiment, approximately 30 mg of the amorphous HCl salt of Compound 1 was suspended in 2 mL of water in a 4 mL vial at 50° C. and stirred. After 6 days, the solid in the slurry was characterized by XRPD and identified as HCl Form A.

[0139] For solid vapor diffusion experiments, approximately 30 mg of the amorphous HCl salt of Compound 1 was kept in a 4 mL vial and placed in a 20 mL glass vial containing water. After 14 days, the solid was characterized by XRPD and identified as HCl Form A.

[0140] For the slow evaporation experiment, evaporation occurred at room temperature. In order to obtain a saturated solution, about 30 mg of the amorphous HCl salt of compound 1 was dissolved in water in a 4 mL vial. The vial was covered with paraffin film with 3-5 holes and left to evaporate at room temperature. The resulting solid was characterized by XRPD and identified as HCl Form A.

[0141] For the slow cooling experiment, approximately 30 mg of the amorphous HCl salt of Compound 1 was dissolved in water in a 4 mL vial using a hot plate at 55° C. to obtain a saturated solution. The solution was slowly cooled to room temperature using the following ramp: 3 hours at 55° C., 4 hours at 40° C., 4 hours at 25° C., 5 hours at 15° C., and 5 hours at 10° C. The resulting solid was characterized by XRPD and identified as HCl Salt Form A.

[0142] Table 3 describes Figure 1B The XRD pattern of the HCl Form A crystalline form of Compound 1 is shown in FIG.

[0143] Table 3.

[0144]

[0145]

[0146] The hygroscopicity of HCl Form A was also evaluated by performing dynamic vapor sorption experiments. Figure 1D A DVS isotherm for HCl Form A is shown, which shows a water uptake of approximately 1.43% between 10% relative humidity and 90% relative humidity at 25° C. No crystalline form changes were observed for the sample after DVS evaluation.

[0147] Example 3: Formation of HCl Form B of Compound 1

[0148] The amorphous HCl salt of compound 1 (30 mg) was suspended in 2 mL of acetonitrile at room temperature. After 14 days, the solid in the slurry was characterized by XRPD, PLM, DSC, TGA, and DVS. The characterization results are summarized in Table 4 and shown in Figures 2A-2D middle.

[0149] Table 4.

[0150]

[0151] Other methods of preparing crystalline forms of Compound 1 were also evaluated to provide HCl Salt Form B. Two additional methods were found to provide HCl Salt Form B: a slurry method and solid vapor diffusion at room temperature.

[0152] For room temperature slurry experiments, approximately 30 mg of the amorphous HCl salt of Compound 1 was suspended in 1.5 mL of IPA / H2O solution in a 4 mL vial at room temperature and stirred. Four IPA / H2O solutions were used at 20%, 40%, 60%, and 80% IPA, respectively. After 6 days, the solid in the slurry was characterized by XRPD and identified as HCl Form B.

[0153] For solid vapor diffusion experiments, approximately 30 mg of the amorphous HCl salt of Compound 1 was kept in a 4 mL vial and placed in a 20 mL glass vial containing acetonitrile. After 14 days, the solid was characterized by XRPD and identified as HCl Form B.

[0154] Table 5 describes Figure 2B The XRD pattern of the HCl Form B crystalline form of Compound 1 is shown in FIG.

[0155] Table 5.

[0156]

[0157]

[0158]

[0159] The hygroscopicity of HCl Form B was also evaluated by performing dynamic vapor sorption experiments. Figure 2D A DVS isotherm is shown for HCl Form B, which shows a water uptake of approximately 1.3% between 10% relative humidity and 90% relative humidity at 25° C. No crystalline form changes were observed for the sample after DVS evaluation.

[0160] Example 4: Formation of HCl Form E of Compound 1

[0161] Various methods for preparing crystalline forms of Compound 1 were evaluated to provide HCl Salt Form E. Eight methods were found to provide HCl Salt Form E: slurry method at room temperature, slurry method at 50°C, antisolvent addition, solid vapor diffusion, liquid vapor diffusion, slow evaporation at room temperature, slow cooling, and polymer-induced crystallization.

[0162] For room temperature slurry experiments, approximately 30 mg of the amorphous HCl salt of Compound 1 was suspended in 1.5-2.0 mL of different solvents in a 4 mL vial at room temperature and stirred. The solids in the slurry were characterized by XRPD after 14 days. Table 6 discloses the parameters for generating HCl Salt Form E in the room temperature slurry experiment.

[0163] Table 6.

[0164] Experiment number Solvent (v:v) observe The resulting crystal form 1 MeOH Off-white solid HCl salt form E 2 NPA Off-white solid HCl salt form E 3 DCM Off-white solid HCl salt form E

[0165] For the 50°C slurry experiment, approximately 30 mg of the amorphous HCl salt of Compound 1 was suspended in different solvents in 4 mL vials at 50°C and stirred, and the solids in the slurry were characterized by XRPD after 6 days. Table 7 discloses the parameters for producing HCl Salt Form E when the slurry experiment was performed at 50°C.

[0166] Table 7.

[0167] Experiment number Solvent (v:v) observe The resulting crystal form 4 EtOH Off-white solid HCl salt form E 5 ACN Off-white solid HCl salt form E 6 IPA / Toluene (1:1) Off-white solid HCl salt form E 7 MeOH Off-white solid HCl salt form E 8 <![CDATA[MeOH / H2O(1:1)]]> Off-white solid HCl salt form E THF / n-heptane (1:1) Off-white solid HCl salt form E

[0168] For the antisolvent addition experiment, approximately 30 mg of the amorphous HCl salt of Compound 1 was dissolved in various solvents to obtain a saturated solution, and the antisolvent was added in an amount up to 20 times the volume. The resulting solid was characterized by XRPD. Table 8 discloses the parameters for generating HCl Form E in the antisolvent addition experiment.

[0169] Table 8.

[0170] Experiment number Solvent (v:v) antisolvent observe The resulting crystal form 9 MeOH MTBE Off-white solid HCl salt form E 10 MeOH ACN Off-white solid HCl salt form E 11 MeOH heptane Off-white solid HCl salt form E

[0171] For the solid vapor diffusion experiment, approximately 30 mg of the amorphous HCl salt of Compound 1 was kept in a 4 mL vial and placed in a 20 mL glass vial containing different solvents. The solid was characterized by XRPD after 14 days. Table 9 discloses the parameters for producing HCl Salt Form E in the solid vapor diffusion experiment.

[0172] Table 9.

[0173] Experiment number Solvent (v:v) observe The resulting crystal form 12 EtOH Off-white solid HCl salt form E

[0174] For the liquid vapor diffusion experiment, approximately 30 mg of the amorphous HCl salt of Compound 1 was dissolved in various solvents in a 4 mL vial to obtain a saturated solution, which was then placed in a 20 mL vial containing an antisolvent. The resulting solid was characterized by XRPD after 12 days. Table 10 discloses the parameters for producing HCl Salt Form E in the liquid vapor diffusion experiment.

[0175] Table 10.

[0176] Experiment number Solvent (v:v) antisolvent observe The resulting crystal form 13 MeOH CPME Off-white solid HCl salt form E 14 MeOH ACN Off-white solid HCl salt form E 15 MeOH IPAC Off-white solid HCl salt form E

[0177] For the slow evaporation experiments, evaporation was performed at room temperature or 50°C. To obtain a saturated solution, approximately 30 mg of the amorphous HCl salt of Compound 1 was dissolved in various solvents in 4 mL vials. The vials were covered with parafilm with 3-5 holes and allowed to evaporate at room temperature or 50°C. The resulting solids were characterized by XRPD. Table 11 discloses the parameters for producing HCl Salt Form E in the slow evaporation experiments.

[0178] Table 11.

[0179] Experiment number Solvent (v:v) Temperature (℃) observe The resulting crystal form 16 MeOH RT Off-white solid HCl salt form E 17 IPA 50 Off-white solid HCl salt form E 18 1-BuOH 50 Off-white solid HCl salt form E

[0180] For the slow cooling experiment, approximately 30 mg of the amorphous HCl salt of Compound 1 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 ramp: 3 hours at 55°C, 4 hours at 40°C, 4 hours at 25°C, 5 hours at 15°C, and 5 hours at 10°C. The resulting solid was characterized by XRPD. Table 12 discloses the parameters for the slow cooling experiment to produce HCl Salt Form E.

[0181] Table 12.

[0182] Experiment number Solvent (v:v) observe The resulting crystal form 19 MeOH Off-white solid HCl salt form E 20 EtOH Off-white solid HCl salt form E

[0183] For polymer-induced crystallization experiments, approximately 30 mg of the amorphous HCl salt of Compound 1 was dissolved in various solvents to produce saturated solutions. One of polyvinyl pyrrolidone (PVP), polyethylene glycol (PEO), polyvinyl alcohol (PVA), or hydroxypropyl methylcellulose (HPMC) was added to the saturated solution to induce heterogeneous nucleation. The resulting solid was characterized by XRPD after 12 days. Table 13 discloses the parameters for producing HCl Salt Form E in the polymer-induced crystallization experiment.

[0184] Table 13.

[0185] Experiment number Solvent (v:v) polymer observe The resulting crystal form 21 MeOH PVP Off-white solid HCl salt form E

[0186] The HCl salt form E was characterized by various methods, including XRPD, DSC, TGA, DVS and 1H-NMR. The characterization results are summarized in Table 14 and shown in Figures 3A-3D middle.

[0187] Table 14.

[0188]

[0189] Table 15 describes Figure 4A The XRD pattern of HCl Form E crystalline form of Compound 1 is shown in FIG.

[0190] Table 15.

[0191]

[0192]

[0193] The hygroscopicity of HCl Form E was also evaluated by performing dynamic vapor sorption experiments. Figure 3C A DVS isotherm is shown for HCl Form E, which shows a water uptake of approximately 2.56% between 0% relative humidity and 80% relative humidity at 25° C. No crystalline form changes were observed for the sample after DVS evaluation.

[0194] Example 5: Formation of HCl Form F of Compound 1

[0195] Compound 1 HCl Form F was formed by liquid vapor diffusion. The amorphous HCl salt of Compound 1 (30 mg) was dissolved in NMP to give a saturated solution in a 4 mL vial, which was placed in a 20 mL glass vial containing an anti-solvent (heptane and MTBE). After 12 days, the resulting solid was characterized by XRPD, DSC, TGA, and 1H-NMR. The resulting crystals were off-white solids. The characterization results are summarized in Table 16 and are shown in Table 16. Figures 4A-4C Shown in.

[0196] Table 16.

[0197]

[0198]

[0199] Table 17 describes Figure 5A The XRD pattern of HCl Form F crystalline form of Compound 1 is shown in FIG.

[0200] Table 17.

[0201]

[0202]

[0203] Example 6: Formation of Compound 1 HCl Form G

[0204] Compound 1 HCl Form G was formed by solid vapor diffusion. The amorphous HCl salt of Compound 1 (30 mg) was stored in a 4 mL vial and placed in a 20 mL glass vial containing NMP. After 14 days, the resulting solid was characterized by XRPD, DSC, TGA, and 1H-NMR. The resulting crystals were off-white solids. The characterization results are summarized in Table 18 and are shown in Table 18. Figures 5A-5C Shown in.

[0205] Table 18.

[0206]

[0207] Table 19 describes Figure 6A The XRD pattern of the HCl Form G crystalline form of Compound 1 is shown in FIG.

[0208] Table 19.

[0209]

[0210]

[0211] Example 7: Competitive slurry experiment

[0212] Table 20 summarizes the results of competitive slurry experiments under different conditions to study the relative stability of HCl Form A, HCl Form B, and HCl Form E. w Experiments CS-1 to CS-6 were performed using a mixture of HCl Form E (30 mg), HCl Form A (5 mg), and HCl Form B (5 mg) in a solution of HCl Form E (5 mg). Experiment CS-7 was set up using only HCl Form E suspended in pure water at room temperature. Experiment CS-8 was performed at 60°C using HCl Form A and HCl Form B in pure water. Experiment CS-9 was performed at room temperature using the amorphous HCl salt in an EtOH / water solution (40:60 v / v). Form A was observed under certain conditions during competitive slurry experiments. Form A was confirmed to be a racemate by chiral HPLC analysis.

[0213] Table 20.

[0214]

[0215]

[0216] Example 8: Preclinical biological performance

[0217] The pharmacokinetics of different crystalline forms of compound 1 were studied after oral administration of free base form A, HCl form A, and HCl form B of compound 1 in male beagle dogs at a dose of 100 mg / dog (~ about 10 mg / kg). The material was filled into empty HPMC capsules after calibration for potency and administered together with 40 mL of water to dogs pretreated with pentagastrin or famotidine. Pentagastrin enhances gastric secretion, while famotidine neutralizes gastric secretion. Therefore, pentagastrin and famotidine pretreatment were used to simulate the effect of gastric pH on bioavailability and reduce the variability of gastric pH between dogs.

[0218] Plasma samples were collected at predetermined intervals and analyzed for the concentration of Compound 1. Plasma concentration versus time data were analyzed by a non-compartmental approach using the WinNonlin software program to estimate PK parameters such as C max 、T max , AUC 0-t and AUC 0-inf These results are shown in Figure 7A and 7B middle.

[0219] The results showed that HCl Form A was less stable than HCl Form B, and the HCl salt showed common ionic effects in the gastric medium, which may have caused high variability in dogs treated with pentagastrin. In addition, when normalized for particle size, the free base Form A and the HCl salt had comparable exposure. In addition, for the two HCl forms tested, there was a significant difference in bioavailability between dogs treated with pentagastrin and famotidine, suggesting that both forms may have a food effect.

[0220] Example 9: Compatibility of excipients

[0221] The compatibility of both free base form A and HCl form B of compound 1 with a variety of excipients commonly used in oral solid dosage form (OSD) formulation development was evaluated. Binary mixtures of samples were produced by mixing each substance with the excipient using a mortar and pestle (1:10 compound to excipient for fillers and 1:1 for all other excipients), accurately weighing the resulting mixture and transferring it to a sample vial. The excipients used were as follows: colloidal silicon dioxide 200, cross-linked sodium carboxymethyl cellulose, crospovidone XL-10, calcium hydrogen phosphate (an), hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, mannitol 100SD, MCC PH102, Opadry TM II, povidone K-30, pregelatinized starch 1500, sodium starch glycolate, and sodium stearyl fumarate. The sample vials were placed under open conditions at 40°C / 75% RH for 8 weeks and then analyzed for impurity levels using HPLC. The results of the total impurity content of these samples are shown in Figure 6 and compared with the free base Form A and HCl Form B of Compound 1 without any excipients.

[0222] from Figure 8 As can be seen, both free base Form A and HCl Form B of Compound 1 exhibit good compatibility with excipients. In addition, free base Form A is more sensitive to colloidal silicon dioxide and lactose monohydrate than HCl Form B. Although the risk of chemical stability of free base Form A and HCl Form B is slightly higher, it is still controllable by influencing the choice of selected excipients.

[0223] Example 10: Manufacturability and physical stability

[0224] The compressibility (i.e., porosity versus compression pressure), tabletability (i.e., tensile strength versus compression pressure), and compactibility (i.e., tensile strength versus porosity) of Compound 1, Compound 1 HCl Form B were determined. The results of these tests are shown in Figures 9A-9C In addition, the phase stability of HCl Form B of Compound 1 under a compression pressure of 300 MPa was studied by XRD. The XRD pattern was compared with that of the uncompressed compound. X-ray powder diffraction patterns were obtained using Cu Kα radiation on a wide-angle X-ray diffractometer (X'Pert Pro; PANalytical, West Borough, MA). The applied voltage and current were 45 kV and 40 mA, respectively. Each measurement was performed in the 2θ range of 5-35° with a step size of 0.0167° and a dwell time of 0.4 s. These results are shown in Figure 10 middle.

[0225] HCl Form B exhibits good compressibility, tabletability, and formability under high pressure, although a loss of crystallinity was observed at high compression pressures.

[0226] Example 11: Intrinsic Dissolution Rate (IDR) and Dissolution of Drug from Capsules in Fasting Gastric Simulated Fluid (FasSSGF) and Fasting Intestinal Simulated Fluid (FasSSIF)

[0227] The intrinsic dissolution rate (IDR) was determined by measuring the amount of free base Form A and HCl Form B of Compound 1 dissolved in buffer and then constructing a linear curve of dissolved compound versus time. The slope of the linear curve was divided by the surface area of ​​the tablet (0.5 cm 2 ) IDR rate was calculated. At 14 MPa, the free base form A and HCl form B of compound 1 were compressed into tablets with a diameter of 0.8 cm. At 37°C, in a USPII type dissolution apparatus with a sinker, capsules of HCl form B in pH 1.2 and pH 6.8 buffers were stirred at 50 rpm, while capsules of free base form A in pH 6.8 buffer were stirred under the same conditions. At each time point, 0.6 mL of liquid was withdrawn with a syringe and filtered. The concentration of the filtrate was analyzed by HPLC. The IDR results are shown in Figure 11A The dissolution in the capsule is shown in Figure 11B middle.

[0228] Free base Form A exhibited faster dissolution in gastric media due to common ionic effects that slowed the dissolution of HCl Form B. In intestinal media, HCl Form B had a slightly faster dissolution rate than free base Form A, however, it was observed that free base Form A was able to maintain supersaturation in intestinal fluids as the pH shifted from the stomach to the intestine after 30 minutes.

[0229] Detailed list of implementation plans

[0230] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 118°C.

[0231] Embodiment 2. The crystalline form of Embodiment 1, wherein the endothermic DSC peak temperature is within ±1% of 118°C.

[0232] Embodiment 3. The crystalline form of Embodiment 1, wherein the endothermic DSC peak temperature is within ±0.5% of 118°C.

[0233] Embodiment 4. The crystalline form of Embodiment 1, wherein the crystalline form has an endothermic DSC peak temperature within ±2% of 211°C.

[0234] Embodiment 5. The crystalline form of Embodiment 4, wherein the endothermic DSC peak temperature is within ±1% of 211°C.

[0235] Embodiment 6. The crystalline form of Embodiment 4, wherein the endothermic DSC peak temperature is within ±0.5% of 211°C.

[0236] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.8°±0.2°.

[0237] Embodiment 8. The crystalline form of Embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at 2θ of 7.4°±0.2°.

[0238] Embodiment 9. The crystalline form of Embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at 2θ of 13.9°±0.2°.

[0239] Embodiment 10. The crystalline form of Embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at 2θ of 23.9°±0.2°.

[0240] Embodiment 11. The crystalline form of Embodiment 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 26.2°±0.2°.

[0241] 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°.

[0242] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having substantially Figure 1B The X-ray powder diffraction pattern is shown in .

[0243] Embodiment 14. The crystalline form of any one of Embodiments 1-13, wherein the crystalline form is a trihydrate.

[0244] Embodiment 15. The crystalline form of any one of Embodiments 1-14, wherein the crystalline form has a thermogravimetric analysis (TGA) trace comprising a mass loss of about 9.7% when heated from about 25°C to about 150°C.

[0245] Embodiment 16. The crystalline form of any one of Embodiments 1-15, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0246] Embodiment 17. The crystalline form of any one of Embodiments 1-16, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0247] Embodiment 18. A pharmaceutical composition comprising the crystalline form of any one of Embodiments 1-17 and a pharmaceutically acceptable carrier.

[0248] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 97°C.

[0249] Embodiment 20. The crystalline form of Embodiment 19, wherein the endothermic DCS peak temperature is within ±1% of 97°C.

[0250] Embodiment 21. The crystalline form of Embodiment 19, wherein the endothermic DCS peak temperature is within ±0.5% of 97°C.

[0251] Embodiment 22. The crystalline form of Embodiment 19, wherein the endothermic crystalline form has a DSC peak temperature within ±2% of 245°C.

[0252] Embodiment 23. The crystalline form of Embodiment 19, wherein the endothermic DCS peak temperature is within ±1% of 245°C.

[0253] Embodiment 24. The crystalline form of Embodiment 19, wherein the endothermic DCS peak temperature is within ±0.5% of 245°C.

[0254] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle of 2θ of 12.2°±0.2°.

[0255] Embodiment 26. The crystalline form of Embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 14.3°±0.2°.

[0256] Embodiment 27. The crystalline form of Embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 18.9°±0.2°.

[0257] Embodiment 28. The crystalline form of Embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 23.2°±0.2°.

[0258] Embodiment 29. The crystalline form of Embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 26.0°±0.2°.

[0259] Embodiment 30. The crystalline form of Embodiment 25, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2θ of 12.2°±0.2°, 14.3°±0.2°, 18.9°±0.2°, 23.2°±0.2°, and 26.0°±0.2°.

[0260] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having substantially Figure 2B The X-ray powder diffraction pattern is shown in .

[0261] Embodiment 32. The crystalline form of any one of Embodiments 19-31, wherein the crystalline form is a monohydrate.

[0262] Embodiment 33. The crystalline form of any one of Embodiments 19-32, wherein the crystalline form has a thermogravimetric analysis (TGA) pattern comprising a 3.6% mass loss when heated from about 25°C to about 150°C.

[0263] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0264] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0265] Embodiment 36. A pharmaceutical composition comprising the crystalline form of any one of Embodiments 19-35 and a pharmaceutically acceptable carrier.

[0266] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 239°C.

[0267] Embodiment 38. The crystalline form of Embodiment 37, wherein the endothermic DSC peak temperature is within ±1% of 239°C.

[0268] Embodiment 39. The crystalline form of Embodiment 37, wherein the endothermic DSC peak temperature is within ±0.5% of 239°C.

[0269] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle of 2θ of 9.7°±0.2°.

[0270] Embodiment 41. The crystalline form of Embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 12.1°±0.2°.

[0271] Embodiment 42. The crystalline form of Embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 14.3°±0.2°.

[0272] Embodiment 43. The crystalline form of Embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 22.3°±0.2°.

[0273] Embodiment 44. The crystalline form of Embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 22.8°±0.2°.

[0274] Embodiment 45. The crystalline form of Embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 24.5°±0.2°.

[0275] Embodiment 46. The crystalline form of Embodiment 40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2θ 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°.

[0276] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having substantially Figure 3B The X-ray powder diffraction pattern is shown in .

[0277] Embodiment 48. The crystalline form of any one of Embodiments 37-47, wherein the crystalline form is an anhydrate.

[0278] Embodiment 49. The crystalline form of any one of Embodiments 37-48, wherein the crystalline form has a thermogravimetric analysis (TGA) pattern comprising a mass loss of about 1.0% when heated from about 25°C to about 150°C.

[0279] Embodiment 50. The crystalline form of any one of Embodiments 37-49, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0280] Embodiment 51. The crystalline form of any one of Embodiments 37-50, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0281] Embodiment 52. A pharmaceutical composition comprising the crystalline form of any one of Embodiments 37-51 and a pharmaceutically acceptable carrier.

[0282] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 15°C.

[0283] Embodiment 54. The crystalline form of Embodiment 53, wherein the endothermic DSC peak temperature is within ±1% of 15°C.

[0284] Embodiment 55. The crystalline form of Embodiment 53, wherein the endothermic DSC peak temperature is within ±0.5% of 15°C.

[0285] Embodiment 56. The crystalline form of Embodiment 53, wherein the crystalline form has an endothermic DSC peak temperature within ±2% of 97°C.

[0286] Embodiment 57. The crystalline form of Embodiment 56, wherein the endothermic DSC peak temperature is within ±1% of 97°C.

[0287] Embodiment 58. The crystalline form of Embodiment 56, wherein the endothermic DSC peak temperature is within ±0.5% of 97°C.

[0288] Embodiment 59. The crystalline form of Embodiment 53, wherein the crystalline form has an endothermic DSC peak temperature within ±2% of 162°C.

[0289] Embodiment 60. The crystalline form of Embodiment 59, wherein the endothermic DSC peak temperature is within ±1% of 162°C.

[0290] Embodiment 61. The crystalline form of Embodiment 59, wherein the endothermic DSC peak temperature is within ±0.5% of 162°C.

[0291] Embodiment 62. The crystalline form of Embodiment 53, wherein the crystalline form has endothermic DSC peak temperatures within ±2% of 15°C, within ±2% of 97°C, and within ±2% of 162°C.

[0292] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle of 2θ of 4.3°±0.2°.

[0293] Embodiment 64. The crystalline form of Embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 6.3°±0.2°.

[0294] Embodiment 65. The crystalline form of Embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 7.9°±0.2°.

[0295] Embodiment 66. The crystalline form of Embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 18.8°±0.2°.

[0296] Embodiment 67. The crystalline form of Embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 20.3°±0.2°.

[0297] Embodiment 68. The crystalline form of Embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 23.7°±0.2°.

[0298] Embodiment 69. The crystalline form of Embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 26.7°±0.2°.

[0299] Embodiment 70. The crystalline form of Embodiment 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2θ 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°.

[0300] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having substantially Figure 4B The X-ray powder diffraction pattern is shown in .

[0301] Embodiment 72. The crystalline form of any one of Embodiments 53-71, wherein the crystalline form is an N-methyl-2-pyrrolidone (NMP) solvate.

[0302] Embodiment 73. The crystalline form of any one of Embodiments 53-72, wherein the crystalline form has a thermogravimetric analysis (TGA) profile comprising a mass loss of about 9.5% when heated from about 25°C to about 150°C.

[0303] Embodiment 74. The crystalline form of any one of Embodiments 53-73, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0304] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0305] Embodiment 76. A pharmaceutical composition comprising the crystalline form of any one of Embodiments 53-75 and a pharmaceutically acceptable carrier.

[0306] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 62°C.

[0307] Embodiment 78. The crystalline form of Embodiment 77, wherein the endothermic DSC peak temperature is within ±1% of 62°C.

[0308] Embodiment 79. The crystalline form of Embodiment 77, wherein the endothermic DSC peak temperature is within ±0.5% of 62°C.

[0309] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.3°±0.2°.

[0310] Embodiment 81. The crystalline form of Embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 18.8°±0.2°.

[0311] Embodiment 82. The crystalline form of Embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 20.3°±0.2°.

[0312] Embodiment 83. The crystalline form of Embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 22.3°±0.2°.

[0313] Embodiment 84. The crystalline form of Embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 23.8°±0.2°.

[0314] Embodiment 85. The crystalline form of Embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2θ of 26.7°±0.2°.

[0315] Embodiment 86. The crystalline form of Embodiment 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2θ 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°.

[0316] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having substantially Figure 5B The X-ray powder diffraction pattern is shown in .

[0317] Embodiment 88. The crystalline form of any one of Embodiments 77-87, wherein the crystalline form is an N-methyl-2-pyrrolidone (NMP) solvate.

[0318] Embodiment 89. The crystalline form of any one of Embodiments 77-88, wherein the crystalline form has a thermogravimetric analysis (TGA) profile comprising a mass loss of about 5.5% when heated from about 25°C to about 150°C.

[0319] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0320] 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

[0321] Embodiment 92. A pharmaceutical composition comprising the crystalline form of any one of Embodiments 77-91 and a pharmaceutically acceptable carrier.

[0322] Embodiment 93. A method for treating cancer in an individual in need thereof, comprising administering to the subject a crystalline form of any one of Embodiments 1-17, 19-35, 37-51, 53-75, or 77-91, or a pharmaceutical composition comprising a crystalline form of any one of Embodiments 18, 36, 52, 76, or 92.

[0323] Embodiment 94. The method according to embodiment 93, wherein the cancer is an MTAP-associated cancer.

[0324] Embodiment 95. The method of embodiment 93, wherein the cancer is selected from ovarian plasma cystadenocarcinoma, squamous cell lung cancer, lung adenocarcinoma, mesothelioma; esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, cholangiocarcinoma; osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial cancer, and thyroid cancer.

[0325] Embodiment 96. The method of embodiment 93, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, and uterine cancer.

[0326] ***

[0327] While the invention has been described with reference to specific embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any changes, uses, or adaptations of the invention which generally follow the principles of the invention and include such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains and which may be applied to the essential features hereinbefore described and which fall within the scope of the appended claims.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 118°C.

2. The crystalline form of claim 1, wherein the endothermic DSC peak temperature is within ±1% of 118°C.

3. The crystalline form of claim 1, wherein the endothermic DSC peak temperature is within ±0.5% of 118°C.

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

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

6. The crystalline form of claim 4, wherein the endothermic DSC peak temperature is within ±0.5% of 211°C.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.8°±0.2°.

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

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

10. 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. 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. 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in Figure 1B.

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

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

16. The crystalline form of any one of claims 1 to 15, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

17. The crystalline form of any one of claims 1 to 16, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

18. A pharmaceutical composition comprising the crystalline form according to 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 97°C.

20. The crystalline form of claim 19, wherein the endothermic DCS peak temperature is within ±1% of 97°C.

21. The crystalline form of claim 19, wherein the endothermic DCS peak temperature is within ±0.5% of 97°C.

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

23. The crystalline form of claim 19, wherein the endothermic DCS peak temperature is within ±1% of 245°C.

24. The crystalline form of claim 19, wherein the endothermic DCS peak temperature is within ±0.5% of 245°C.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at 2θ of 12.2°±0.2°.

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

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

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

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

30. 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in Figure 2B.

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

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

34. The crystalline form of any one of claims 19-33, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

35. The crystalline form of any one of claims 19-34, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 239°C.

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

39. The crystalline form of claim 37, wherein the endothermic DSC peak temperature is within ±0.5% of 239°C.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at 2θ angles of 9.7°±0.2°.

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

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

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

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

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

46. ​​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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in Figure 3B.

48. The crystalline form of any one of claims 37-47, wherein the crystalline form is an anhydrate.

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

50. The crystalline form of any one of claims 37-49, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

51. The crystalline form of any one of claims 37-50, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 15°C.

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

55. The crystalline form of claim 53, wherein the endothermic DSC peak temperature is within ±0.5% of 15°C.

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

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

58. The crystalline form of claim 56, wherein the endothermic DSC peak temperature is within ±0.5% of 97°C.

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

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

61. The crystalline form of claim 59, wherein the endothermic DSC peak temperature is within ±0.5% of 162°C.

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

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 4.3°±0.2°.

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

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

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

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

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

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

70. The crystalline form of claim 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2θ 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in Figure 4B.

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

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

74. The crystalline form of any one of claims 53-73, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

75. The crystalline form of any one of claims 53-74, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an endothermic differential scanning calorimetry (DSC) peak temperature within ±2% of 62°C.

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

79. The crystalline form of claim 77, wherein the endothermic DSC peak temperature is within ±0.5% of 62°C.

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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.3°±0.2°.

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

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

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

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

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

86. The crystalline form of claim 80, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2θ 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in Figure 5B.

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

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

90. The crystalline form of any one of claims 77-89, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

91. The crystalline form of any one of claims 77-90, wherein the purity of the crystalline form is 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-cyclopropyloxy-3-fluorobenzonitrile hydrochloride.

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

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

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

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

96. The method according to 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, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, and uterine cancer.

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