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

Abstract

Disclosed herein are 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 free base, pharmaceutically acceptable compositions containing these crystalline forms, and methods of using these crystalline forms.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 63 / 484,599, filed February 13, 2023, and U.S. Provisional Application No. 63 / 516,673, filed July 31, 2023, the disclosures of each of which are incorporated herein by reference in their entirety. [Technical Field]

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

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

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

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

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

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

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

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

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

[0011] In another aspect, the present disclosure also provides a particular crystalline form of Compound 1 (hereinafter Form C of the free base). The present disclosure further provides a method of making Form C of the free base. The present disclosure further provides a pharmaceutical composition comprising Form C of the free base and a pharmaceutically acceptable carrier.

[0012] In another embodiment, the present disclosure also provides a particular crystalline form of Compound 1 (hereinafter Form D of the free base). The present disclosure further provides a method of making Form D of the free base.

[0013] The present disclosure further provides a pharmaceutical composition comprising Form D of the free base and a pharmaceutically acceptable carrier.

[0014] The present disclosure further provides a method for treating cancer, comprising administering to a subject in need thereof a crystalline form of Compound 1 or a pharmaceutical composition comprising a crystalline form of Compound 1 disclosed herein. [Brief explanation of the drawings]

[0015] [Figure 1A] FIG. 1A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay of Form A of the free base. [Figure 1B] FIG. 1B is an X-ray powder diffraction (XRPD) pattern of Form A of the free base. [Figure 2A] FIG. 2A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay of Form B of the free base. [Figure 2B] FIG. 2B is an X-ray powder diffraction (XRPD) pattern of Form B of the free base. [Figure 3A]FIG. 3A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay of Form C of the free base. [Figure 3B] FIG. 3B is an X-ray powder diffraction (XRPD) pattern of Form C of the free base. [Figure 4A] FIG. 4A is a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay of Form D of the free base. [Figure 4B] FIG. 4B is an X-ray powder diffraction (XRPD) pattern of Form D of the free base. [Figure 5A] FIG. 5A is an area under the plasma concentration curve graph of free base Form A administered to a mammal. [Figure 5B] FIG. 5B is an area under the plasma concentration curve graph of Form A of the free base administered to a mammal. [Figure 6] FIG. 6 is a graph of the total impurity content of Compound 1 free base Form A versus excipients. [Figure 7A] FIG. 7A is a graph of porosity versus compaction pressure for Form A of the free base of Compound 1. [Figure 7B] FIG. 7B is a graph of tensile strength versus compressive pressure for Form A of the free base of Compound 1. [Figure 7C] FIG. 7C is a graph of tensile strength vs. porosity for Compound 1 free base Form A. [Figure 8] FIG. 8 is an X-ray powder diffraction (XRPD) pattern of Form A of the free base of Compound 1 before and after high compression. [Figure 9A] FIG. 9A is a graph of the intrinsic dissolution rate of Form A of the free base of Compound 1. [Figure 9B] FIG. 9B is a graph of the dissolution of Form A of the free base of Compound 1 in capsules in biorelevant media. Detailed Description of the Invention

[0016] As noted above, the present invention provides a particular crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

[0017] In some embodiments, the present invention also provides Form A of the free base, i.e., a particular crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

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

[0019] In some embodiments, the present invention also provides Form C of the free base, i.e., a particular crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

[0020] In some embodiments, the present invention also provides Form D of the free base, i.e., a particular crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

[0021] Crystalline forms as described herein can be identified by numerous methods known to those skilled in the art, such as thermal analysis [e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)], powder X-ray diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM), polarizing microscopy) and spectroscopy [e.g., infrared, Raman, solid-state nuclear magnetic resonance and proton nuclear magnetic resonance ( 1 The purity of the crystalline forms provided herein can be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC) and mass spectrometry (MS).

[0022] Free base form A In one embodiment, the disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base, i.e., Form A of the free base. In various embodiments, Form A of the free base exhibits a differential scanning calorimetry (DSC) thermogram. In some embodiments described herein, Form A of the free base exhibits a DSC thermogram having both an exothermic peak and an endothermic peak. For example, in some embodiments, Form A of the free base has an endothermic DSC peak temperature of about 86°C (e.g., within about 86°C ± 2%). In some embodiments, Form A of the free base has an endothermic DSC peak temperature within 86°C ± 1% or within 86°C ± 0.5%. In some embodiments, Form A of the free base has an endothermic DSC peak temperature of about 154°C (e.g., within 154°C ± 2%). In some embodiments, free base Form A has an endothermic DSC peak temperature within 154°C ± 1% or within 154°C ± 0.5%. In some embodiments, free base Form A exhibits an exothermic DSC peak temperature of about 166°C (e.g., within 166°C ± 2%). In some embodiments, free base Form A exhibits an exothermic DSC peak temperature within 166°C ± 1% or within 166°C ± 0.5%. In some embodiments, free base Form A exhibits an endothermic DSC peak temperature of about 261°C (e.g., within 261°C ± about 2%). In some embodiments, free base Form A exhibits an endothermic DSC peak temperature within 261°C ± 1% or within 261°C ± 0.5%. In some embodiments, free base Form A exhibits an exothermic DSC peak temperature of about 270°C (e.g., within 270°C ± 2%). In some embodiments, Form A of the free base has an exothermic DSC peak temperature within ±1% of 270° C. or within ±0.5% of 270° C. For example, in some embodiments, Form A of the free base has a DSC thermogram substantially as shown in FIG. 1A.

[0023] In various embodiments, Form A of the free base has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Form A of the free base has an XRPD pattern including a peak at a 2θ angle of 3.1°±0.2°. In some embodiments, Form A of the free base has an XRPD pattern including a peak at a 2θ angle of 6.2°±0.2°. In some embodiments, Form A of the free base has an XRPD pattern including a peak at a 2θ angle of 10.2°±0.2°. In some embodiments, Form A of the free base has an XRPD pattern including a peak at a 2θ angle of 14.3°±0.2°. In some embodiments, Form A of the free base has an XRPD pattern including peaks at 2θ angles of 3.1°±0.2°, 6.2°±0.2°, 10.2°±0.2°, and 14.3°±0.2°. For example, in some embodiments, Form A of the free base has an XRPD pattern substantially as shown in FIG. 1B. In some embodiments described herein, Form A of the free base is a sesquihydrate.

[0024] In some embodiments described herein, Form A of the free base has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 4.4% when heated from about 25° C. to about 150° C. For example, in some embodiments, Form A of the free base has a TGA plot substantially as shown in FIG. 1A.

[0025] In some embodiments described herein, Form A of the free base has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. In some embodiments, Form A of the free base has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

[0026] Free base form B Another embodiment described herein, this disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base, i.e., Form B of the free base. In various embodiments, Form B of the free base has a differential scanning calorimetry (DSC) thermogram. In some embodiments described herein, Form B of the free base has a DSC thermogram with both an exothermic peak and an endothermic peak. For example, in some embodiments, Form B of the free base has an endothermic DSC peak temperature of about 55° C. (e.g., within about 55° C. ± 2%). In some embodiments, Form B of the free base has an endothermic DSC peak temperature within 55° C. ± 1% or within 55° C. ± 0.5%. In some embodiments, free base Form B has an endothermic DSC peak temperature of about 144°C (e.g., within about 2% of 144°C). In some embodiments, free base Form B has an endothermic DSC peak temperature within 144°C ± 1% or within 0.5% of 144°C. In some embodiments, free base Form B has an exothermic DSC peak temperature of about 168°C (e.g., within 2% of 168°C). In some embodiments, free base Form B has an exothermic DSC peak temperature within 168°C ± 1% or within 0.5% of 168°C. In some embodiments, free base Form B has an endothermic DSC peak temperature of about 260°C (e.g., within 2% of 260°C). In some embodiments, free base Form B has an endothermic DSC peak temperature within 1% of 260°C ± 1% or within 0.5% of 260°C. In some embodiments, Form B of the free base has a DSC peak exotherm temperature of about 268° C. (e.g., within about 2% of 268° C.). In some embodiments, Form B of the free base has a DSC peak exotherm temperature within 1% of 268° C. or within 0.5% of 268° C. For example, in some embodiments, Form B of the free base has a DSC thermogram substantially as shown in FIG. 2A.

[0027] In various embodiments, Form B of the free base has an X-ray powder diffraction (XRPD) pattern. In some embodiments, crystalline Form B of the free base has an XRPD pattern comprising a peak at a 2θ angle of 6.4°±0.2°. In some embodiments, Form B of the free base has an XRPD pattern comprising a peak at a 2θ angle of 12.2°±0.2°. In some embodiments, Form B of the free base has an XRPD pattern comprising a peak at a 2θ angle of 12.8°±0.2°. In some embodiments, Form B of the free base has an XRPD pattern comprising a peak at a 2θ angle of 24.5°±0.2°. In some embodiments, Form B of the free base has an XRPD pattern comprising a peak at a 2θ angle of 25.0°±0.2°. In some embodiments, Form B of the free base has an XRPD pattern comprising peaks at 2θ angles of 6.4°±0.2°, 12.2°±0.2°, 12.8°±0.2°, 24.5°±0.2°, and 25.0°±0.2°. For example, in some embodiments, Form B of the free base has an XRPD pattern substantially as shown in Figure 2B. In some embodiments described herein, Form B of the free base is a dihydrate.

[0028] In some embodiments described herein, Form B of the free base has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 6.5% when heated from about 25° C. to about 150° C. For example, free base B has a TGA plot substantially as shown in FIG. 2A.

[0029] In some embodiments described herein, Form B of the free base has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. In some embodiments, Form B of the free base has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

[0030] Free base form C

[0010] Another embodiment described herein, this disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base, i.e., Form C of the free base. In various embodiments, Form C of the free base exhibits a differential scanning calorimetry (DSC) thermogram. In some embodiments described herein, Form C of the free base has a DSC thermogram having both an exothermic peak and an endothermic peak. For example, in some embodiments, Form C of the free base has an endothermic DSC peak temperature of about 28°C (e.g., within about 28°C ± 2%). In some embodiments, Form C of the free base has an endothermic DSC peak temperature within 28°C ± 1% or within 28°C ± 0.5%. In some embodiments, Form C of the free base has an endothermic DSC peak temperature of about 100°C (e.g., within about 100°C ± 2%). In some embodiments, Form C of the free base has an endothermic DSC peak temperature within 100°C ± 1% or within 100°C ± 0.5%. In some embodiments, Form C of the free base has an exothermic DSC peak temperature of about 161°C (e.g., within about 161°C ± 2%). In some embodiments, Form C of the free base has an exothermic DSC peak temperature within 161°C ± 1% or within 161°C ± 0.5%. In some embodiments, Form C of the free base has an endothermic DSC peak temperature of about 269°C (e.g., within about 269°C ± 2%). In some embodiments, Form C of the free base has an endothermic DSC peak temperature within 269°C ± 1% or within 269°C ± 0.5%. In some embodiments, Form C of the free base has an exothermic DSC peak temperature of about 276°C (e.g., within about 276°C ± 2%). In some embodiments, Form C of the free base has an exothermic DSC peak temperature within 276°C ± 1% or within 276°C ± 0.5%. For example, in some embodiments, Form C of the free base has a DSC thermogram substantially as shown in Figure 3A.

[0031] In various embodiments, Form C of the free base has an X-ray powder diffraction (XRPD) pattern. In some embodiments, crystalline Form C of the free base has an XRPD pattern including a peak at a 2θ angle of 8.2°±0.2°. In some embodiments, Form C of the free base has an XRPD pattern including a peak at a 2θ angle of 9.7°±0.2°. In some embodiments, Form C of the free base has an XRPD pattern including a peak at a 2θ angle of 15.1°±0.2°. In some embodiments, Form C of the free base has an XRPD pattern including a peak at a 2θ angle of 24.8°±0.2°. In some embodiments, Form C of the free base has an XRPD pattern including peaks at 2θ angles of 8.2°±0.2°, 9.7°±0.2°, 15.1°±0.2°, and 24.8°±0.2°. For example, in some embodiments, Form C of the free base has an XRPD pattern substantially as shown in FIG. 3B. In some embodiments described herein, Form C of the free base is a channel hydrate (eg, a solvate, a racemate).

[0032] In some embodiments described herein, Form C of the free base has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 3.3% when heated from about 25° C. to about 200° C. For example, in some embodiments, Form C of the free base has a TGA plot substantially as shown in FIG.

[0033] In some embodiments described herein, Form C of the free base has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. In some embodiments, Form C of the free base has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

[0034] Free base form D

[0010] Another embodiment described herein, this disclosure provides a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base, i.e., Form D of the free base. In various embodiments, Form D of the free base has a differential scanning calorimetry (DSC) thermogram. In some embodiments described herein, Form D of the free base has a DSC thermogram with both an exothermic peak and an endothermic peak. For example, in some embodiments, Form D of the free base has an endothermic DSC peak temperature of about 59°C (e.g., within about 59°C ± 2%). In some embodiments, Form D of the free base has an endothermic DSC peak temperature within 59°C ± 1% or within 59°C ± 0.5%. In some embodiments, free base Form D has an endothermic DSC peak temperature of about 140°C (e.g., within about 140°C ± 2%). In some embodiments, free base Form D has an endothermic DSC peak temperature within 140°C ± 1% or within 140°C ± 0.5%. In some embodiments, free base Form D has an exothermic DSC peak temperature of about 161°C (e.g., within 161°C ± 2%). In some embodiments, free base Form D has an exothermic DSC peak temperature within 161°C ± 1% or within 161°C ± 0.5%. In some embodiments, free base Form D has an endothermic DSC peak temperature of about 258°C (e.g., within about 258°C ± 2%). In some embodiments, free base Form D has an endothermic DSC peak temperature within 258°C ± 1% or within 258°C ± 0.5%. In some embodiments, free base Form D has an exothermic DSC peak temperature of about 267° C. (e.g., within about 267° C. ±2%). In some embodiments, free base Form D has an exothermic DSC peak temperature within 267° C. ±1% or within 267° C. ±0.5%. For example, in some embodiments, free base Form D has a DSC thermogram substantially as shown in FIG. 4A.

[0035] In various embodiments, Form D of the free base has an X-ray powder diffraction (XRPD) pattern. In some embodiments, Form D of the free base has an XRPD pattern including a peak at a 2θ angle of 5.4°±0.2°. In some embodiments, Form D of the free base has an XRPD pattern including a peak at a 2θ angle of 9.9°±0.2°. In some embodiments, Form D of the free base has an XRPD pattern including a peak at a 2θ angle of 13.7°±0.2°. In some embodiments, Form D of the free base has an XRPD pattern including a peak at a 2θ angle of 27.1°±0.2°. In some embodiments, Form D of the free base has an XRPD pattern including peaks at 2θ angles of 5.4°±0.2°, 9.9°±0.2°, 13.7°±0.2°, and 27.1°±0.2°. For example, in some embodiments, Form D of the free base has an XRPD pattern substantially as shown in FIG. 4B. In some embodiments described herein, Form D of the free base is a hydrate.

[0036] In some embodiments described herein, Form D of the free base has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 6.9% when heated from about 25° C. to about 150° C. For example, in some embodiments, Form D of the free base has a TGA plot substantially as shown in FIG.

[0037] In some embodiments described herein, Form D of the free base has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. In some embodiments, Form D of the free base has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

[0038] Methods for preparing the crystalline form of the free base of Compound 1 In another aspect, the disclosure provides methods of preparing crystalline forms of the free base of Compound 1 (e.g., free base form A, free base form B, free base form C, and free base form D). The crystalline forms of free base form A, free base form B, free base form C, and free base form D can be prepared by various methods, as discussed in the Examples below. For example, the crystalline forms described herein may be prepared by a slurry method, an antisolvent addition method, a solid vapor diffusion method, a liquid vapor diffusion method, a slow evaporation method at room temperature, a slow cooling method, or a polymer-induced crystallization method.

[0039] In various embodiments, the slurry method can be carried out at various temperatures and with various solvents.For example, in some embodiments, the slurry method is carried out at room temperature or at an elevated temperature (for example, 50°C).To prepare crystalline form using the slurry method, the free base of Compound 1 is suspended in a solvent at a certain temperature (for example, room temperature or at an elevated temperature) and stirred to obtain a solid.

[0040] In various embodiments, antisolvent addition can be carried out at various temperatures and with various solvents.For example, in some embodiments, antisolvent addition is carried out at room temperature.To prepare crystals by antisolvent addition, the free base of Compound 1 is dissolved in a solvent to obtain a saturated solution, and an antisolvent is added, for example, up to 20 times in volume, to obtain a solid.

[0041] In various embodiments, solid vapor diffusion can be carried out at various temperatures and with various solvents.For example, in some embodiments, solid vapor diffusion is carried out at room temperature.To prepare crystalline form by solid vapor diffusion, the free base of Compound 1 is placed in a first vial and placed in a second vial containing a solvent.There is no physical contact between the solid free base of Compound 1 in the first vial and the solvent in the second vial.The solid is then characterized after 14 days.

[0042] In various embodiments, liquid vapor diffusion method can be carried out at various temperatures and with various solvents.For example, in some embodiments, liquid vapor diffusion method is carried out at room temperature.To prepare crystals by liquid vapor diffusion method, the free base of compound 1 is dissolved in a solvent to obtain a saturated solution in a first vial, and then the first vial is placed in a second vial that contains an anti-solvent to obtain a solid.

[0043] In various embodiments, the slow evaporation method can be carried out at various temperatures and using various solvents. For example, in some embodiments, the slow evaporation method is carried out at room temperature or at an elevated temperature (e.g., 50°C). To prepare a crystalline form by the slow evaporation method, the free base of Compound 1 is dissolved in a solvent to obtain a saturated solution. The vial is then covered with paraffin film with multiple holes (e.g., 3-5 holes) and evaporated to obtain a solid.

[0044] In various 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 a high temperature (e.g., 55°C). To prepare crystals by the slow cooling method, the free base of Compound 1 is dissolved in a solvent to obtain a saturated solution at, for example, 40-70°C, 45-70°C, 50-70°C, 40-65°C, 45-65°C, 50-65°C, 40-60°C, 45-60°C, or 50-60°C. In some embodiments, to prepare crystalline forms by the slow cooling method, the free base of Compound 1 is dissolved in a solvent to obtain a saturated solution at, for example, about 55°C. The solution is then slowly cooled to room temperature to obtain a solid.

[0045] In various embodiments, polymer-induced crystallization can be carried out at various temperatures and with various solvents.For example, in some embodiments, polymer-induced crystallization is carried out at room temperature.To produce crystals by polymer-induced crystallization, the free base of Compound 1 is dissolved in a solvent to form a saturated solution.Then, a polymer is added to the saturated solution to induce heterogeneous nucleation and obtain a solid.

[0046] In some embodiments, the slurry method, anti-solvent addition method, solid vapor diffusion method, liquid vapor diffusion method, or slow cooling method can be used to obtain Form A of the free base. When using the slurry method, the solvent can be selected from isopropyl alcohol (IPA), ethyl acetate (EtOAc), isopropyl acetate (IPAc), chloroform (CHCl), dimethoxyethane, methyl tert-butyl ether (MTBE), acetonitrile (ACN), anisole, cyclopentyl methyl ether (CPME), toluene, tetrahydrofuran (THF) / water, 2-methyltetrahydrofuran (2-MeTHF), or n-heptane. When using the anti-solvent addition method, the solvent can be selected from THF, dimethyl sulfoxide (DMSO), and dichloromethane (DCM), and the anti-solvent can be selected from water and heptane. When using the solid vapor diffusion method, the solvent can be selected from ethanol, 1-butanol, 2Me-THF, dimethoxyethane, MTBE, toluene, EtOAc, IPAc, and HO. When using the liquid vapor diffusion method, the solvent may be n-methylpyrrolidone (NMP) and the anti-solvent may be water. When using the slow cooling method, the solvent may be ACN.

[0047] In some embodiments, a slurry method, a slow cooling method, or a polymer-induced crystallization method can be used to obtain Form B of the free base. When using the slurry method, the solvent can be selected from ethanol (EtOH), IPA, methyl isobutyl ketone (MIBK), and methanol (MeOH). When using the slow cooling method, the solvent can be EtOH. When using the polymer-induced crystallization method, the solvent can be 2-butanol, and the polymer can be hydroxypropylmethylcellulose (HPMC).

[0048] In some embodiments, solid vapor diffusion, liquid vapor diffusion, slow evaporation, or slow cooling can be used to form Form C of the free base. When using solid vapor diffusion, the solvent can be selected from ACN and 1,4-dioxane. When using liquid vapor diffusion, the solvent can be NMP, and the anti-solvent can be IPA or MTBE. When using slow evaporation, the solvent can be ACN, IPAc, or 2-MeTHF. When using slow cooling, the solvent can be any of 2-MeTHF, MeOH, and IPAc.

[0049] In some embodiments, a slurry method or a polymer-induced crystallization method can be used to obtain Form D of the free base. When using a slurry method, the solvent can be selected from MeOH. When using a polymer-induced crystallization method, the solvent can be MeOH and the polymer can be polyvinylpyrrolidone (PVP) or polyvinyl alcohol (PVA).

[0050] Pharmaceutical Composition In another aspect, the present disclosure provides pharmaceutical compositions comprising a crystalline form of Compound 1 (e.g., free base Form A, free base Form B, free base Form C, and free base Form D) and a suitable carrier, excipient, or diluent. The exact nature of the carrier, excipient, or diluent will vary depending on the desired use of the composition and may be suitable or acceptable for a range of uses, from veterinary to human. The compositions may optionally include one or more additional compounds. In certain embodiments, the compositions may include one or more antibiotics. In another aspect, the present disclosure provides pharmaceutical compositions comprising free base Form A and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides pharmaceutical compositions comprising free base Form B and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides pharmaceutical compositions comprising free base Form C and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides pharmaceutical compositions comprising free base Form D and a pharmaceutically acceptable carrier.

[0051] When used to treat or prevent the above-described diseases, Compound 1 described herein can be administered alone, as a mixture of one or more compounds, or as a mixture or combination with other drugs useful for treating the above-described diseases and / or symptoms associated with the above-described diseases. The compound can also be administered in combination with or in admixture with drugs useful for treating other disorders or diseases, such as steroids, membrane stabilizers, 5LO inhibitors, leukotriene synthesis inhibitors and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, β-agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines. Compound 1 can be administered in the crystalline form described herein or as a pharmaceutical composition comprising the crystalline form described herein.

[0052] Pharmaceutical compositions containing various crystalline forms of Compound 1 can be prepared by conventional mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. The compositions may be formulated by conventional methods using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants to facilitate processing of the compound into pharmaceutically usable preparations.

[0053] Pharmaceutical compositions can be in a form suitable for virtually any mode of administration (e.g., topical, ophthalmic, oral, buccal, systemic, nasal, injectable, transdermal, rectal, vaginal, etc.) or for administration by inhalation or insufflation.

[0054] For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. Systemic formulations include formulations designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as formulations designed for transdermal, transmucosal oral, or pulmonary administration.

[0055] Useful injection preparations include sterile suspensions, solutions, or emulsions of the active compound in aqueous or oily vehicles. The compositions may also contain compounding agents such as suspending agents, stabilizing agents, and / or dispersing agents. The injection preparations may be in unit dosage forms, such as ampoules or multi-dose containers, and may contain additional preservatives. Alternatively, the injection preparations may be provided in powder form, for dissolving in a suitable vehicle (including, but not limited to, sterile pyrogen-free water, buffer, glucose solution, etc.) before use. For this purpose, the active compound can be dried using techniques known in the art, such as lyophilization, and then dissolved before use.

[0056] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0057] For oral administration, the pharmaceutical compositions may be in the form of lozenges, tablets, or capsules prepared by conventional techniques with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art, such as with sugars, films, or enteric coatings.

[0058] Liquid preparations for oral administration may be in the form of, for example, elixirs, solutions, syrups, or suspensions, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats and oils); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, Cremophor®, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners, as desired.

[0059] As is well known, the preparation for oral administration can be appropriately formulated to control the release of compound.For oral administration, composition can be in the form of tablets or lozenges that are formulated by conventional methods.For rectal and vaginal administration, compound can be formulated as a solution (for enemas) suppository or ointment that contains conventional suppository bases such as cocoa butter or other glycerides.

[0060] For nasal administration or administration by inhalation or insufflation, the compounds can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. Capsules and cartridges (e.g., capsules and cartridges made of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0061] When administered to the eye, the compounds may be formulated as solutions, emulsions, suspensions, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art.

[0062] For long-term delivery, the compound can be formulated as a depot preparation and administered by implantation or intramuscular injection.The compound(s) can be formulated with suitable polymer or hydrophobic material (for example, emulsion in acceptable oil) or ion exchange resin, or as a poorly soluble derivative (for example, as a poorly soluble salt).Alternatively, for transdermal absorption, a transdermal administration system can be used, which is manufactured as an adhesive disk or patch that releases the compound in a sustained release.For this reason, a penetration enhancer can be used to promote the percutaneous penetration of the compound.

[0063] Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver compounds. Organic solvents such as dimethyl sulfoxide (DMSO) can also be used, but are usually more toxic.

[0064] The pharmaceutical compositions may optionally be placed in a pack or dispenser device that can contain one or more unit dosage forms containing the compound. The pack can be, for example, a metal or plastic foil, such as a blister pack. The pack or dispenser may be accompanied by instructions for administration.

[0065] How to use The crystalline forms or compositions thereof described herein are generally used in an amount effective to achieve the intended result (e.g., an amount effective to treat or prevent the particular disease being treated). Therapeutic benefit refers to eradication or alleviation of the underlying disease being treated and / or eradication or alleviation of one or more symptoms associated with the underlying disease, such that the patient reports an improvement in mood or condition. Therapeutic benefit also generally includes halting or slowing the progression of the disease, regardless of whether improvement is achieved.

[0066] In yet another aspect, the present invention provides a method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired in vitro with an effective amount of a crystalline form of Compound 1, as described herein, or a pharmaceutical composition comprising an effective amount of a crystalline form of Compound 1, as described herein. In one embodiment, the cell is an MTAP-deficient cell.

[0067] The compositions and methods provided herein are believed to be particularly useful for inhibiting PRMT5 activity in cells in vivo. In one embodiment, cells in which inhibition of PRMT5 activity is desired are contacted in vivo with a therapeutically effective amount of a crystalline form of Compound 1 described herein or a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound 1 described herein. In one embodiment, the cells are MTAP-deficient cells. In one embodiment, negatively regulating PRMT5 activity occurs in the presence of bound MTA.

[0068] In particular, for cells lacking MTAP activity, negatively regulating PRMT5 activity can be used to inhibit PRMT5 activity and prevent cell proliferation. Cells can be contacted with a single or multiple doses according to a specific treatment regimen to negatively regulate the desired PRMT5 activity. The degree of PRMT5 inhibition can be monitored in vitro against the intracellular enzyme in the presence and absence of MTA using well-known methods, including the method described in Example B below, to evaluate the effectiveness of the treatment and dosage.

[0069] In another aspect, there is provided a method of treating cancer, comprising administering to a patient suffering from cancer a therapeutically effective amount of a crystalline form of Compound 1 described herein or a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound 1 described herein. In one embodiment, the cancer is an MTAP-associated cancer.

[0070] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors (e.g., prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc.). More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds can be used to treat the following: cardiac system: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; pulmonary system: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolopulmonary) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; digestive system Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, lipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth muscle tumors); genitourinary system: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma tumor, hepatic hemangioma; biliary tract: gallbladder cancer, duodenal papilla, bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), benign chondroma, chondroblastoma, chondrodysplastic fibroma, osteoid osteoma, and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary [ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma], vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma) tumor, melanoma), granulosa cell tumor, vagina [(clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)], fallopian tube (cancer); blood system: blood [myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome], Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL);

[0071] 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.

[0072] In other embodiments, the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma, and thyroid carcinoma.

[0073] In other embodiments, the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, and uterine cancer.

[0074] The concentration and route of administration to a patient will vary depending on the cancer being treated. The crystalline forms of Compound 1 described herein or pharmaceutical compositions comprising the crystalline forms of Compound 1 described herein may also be co-administered with other anti-neoplastic compounds (e.g., chemotherapy) or used as a pre- or post-surgical adjuvant in combination with other treatments, such as radiation or surgical intervention. [Example]

[0075] The following examples are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0076] Example 1: Formation of a crystalline form of Form A of the free base of Compound 1 Compound 1 can be prepared as a gum according to the procedures disclosed in International Publication No. WO2021050915. See Example 16-8.

[0077] Crystallization of compound 1 was achieved by slurrying the amorphous form and / or mixture of forms in 9:1 isopropanol:water (v / v) for 24 hours and isolating the resulting crystalline solid by filtration. The resulting crystals were a white solid powder. Characterization results are summarized in Table 1 and shown in Figures 1A and 1B. [Table 1]

[0078] Table 2 shows the XRD pattern of Form A of the free base of Compound 1 shown in Figure 1B. [Table 2]

[0079] Example 2: Formation of a crystalline form of Compound 1, Form B of the free base Approximately 30 mg of Form A of the free base from Example 1 was suspended in ethanol (0.2 mL) in a 4 mL vial to obtain a concentrated slurry. The slurry was stirred at 300-400 rpm at 50°C for 6 days. A drop of the concentrated slurry was taken for analysis. Characterization results are summarized in Table 3 and shown in Figures 2A and 2B. [Table 3]

[0080] Table 4 shows the XRD pattern of Form B of the free base of Compound 1 shown in Figure 2B. [Table 4] [Table 4-2]

[0081] Example 3: Formation of a crystalline form of Compound 1, Form C of the free base Approximately 30 mg of Form A of the free base from Example 1 was dissolved in methanol (1.3 mL) in a 4 mL vial at 55° C. to give a clear solution. The solution was cooled to 10° C. using the following temperature gradient: 55° C. for 3 hours, 40° C. for 4 hours, 25° C. for 4 hours, 15° C. for 5 hours, and 10° C. for 5 hours. After the cooling cycle, a white solid crystallized and was collected for analysis. Characterization results are summarized in Table 5 and shown in FIGS. 3A and 3B. [Table 5]

[0082] Table 6 shows the XRD pattern of Form C of the free base of Compound 1 shown in Figure 3B. [Table 6]

[0083] Example 4: Formation of a crystalline form of Compound 1, Form D of the free base Approximately 30 mg of Form A of the free base from Example 1 was suspended in methanol (0.2 mL) in a 4 mL vial to obtain a concentrated slurry. The slurry was stirred at 300-400 rpm at room temperature for 14 days. A drop of the concentrated slurry was taken for analysis. Characterization results are summarized in Table 7 and shown in Figures 4A and 4B. [Table 7]

[0084] Table 8 shows the XRD pattern of Form D of the free base of Compound 1 shown in Figure 4B. [Table 8]

[0085] Example 5: Testing the relative stability of hydrates A competitive slurry experiment was conducted in an isopropyl alcohol (IPA) / water system at room temperature to test the relative stability of free base Form A, Form B, and Form D. As shown in Table 9, after 1 day of stirring at room temperature, all forms exhibited a higher stability than pure IPA ( w = 0), it was converted to Form B. This result was verified by adding Form A to the experiment. w In systems with α > 0.37, only Form A was observed after stirring at room temperature for 1 day. Forms B and D were also included in the experiment to confirm the results. w At 0.13, Forms B and D also eventually converted to Form A, but the conversion rate was slightly slower than at higher water activities. [Table 9]

[0086] Example 6: Alternative Methods for Preparing Forms A, B, C, and D of the Free Base of Compound 1 Alternative methods for producing crystalline forms of Compound 1 were evaluated to obtain free base Form A, free base Form B, free base Form C, and free base Form D. Eight different methods were used: slurry at room temperature, slurry at 50°C, antisolvent addition, solid vapor diffusion, liquid vapor diffusion, slow evaporation at room temperature, slow cooling, and polymer-induced crystallization.

[0087] For room temperature slurry experiments, Form A of the free base of Compound 1 (discussed in Example 1) (approximately 30 mg) was suspended and stirred in various solvents (approximately 0.2 mL) in 4 mL vials at room temperature. After 14 days, the solids in the slurries were analyzed by XRPD. Table 10 shows the parameters and resulting crystalline forms for the room temperature slurry experiments. [Table 10]

[0088] For the 50° C. slurry experiments, Form A of the free base of Compound 1 (approximately 30 mg) discussed in Example 1 was suspended in various solvents (approximately 0.2 mL) in 4 mL vials and stirred at 50° C. After 6 days, the solids in the slurries were analyzed by XRPD. Table 11 shows the parameters of the 50° C. slurry experiments and the resulting crystalline forms. [Table 11]

[0089] In antisolvent addition experiments, Form A of the free base of Compound 1 (discussed in Example 1) (approximately 30 mg) was dissolved in various solvents to obtain saturated solutions, and up to 20 times the amount of antisolvent was added. The resulting solids were characterized by XRPD. Table 12 shows the parameters of the antisolvent addition experiments and the resulting crystalline forms. [Table 12]

[0090] For solid vapor diffusion experiments, Form A of the free base of Compound 1 (discussed in Example 1) (approximately 30 mg) was placed in a 4 mL vial and placed in a 20 mL glass vial containing various solvents. The solid was characterized by XRPD after 14 days. Table 13 shows the parameters of the solid vapor diffusion experiment and the resulting crystalline forms. [Table 13]

[0091] For the liquid vapor diffusion experiments, Form A of the free base of Compound 1 (discussed in Example 1) (approximately 30 mg) was dissolved in various solvents in a 4 mL vial to obtain a saturated solution. This was then placed in a 20 mL vial containing an antisolvent. The resulting solid was characterized by XRPD after 12 days. Table 14 shows the liquid vapor diffusion experiment parameters and the resulting crystalline forms. [Table 14]

[0092] For the slow evaporation experiments, evaporation was carried out at 50°C or room temperature. Approximately 30 mg of Form A of the free base of Compound 1 discussed in Example 1 was dissolved in various solvents in 4 mL vials to obtain saturated solutions. The vials were covered with paraffin film with 3-5 holes punctured and placed at room temperature or 50°C during evaporation. The resulting solids were characterized by XRPD. Table 15 shows the parameters of the slow evaporation experiments and the resulting crystalline forms. [Table 15]

[0093] In the slow-cooling experiments, Form A of the free base of Compound 1 (discussed in Example 1) (approximately 30 mg) was dissolved in various solvents at 55° C. using a hot plate to obtain saturated solutions in 4 mL vials. The solutions were slowly cooled to room temperature using the following temperature gradient: 55° C. for 3 hours, 40° C. for 4 hours, 25° C. for 4 hours, 15° C. for 5 hours, and 10° C. for 5 hours. The resulting solids were characterized by XRPD. Table 16 shows the parameters of the slow-cooling experiments and the resulting crystalline forms. [Table 16]

[0094] For the polymer-induced crystallization experiments, Form A of the free base of Compound 1 (discussed in Example 1) (approximately 30 mg) was dissolved in various solvents to create saturated solutions. Either polyvinylpyrrolidone (PVP), polyethylene glycol (PEO), polyvinyl alcohol (PVA), or hydroxypropylmethylcellulose (HPMC) was added to the saturated solution to induce heterogeneous nucleation. The resulting solids were characterized by XRPD after 12 days. Table 17 discloses the experimental parameters and the resulting crystalline morphologies for the polymer-induced crystallization method. [Table 17]

[0095] Example 7: Preclinical bioavailability The pharmacokinetics of different crystalline forms of Compound 1 were investigated after oral administration of Compound 1 free base Form A, HCl salt Form A, and HCl salt Form B to male beagle dogs at a dose of 100 mg / dog (approximately 10 mg / kg). After potency correction, the active ingredient was filled into empty HPMC capsules and administered with 40 mL of water to dogs pretreated with pentagastrin or famotidine. Pentagastrin stimulates gastric acid secretion, while famotidine neutralizes gastric acid. Therefore, pretreatment with pentagastrin and famotidine was performed to simulate the effect of gastric pH on bioavailability and reduce variability in gastric pH among dogs.

[0096] Plasma samples were collected at predetermined intervals and analyzed for Compound 1 concentration. max , T max , AUC 0-t and AUC 0-inf The plasma concentration versus time data were analyzed by non-compartmental methods using the Win Nonlin software program to estimate PK parameters such as: The results are shown in Figures 5A and 5B.

[0097] The results indicate that HCl salt Form A is less stable than HCl salt Form B, and that the HCl salt exhibits common ion effects in the gastric medium, which may have contributed to the high variability in pentagastrin-treated dogs. Furthermore, free base Form A exhibits exposures comparable to the HCl salt when normalized for particle size. Furthermore, significant differences in bioavailability were observed between pentagastrin-treated dogs and famotidine-treated dogs for both HCl salt forms tested, suggesting that both forms may be affected by food.

[0098] Example 8: Excipient Compatibility The compatibility of both Compound 1 free base Form A and HCl salt Form B with several excipients commonly used in oral solid dosage (OSD) formulation development was evaluated. Sample mixtures were prepared by mixing the active ingredient and excipients (filler: compound to excipient ratio 1:10, other excipients: 1:1) using a mortar and pestle, accurately weighing the resulting mixture, and transferring it to a sample vial. The excipients used were: colloidal silicon dioxide 200, croscarmellose sodium, crosprovidone XL-10, dibasic calcium phosphate (an), hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, mannitol 100SD, MCC PH102, Opadry® II, povidone K-30, pregelatinized starch 1500, sodium starch glycolate, and sodium stearyl fumarate. The sample vials were left unsealed at 40°C / 75% RH for 8 weeks and then analyzed for impurity levels using HPLC. The total impurity content results for these samples are shown in Figure 6 and are compared to Compound 1 free base Form A and HCl salt Form B without any excipients.

[0099] 6 shows that both Form A of the free base and Form B of the HCl salt of Compound 1 exhibit good compatibility with excipients. Furthermore, Form A of the free base was more sensitive to colloidal silicon dioxide and lactose monohydrate than Form B of the HCl salt. Although the risk of chemical stability is slightly higher for Form A of the free base and Form B of the HCl salt, this can be successfully addressed by considering the choice of excipients.

[0100] Example 9: Ease of Manufacturing and Physical Stability The compressibility (i.e., porosity vs. compression pressure), tabletability (i.e., tensile strength vs. compression pressure), and compatibility (i.e., tensile strength vs. porosity) of Form A of the free base of Compound 1 were measured. The results of these tests are shown in Figures 7A-7C. Form A of the free base exhibited good compressibility, tabletability, and compatibility. No apparent decrease in crystallinity was observed for the free base, even at high compression pressures (Figure 8).

[0101] Example 10: Intrinsic Dissolution Rate (IDR) and Capsule Drug Solubility in Fasted Simulated Gastric Fluid (FaSSGF) and Fasted Simulated Intestinal Fluid (FaSSIF) The intrinsic dissolution rate (IDR) was determined by measuring the amount of dissolved compound in buffer solution (Form A of the free base and Form B of the HCl salt) and then constructing a linear curve of dissolved compound versus time. The IDR rate was calculated by plotting the slope of the line as a function of the surface area of ​​the tablet (0.5 cm). 2 The dissolution rate was calculated by dividing the dissolution rate by the average dissolution rate (IRR) of the free base of Compound 1 by the average dissolution rate (IRR). Form A of the free base and Form B of the HCl salt of Compound 1 were each compressed into 0.8 cm diameter tablets at 14 MPa. Capsules of Form B of the HCl salt were stirred at 50 rpm at 37°C in pH 1.2 and pH 6.8 buffer solutions using a USP Type II dissolution apparatus with a sinker, while tablets of Form A of the free base were stirred under the same conditions in a pH 6.8 buffer solution. 0.6 mL of liquid was withdrawn at each time point using a syringe and filtered. The concentration of the filtrate was analyzed by HPLC. The IDR results are shown in Figure 9A, and the dissolution of the capsules is shown in Figure 9B.

[0102] The dissolution of HCl salt Form B was slow due to the common ion effect, while the free base Form A showed more rapid dissolution in the stomach. In the intestinal medium, HCl salt Form B dissolves slightly faster than free base Form A, but after 30 minutes, as the pH shifts from gastric to intestinal pH, it was determined that free base Form A is able to maintain a supersaturated state in the intestinal fluid.

[0103] List of Items of Implementation Embodiment 1. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 86°C ± 2%. Embodiment 2. The crystalline form of embodiment 1, wherein the endothermic DSC peak temperature is within 86°C ± 1%. Embodiment 3. The crystalline form of embodiment 1, wherein the endothermic DSC peak temperature is within 86°C ± 0.5%. Embodiment 4. The crystalline form of embodiment 1, wherein the crystalline form has an endothermic DSC peak temperature within 154°C ± 2%. Embodiment 5. The crystalline form of embodiment 4, having an endothermic DSC peak temperature within 154°C ± 1%. Embodiment 6. The crystalline form of embodiment 4, having an endothermic DSC peak temperature within 154°C ± 0.5%. Embodiment 7. The crystalline form of embodiment 1, wherein the crystalline form has an exothermic DSC peak temperature within 166°C ± 2%. Embodiment 8. The crystalline form of embodiment 7, wherein the exothermic DSC peak temperature is within 166°C ± 1%. Embodiment 9. The crystalline form of embodiment 7, wherein the exothermic DSC peak temperature is within 166°C ± 0.5%. Embodiment 10. The crystalline form of embodiment 1, wherein the crystalline form has an endothermic DSC peak temperature within 261°C ± 2%. Embodiment 11. The crystalline form of embodiment 10, having an endothermic DSC peak temperature within 261°C ± 1%. Embodiment 12. The crystalline form of embodiment 10, having an endothermic DSC peak temperature within 261°C ± 0.5%. Embodiment 13. The crystalline form of embodiment 1, wherein the crystalline form has an exothermic DSC peak temperature within 270°C ± 2%. Embodiment 14. The crystalline form of embodiment 13, wherein the exothermic DSC peak temperature is within 270°C ± 1%. Embodiment 15. The crystalline form of embodiment 13, wherein the exothermic DSC peak temperature is within 270°C ± 0.5%. Embodiment 16.3. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 1°±0.2°. Embodiment 17. The crystalline form of embodiment 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.2°±0.2°. Embodiment 18. The crystalline form of embodiment 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 10.2°±0.2°. Embodiment 19. The crystalline form of embodiment 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 14.3°±0.2°. Embodiment 20. The crystalline form of embodiment 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 3.1°±0.2°, 6.2°±0.2°, 10.2°±0.2°, and 14.3°±0.2°. Embodiment 21. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction pattern substantially as shown in FIG. 1B. Embodiment 22. The crystalline form of any one of embodiments 1 to 21, wherein the crystalline form is a hemihydrate. Embodiment 23. The crystalline form of any one of embodiments 1-22, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of about 4.4% when heated from about 25°C to about 150°C. Embodiment 24. The crystalline form of any one of embodiments 1-23, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 25. The crystalline form of any one of embodiments 1-24, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 26. A pharmaceutical composition comprising the crystalline form of any one of embodiments 1 to 25 and a pharmaceutically acceptable carrier. Embodiment 27. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 55°C ± 2%. Embodiment 28. The crystalline form of embodiment 27, having an endothermic DSC peak temperature within 55°C ± 1%. Embodiment 29. The crystalline form of embodiment 27, having an endothermic DSC peak temperature within 55°C ± 0.5%. Embodiment 30. The crystalline form of embodiment 27, wherein the crystalline form has an endothermic DSC peak temperature within 144°C ± 2%. Embodiment 31. The crystalline form of embodiment 30, having an endothermic DSC peak temperature within 144°C ± 1%. Embodiment 32. The crystalline form of embodiment 30, having an endothermic DSC peak temperature within 144°C ± 0.5%. Embodiment 33. The crystalline form of embodiment 27, wherein the crystalline form has an exothermic DSC peak temperature within 168°C ± 2%. Embodiment 34. The crystalline form of embodiment 33, wherein the exothermic DSC peak temperature is within 168°C ± 1%. Embodiment 35. The crystalline form of embodiment 33, having an exothermic DSC peak temperature within 168°C ± 0.5%. Embodiment 36. The crystalline form of embodiment 27, wherein the crystalline form has an endothermic DSC peak temperature within 260°C ± 2%. Embodiment 37. The crystalline form of embodiment 36, having an endothermic DSC peak temperature within 260°C ± 1%. Embodiment 38. The crystalline form of embodiment 36, having an endothermic DSC peak temperature within 260°C ± 0.5%. Embodiment 39. The crystalline form of embodiment 27, wherein the crystalline form has an exothermic DSC peak temperature within 268°C ± 2%. Embodiment 40. The crystalline form of embodiment 39, wherein the exothermic DSC peak temperature is within 268°C ± 1%. Embodiment 41. The crystalline form of embodiment 39, having an exothermic DSC peak temperature within 268°C ± 0.5%. Embodiment 42. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.4°±0.2°. Embodiment 43. The crystalline form of embodiment 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 12.2°±0.2°. Embodiment 44. The crystalline form of embodiment 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 12.8°±0.2°. Embodiment 45. The crystalline form of embodiment 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 24.5°±0.2°. Embodiment 46. The crystalline form of embodiment 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 25.0°±0.2°. Embodiment 47. The crystalline form of embodiment 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.4°±0.2°, 12.2°±0.2°, 12.8°±0.2°, 24.5°±0.2°, and 25.0°±0.2°. Embodiment 48. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction pattern substantially as shown in FIG. 2B. Embodiment 49. The crystalline form of any one of embodiments 27 to 48, wherein the crystalline form is a dihydrate. Embodiment 50. The crystalline form of any one of embodiments 27-49, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of about 6.5% when heated from about 25°C to about 150°C. Embodiment 51. The crystalline form of any one of embodiments 27-50, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 52. The crystalline form of any one of embodiments 27-51, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 53. A pharmaceutical composition comprising the crystalline form of any one of embodiments 27-52 and a pharmaceutically acceptable carrier. Embodiment 54. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 28°C ± 2%. Embodiment 55. The crystalline form of embodiment 54, having an endothermic DSC peak temperature within 28°C ± 1%. Embodiment 56. The crystalline form of embodiment 54, having an endothermic DSC peak temperature within 28°C ± 0.5%. Embodiment 57. The crystalline form of embodiment 54, wherein the crystalline form has an endothermic DSC peak temperature within 100°C ± 2%. Embodiment 58. The crystalline form of embodiment 57, having an endothermic DSC peak temperature within 100°C ± 1%. Embodiment 59. The crystalline form of embodiment 57, having an endothermic DSC peak temperature within 100°C ± 0.5%. Embodiment 60. The crystalline form of embodiment 54, wherein the crystalline form has an exothermic DSC peak temperature within 161°C ± 2%. Embodiment 61. The crystalline form of embodiment 60, having an exothermic DSC peak temperature within 161°C ± 1%. Embodiment 62. The crystalline form of embodiment 60, wherein the exothermic DSC peak temperature is within 161°C ± 0.5%. Embodiment 63. The crystalline form of embodiment 54, wherein the crystalline form has an endothermic DSC peak temperature within 269°C ± 2%. Embodiment 64. The crystalline form of embodiment 63, having an endothermic DSC peak temperature within 269°C ± 1%. Embodiment 65. The crystalline form of embodiment 63, having an endothermic DSC peak temperature within 269°C ± 0.5%. Embodiment 66. The crystalline form of embodiment 54, wherein the crystalline form has an exothermic DSC peak temperature within 276°C ± 2%. Embodiment 67. The crystalline form of embodiment 66, having an exothermic DSC peak temperature within 276°C ± 1%. Embodiment 68. The crystalline form of embodiment 66, having an exothermic DSC peak temperature within 276°C ± 0.5%. Embodiment 69. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 8.2°±0.2°. Embodiment 70 The crystalline form of embodiment 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 9.7°±0.2°. Embodiment 71. The crystalline form of embodiment 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 15.1°±0.2°. Embodiment 72. The crystalline form of embodiment 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 24.8°±0.2°. Embodiment 73. The crystalline form of embodiment 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 8.2°±0.2°, 9.7°±0.2°, 15.1°±0.2°, and 24.8°±0.2°. Embodiment 74. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction pattern substantially as shown in FIG. 3B. Embodiment 75. The crystalline form of any one of embodiments 54 to 74, wherein the crystalline form is a channel hydrate (e.g., a solvate, a racemate). Embodiment 76. The crystalline form of any one of embodiments 54-75, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of about 3.3% when heated from about 25°C to about 200°C. Embodiment 77. The crystalline form of any one of embodiments 54-76, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 78. The crystalline form of any one of embodiments 54 to 77, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 79. A pharmaceutical composition comprising the crystalline form of any one of embodiments 54 to 78 and a pharmaceutically acceptable carrier. Embodiment 8. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 0.59°C ± 2%. Embodiment 81. The crystalline form of embodiment 80, having an endothermic DSC peak temperature within 59°C ± 1%. Embodiment 82. The crystalline form of embodiment 80, having an endothermic DSC peak temperature within 59°C ± 0.5%. Embodiment 83. The crystalline form of embodiment 80, wherein the endothermic crystalline form has an endothermic DSC peak temperature within 140°C ± 2%. Embodiment 84. The crystalline form of embodiment 83, having an endothermic DSC peak temperature within 140°C ± 1%. Embodiment 85. The crystalline form of embodiment 83, having an endothermic DSC peak temperature within 140°C ± 0.5%. Embodiment 86. The crystalline form of embodiment 80, wherein the crystalline form has an exothermic DSC peak temperature within 161°C ± 2%. Embodiment 87. The crystalline form of embodiment 86, wherein the exothermic DSC peak temperature is within 161°C ± 1%. Embodiment 88. The crystalline form of embodiment 86, wherein the exothermic DSC peak temperature is within 161°C ± 0.5%. Embodiment 89. The crystalline form of embodiment 80, wherein the crystalline form has an endothermic DSC peak temperature within 258°C ± 2%. Embodiment 90. The crystalline form of embodiment 89, having an endothermic DSC peak temperature within 258°C ± 1%. Embodiment 91. The crystalline form of embodiment 89, having an endothermic DSC peak temperature within 258°C ± 0.5%. Embodiment 92. The crystalline form of embodiment 80, wherein the crystalline form has an exothermic DSC peak temperature within 267°C ± 2%. Embodiment 93. The crystalline form of embodiment 92, having an exothermic DSC peak temperature within 267°C ± 1%. Embodiment 94. The crystalline form of embodiment 92, wherein the exothermic DSC peak temperature is within 267°C ± 0.5%. Embodiment 95. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 5.4°±0.2°. Embodiment 96. The crystalline form of embodiment 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 9.9°±0.2°. Embodiment 97. The crystalline form of embodiment 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 13.7°±0.2°. Embodiment 98. The crystalline form of embodiment 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 27.1°±0.2°. Embodiment 99. The crystalline form of embodiment 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 5.4°±0.2°, 9.9°±0.2°, 13.7°±0.2°, and 27.1°±0.2°. Embodiment 100. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction pattern substantially as shown in FIG. 4B. Embodiment 101. The crystalline form of any one of embodiments 80 to 100, wherein the crystalline form is a hydrate. Embodiment 102. The crystalline form of any one of embodiments 80-101, wherein the crystalline form has a thermogravimetric analysis (TGA) plot showing a mass loss of about 6.9% when heated from about 25°C to about 150°C. Embodiment 103. The crystalline form of any one of embodiments 80-102, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 104. The crystalline form of any one of embodiments 80 to 103, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base. Embodiment 105. A pharmaceutical composition comprising the crystalline form of any one of embodiments 80-104 and a pharmaceutically acceptable carrier. Embodiment 106. A method for treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the crystalline form of any one of embodiments 1-25, 27-52, 54-78, or 80-104, or the crystalline form of any one of embodiments 26, 53, 79, or 105. Embodiment 107. The method of embodiment 106, wherein the cancer is an MTAP-associated cancer. Embodiment 108. The method of embodiment 106, wherein the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma, and thyroid carcinoma. Embodiment 109. The method of embodiment 106, wherein the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer and uterine cancer.

[0104] While the invention has been described in relation to particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is generally intended to cover such modifications, uses, or adaptations of the invention as fall within the scope of the appended claims, in accordance with the principles of the invention, including departures from the present disclosure as may be applicable to the essential features hereinabove described, which are within known or customary practice in the art to which this invention pertains.

Claims

1. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 86°C ± 2%.

2. 2. The crystalline form of claim 1, having an endothermic DSC peak temperature within 86°C ± 1%.

3. 2. The crystalline form of claim 1, having an endothermic DSC peak temperature within 86°C ± 0.5%.

4. 10. The crystalline form of claim 1, wherein the crystalline form exhibits an endothermic DSC peak temperature within 154°C ± 2%.

5. 5. The crystalline form of claim 4, having an endothermic DSC peak temperature within 154°C ± 1%.

6. 5. The crystalline form of claim 4, having an endothermic DSC peak temperature within 154°C ± 0.5%.

7. 10. The crystalline form of claim 1, wherein the crystalline form has an exothermic DSC peak temperature within 166°C ± 2%.

8. 8. The crystalline form of claim 7, having an exothermic DSC peak temperature within 166°C ± 1%.

9. 8. The crystalline form of claim 7, having an exothermic DSC peak temperature within 166°C ± 0.5%.

10. 10. The crystalline form of claim 1, wherein the crystalline form has an endothermic DSC peak temperature within 261°C ± 2%.

11. 11. The crystalline form of claim 10, having an endothermic DSC peak temperature within 261°C ± 1%.

12. 11. The crystalline form of claim 10, having an endothermic DSC peak temperature within 261°C ± 0.5%.

13. 10. The crystalline form of claim 1, wherein the crystalline form has an exothermic DSC peak temperature within 270°C ± 2%.

14. 14. The crystalline form of claim 13, having an exothermic DSC peak temperature within 270°C ± 1%.

15. 14. The crystalline form of claim 13, having an exothermic DSC peak temperature within 270°C ± 0.5%.

16. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction (XRPD) pattern containing peaks at 2θ angles of 3.1°±0.2°.

17. 17. The crystalline form of claim 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 6.2°±0.2°.

18. 17. The crystalline form of claim 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 10.2°±0.2°.

19. 17. The crystalline form of claim 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 14.3°±0.2°.

20. 17. The crystalline form of claim 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 3.1°±0.2°, 6.2°±0.2°, 10.2°±0.2°, and 14.3°±0.2°.

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

22. 22. The crystalline form of any one of claims 1 to 21, wherein the crystalline form is a hemihydrate.

23. 23. The crystalline form of any one of claims 1-22, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 4.4% when heated from about 25°C to about 150°C.

24. 24. The crystalline form of any one of claims 1 to 23, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

25. 25. The crystalline form of any one of claims 1 to 24, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

26. 26. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 25 and a pharmaceutically acceptable carrier.

27. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 55°C ± 2%.

28. 28. The crystalline form of claim 27, having an endothermic DSC peak temperature within 55°C ± 1%.

29. 28. The crystalline form of claim 27, having an endothermic DSC peak temperature within 55°C ± 0.5%.

30. 28. The crystalline form of claim 27, wherein the crystalline form has an endothermic DSC peak temperature within 144°C ± 2%.

31. 31. The crystalline form of claim 30, having an endothermic DSC peak temperature within 144°C ± 1%.

32. 31. The crystalline form of claim 30, having an endothermic DSC peak temperature within 144°C ± 0.5%.

33. 28. The crystalline form of claim 27, wherein the crystalline form has an exothermic DSC peak temperature within 168°C ± 2%.

34. 34. The crystalline form of claim 33, having an exothermic DSC peak temperature within 168°C ± 1%.

35. 34. The crystalline form of claim 33, having an exothermic DSC peak temperature within 168°C ± 0.5%.

36. 28. The crystalline form of claim 27, wherein the crystalline form has an endothermic DSC peak temperature within 260°C ± 2%.

37. 37. The crystalline form of claim 36, having an endothermic DSC peak temperature within 260°C ± 1%.

38. 37. The crystalline form of claim 36, wherein the endothermic DSC peak temperature is within 260°C ± 0.5%.

39. 28. The crystalline form of claim 27, wherein the crystalline form has an exothermic DSC peak temperature within 268°C ± 2%.

40. 40. The crystalline form of claim 39, wherein the exothermic DSC peak temperature is within 268°C ± 1%.

41. 40. The crystalline form of claim 39, wherein the exothermic DSC peak temperature is within 268°C ± 0.5%.

42. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base, having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ angle of 6.4°±0.2°.

43. 43. The crystalline form of claim 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 12.2°±0.2°.

44. 43. The crystalline form of claim 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 12.8°±0.2°.

45. 43. The crystalline form of claim 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 24.5°±0.2°.

46. 43. The crystalline form of claim 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 25.0°±0.2°.

47. 43. The crystalline form of claim 42, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 6.4°±0.2°, 12.2°±0.2°, 12.8°±0.2°, 24.5°±0.2°, and 25.0°±0.2°.

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

49. 49. The crystalline form of any one of claims 27 to 48, wherein the crystalline form is a dihydrate.

50. 50. The crystalline form of any one of claims 27-49, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 6.5% when heated from about 25°C to about 150°C.

51. 51. The crystalline form of any one of claims 27-50, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

52. 52. The crystalline form of any one of claims 27-51, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

53. 53. A pharmaceutical composition comprising the crystalline form of any one of claims 27 to 52 and a pharmaceutically acceptable carrier.

54. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 28°C ± 2%.

55. 55. The crystalline form of claim 54, wherein the endothermic DSC peak temperature is within 28°C ± 1%.

56. 55. The crystalline form of claim 54, wherein the endothermic DSC peak temperature is within 28°C ± 0.5%.

57. 55. The crystalline form of claim 54, wherein the crystalline form has an endothermic DSC peak temperature within 100°C ± 2%.

58. 58. The crystalline form of claim 57, wherein the endothermic DSC peak temperature is within 100°C ± 1%.

59. 58. The crystalline form of claim 57, wherein the endothermic DSC peak temperature is within 100°C ± 0.5%.

60. 55. The crystalline form of claim 54, wherein the crystalline form has an exothermic DSC peak temperature within 161°C ± 2%.

61. 61. The crystalline form of claim 60, wherein the exothermic DSC peak temperature is within 161°C ± 1%.

62. 61. The crystalline form of claim 60, wherein the exothermic DSC peak temperature is within 161°C ± 0.5%.

63. 55. The crystalline form of claim 54, wherein the crystalline form has an endothermic DSC peak temperature within 269°C ± 2%.

64. 64. The crystalline form of claim 63, having an endothermic DSC peak temperature within 269°C ± 1%.

65. 64. The crystalline form of claim 63, having an endothermic DSC peak temperature within 269°C ± 0.5%.

66. 55. The crystalline form of claim 54, wherein the crystalline form has an exothermic DSC peak temperature within 276°C ± 2%.

67. 67. The crystalline form of claim 66, wherein the exothermic DSC peak temperature is within 276°C ± 1%.

68. 67. The crystalline form of claim 66, having an exothermic DSC peak temperature within 276°C ± 0.5%.

69. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ angle of 8.2°±0.2°.

70. 70. The crystalline form of claim 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 9.7°±0.2°.

71. 70. The crystalline form of claim 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 15.1°±0.2°.

72. 70. The crystalline form of claim 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 24.8°±0.2°.

73. 70. The crystalline form of claim 69, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 8.2°±0.2°, 9.7°±0.2°, 15.1°±0.2°, and 24.8°±0.2°.

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

75. 75. The crystalline form of any one of claims 54 to 74, wherein the crystalline form is a channel hydrate (e.g., a solvate, a racemate).

76. 76. The crystalline form of any one of claims 54-75, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 3.3% when heated from about 25°C to about 200°C.

77. 77. The crystalline form of any one of claims 54-76, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

78. 78. The crystalline form of any one of claims 54-77, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

79. 79. A pharmaceutical composition comprising the crystalline form of any one of claims 54 to 78 and a pharmaceutically acceptable carrier.

80. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having a differential scanning calorimetry (DSC) endothermic peak temperature within 59°C ± 2%.

81. 81. The crystalline form of claim 80, wherein the endothermic DSC peak temperature is within 59°C ± 1%.

82. 81. The crystalline form of claim 80, wherein the endothermic DSC peak temperature is within 59°C ± 0.5%.

83. 81. The crystalline form of claim 80, wherein the endothermic crystalline form has an endothermic DSC peak temperature within 140°C ± 2%.

84. 84. The crystalline form of claim 83, wherein the endothermic DSC peak temperature is within 140°C ± 1%.

85. 84. The crystalline form of claim 83, having an endothermic DSC peak temperature within 140°C ± 0.5%.

86. 81. The crystalline form of claim 80, wherein the crystalline form has an exothermic DSC peak temperature within 161°C ± 2%.

87. 87. The crystalline form of claim 86, wherein the exothermic DSC peak temperature is within 161°C ± 1%.

88. 87. The crystalline form of claim 86, wherein the exothermic DSC peak temperature is within 161°C ± 0.5%.

89. 81. The crystalline form of claim 80, wherein the crystalline form has an endothermic DSC peak temperature within 258°C ± 2%.

90. 90. The crystalline form of claim 89, having an endothermic DSC peak temperature within 258°C ± 1%.

91. 90. The crystalline form of claim 89, having an endothermic DSC peak temperature within 258°C ± 0.5%.

92. 81. The crystalline form of claim 80, wherein the crystalline form has an exothermic DSC peak temperature within 267°C ± 2%.

93. 93. The crystalline form of claim 92, having an exothermic DSC peak temperature within 267°C ± 1%.

94. 93. The crystalline form of claim 92, having an exothermic DSC peak temperature within 267°C ± 0.5%.

95. A crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ angle of 5.4°±0.2°.

96. 96. The crystalline form of claim 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 9.9°±0.2°.

97. 96. The crystalline form of claim 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 13.7°±0.2°.

98. 96. The crystalline form of claim 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a 2θ angle of 27.1°±0.2°.

99. 96. The crystalline form of claim 95, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ angles of 5.4°±0.2°, 9.9°±0.2°, 13.7°±0.2°, and 27.1°±0.2°.

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

101. 101. The crystalline form of any one of claims 80 to 100, wherein the crystalline form is a hydrate.

102. 102. The crystalline form of any one of claims 80-101, wherein the crystalline form has a thermogravimetric analysis (TGA) plot that exhibits a mass loss of about 6.9% when heated from about 25°C to about 150°C.

103. 103. The crystalline form of any one of claims 80-102, wherein the crystalline form has a purity of at least 97% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

104. 104. The crystalline form of any one of claims 80-103, wherein the crystalline form has a purity of at least 98% by weight of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile free base.

105. 105. A pharmaceutical composition comprising the crystalline form of any one of claims 80 to 104 and a pharmaceutically acceptable carrier.

106. 10. A method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the crystalline form of any one of claims 1-25, 27-52, 54-78 or 80-104, or the crystalline form of any one of claims 26, 53, 79 or 105.

107. The method of claim 106, wherein the cancer is an MTAP-associated cancer.

108. 107. The method of claim 106, wherein the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, renal adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma, and thyroid carcinoma.

109. 107. The method of claim 106, wherein the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer and uterine cancer.

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