PARG inhibitors

Abstract

Provided herein are crystalline forms of a PARG inhibitor having the structural formula of Compound 1. Also provided herein are pharmaceutical compositions and methods of treatment using the crystalline forms of Compound 1 described herein. (Compound 1)

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 584,035, filed September 20, 2023, and U.S. Provisional Application No. 63 / 605,189, filed December 1, 2023, pursuant to 35 s.119(e) of the United States Code, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] Declaration of rights to an invention made in connection with federally funded research and development. not applicable References to the "Sequence List", a table of sequences, or an appendix listing computer programs submitted on CD. not applicable Background Technology

[0003] Cancer is caused by uncontrolled and unregulated cell proliferation. This often rapid proliferation results in high levels of oxidative stress within the tumor, which can damage DNA and lead to a significantly increased mutation rate. Consequently, tumor cells initiate and become highly dependent on DNA damage repair mechanisms.

[0004] Single-strand breaks (SSBs) are the most common type of lesion occurring in cells. PARG (poly-ADP-riboglycoside hydrolase) and PARP (poly-ADP-ribose polymerase), along with many other proteins, are involved in single-strand break repair (SSBR) and another repair mechanism called base excision repair (BER).

[0005] One of the earliest events occurring during single-stranded DNA repair is the binding of PARP (poly-ADP-ribose polymerase) to the break and the rapid synthesis of poly-ADP-ribose (PAR) on PARP itself. This molecular structure acts as a signal to recruit other DNA repair proteins, initially XRCC1, which subsequently repairs the break (Mortusewicz, Fouquerel et al., 2011). The signals initiated by these PAR chains are short-lived because they are rapidly degraded by the enzyme PARG. When PARP binds to PAR, its catalytic activity decreases, and therefore the activity of PARG helps to restore PARP to its catalytically active form (Curtin and Szabo, 2013).

[0006] PARG originates from a single gene, and its isoforms are located in the nucleus, mitochondria, and cytoplasm. Another known protein with glycoside hydrolase activity is ARH3, which is located in the mitochondria (Mashimo, Kato et al., 2014). Although PARG is primarily known for its direct role in DNA repair, it also affects PAR signaling in splicing, transcription, and epigenetic pathways (Ji and Tulin 2009) (Le May, Iltis et al., 2012) (Dahl, Maturi et al., 2014) (Guastafierro, Catizone et al., 2013) (Caiafa, Guastafierro et al., 2009).

[0007] When other mechanisms of DNA repair fail, cancer cells may become dependent on specific DNA repair pathways. Tumors carrying mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors of the SSBR. There is some evidence that PARG depletion inhibits the SSBR and reduces the survival rate of BRCA2-deficient cells (Fathers, Drayton et al., 2012). However, other tumor mutations can also lead to defects in double-strand DNA repair mechanisms (i.e., so-called "BRCA-ness"), making tumor cells sensitive to PARG inhibition.

[0008] PARG depletion studies have been conducted in various mouse and human model systems. Mouse cells lacking or depleted of PARG have shown increased sensitivity to experimental and clinical DNA-damaging agents. However, since PARG deficiency does not result in sensitivity to all agents (e.g., gemcitabine, camptothecin), this suggests that PARG function is specific to certain DNA damage repair pathways, as well as chemotherapy and radiotherapy (Fujihara, Ogino et al., 2009); (Shirai, Fujimori et al., 2013); (Zhou, Feng et al., 2010); (Zhou, Feng et al., 2011).

[0009] In humans, PARG depletion sensitizes lung, cervical, and pancreatic cancer cells to gamma radiation or experimental DNA-damaging agents such as hydrogen peroxide and methyl methanesulfonate (Ame, Fouquerel et al., 2009) (Nakadate, Kodera et al., 2013) (Shirai, Poetsch et al., 2013).

[0010] Currently, multiple clinical trials are underway for PARP inhibitors to explore the concepts of synthetic lethality or chemosensitization. Clinical resistance to PARP inhibitors has been described (Drost and Jonkers 2014) (Barber, Sandhu et al., 2013), thus necessitating the search for alternative inhibitors targeting DNA damage repair mechanisms.

[0011] Although existing models suggest that PARG depletion leads to a PARP-dependent effect on DNA repair, recent studies have shown a mechanistic difference between it and PARP inhibition. In contrast to PARP depletion, PARG depletion following genotoxic stimulation leads to a decrease in NAD levels. This results in lung cancer cell death due to energy exhaustion (Erdelyi, Bai et al., 2009).

[0012] These results demonstrate that PARG inhibitors and their polycrystalline forms could provide useful therapies for cancer. This disclosure addresses these needs and also offers related advantages. Summary of the Invention

[0013] This disclosure provides the salt and free base crystalline forms of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 1) represented by the following formula: (Compound 1).

[0014] In some aspects, this document provides an HCl salt of compound 1. In some embodiments, this document provides a crystalline form of compound 1, which is HCl salt crystal form I. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0015] In some aspects, this document provides a free base of compound 1. In some embodiments, this document provides a crystalline form of compound 1, which is free base crystal form I. In some embodiments, this document provides a crystalline form of compound 1, which is free base crystal form II. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0016] In some aspects, this document provides a sulfate of compound 1. In some embodiments, this document provides a crystalline form of compound 1, which is sulfate crystal form I. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0017] In some aspects, this document provides toluenesulfonate salts of compound 1. In some embodiments, this document provides crystalline forms of compound 1, specifically toluenesulfonate crystal form I. In some embodiments, this document provides crystalline forms of compound 1, specifically toluenesulfonate crystal form II. In some embodiments, this document provides crystalline forms of compound 1, specifically toluenesulfonate crystal form III. In some embodiments, the crystalline form is a monocrystalline form, substantially free of other crystalline or amorphous forms.

[0018] In some aspects, this document provides benzenesulfonate salts of compound 1. In some embodiments, this document provides a crystalline form of compound 1, which is benzenesulfonate crystal form I. In some embodiments, this document provides a crystalline form of compound 1, which is benzenesulfonate crystal form II. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0019] In some aspects, this document provides a methanesulfonate salt of compound 1. In some embodiments, this document provides a crystalline form of compound 1, which is methanesulfonate crystal form I. In some embodiments, this document provides a crystalline form of compound 1, which is methanesulfonate crystal form II. In some embodiments, this document provides a crystalline form of compound 1, which is methanesulfonate crystal form III. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0020] In some aspects, this document provides maleate salts of compound 1. In some embodiments, this document provides crystalline form of compound 1, which is maleate crystal form I. In some embodiments, this document provides crystalline form of compound 1, which is maleate crystal form II. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0021] In some aspects, this document provides citrate salts of compound 1. In some embodiments, this document provides crystalline form of compound 1, which is citrate crystal form I. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0022] In some aspects, this document provides fumarate salts of compound 1. In some embodiments, this document provides crystalline forms of compound 1, specifically fumarate crystal form I. In some embodiments, this document provides crystalline forms of compound 1, specifically fumarate crystal form II. In some embodiments, this document provides crystalline forms of compound 1, specifically fumarate crystal form III. In some embodiments, the crystalline form is a monocrystalline form, substantially free of other crystalline or amorphous forms.

[0023] In some aspects, this document provides malate salts of compound 1. In some embodiments, this document provides crystalline forms of compound 1, specifically malate crystal form I. In some embodiments, this document provides crystalline forms of compound 1, specifically malate crystal form II. In some embodiments, the crystalline form is a monocrystalline form, substantially free of other crystalline or amorphous forms.

[0024] In some aspects, this document provides a succinate of compound 1. In some embodiments, this document provides a crystalline form of compound 1, which is succinate crystal form I. In some embodiments, the crystalline form is a monocrystalline form that is substantially free of other crystalline or amorphous forms.

[0025] Each of the crystal forms provided can be further characterized as described herein.

[0026] In a further aspect, this document provides various solid forms of compound 1 comprising at least 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, or 99 wt% of the specific crystalline form as described herein.

[0027] In a further aspect, this document provides pharmaceutical compositions of compound 1 in crystalline form.

[0028] In a further aspect, this document provides pharmaceutical compositions comprising, or prepared using, the crystalline form of compound 1 described herein. Pharmaceutical compositions comprising, or prepared using, the solid form as described herein are also provided. The pharmaceutical compositions may comprise one or more pharmaceutically acceptable excipients.

[0029] In an additional aspect, this document provides a method for inhibiting PARG in a patient, comprising administering to the patient an effective amount of the crystalline form of compound 1 described herein. In an additional aspect, this document provides a method for inhibiting PARG in a patient, comprising administering to the patient an effective amount of the solid form of compound 1 described herein.

[0030] In an additional aspect, this document provides a method for inhibiting PARG in a patient, comprising administering to the patient an effective amount of the pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of compound 1 described herein, ii) is prepared using the crystalline form of compound 1 described herein, iii) comprises a solid form as described herein, or iv) is prepared using the solid form described herein.

[0031] In an additional aspect, this document provides methods for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of the crystalline form of compound 1 described herein. In an additional aspect, this document provides methods for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of the solid form of compound 1 described herein.

[0032] In an additional aspect, this document provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of compound 1 described herein, ii) is prepared using the crystalline form of compound 1 described herein, iii) comprises a solid form as described herein, or iv) is prepared using the solid form described herein.

[0033] In an additional aspect, this document provides a method for treating cancers resistant to one or more platinum-based drugs or one or more PARP inhibitors in patients in need, comprising administering to the patient an effective amount of the crystalline form of compound 1 described herein. In an additional aspect, this document provides a method for treating cancers resistant to one or more platinum-based drugs or one or more PARP inhibitors in patients in need, comprising administering to the patient an effective amount of the solid form of compound 1 described herein.

[0034] In an additional aspect, this document provides a method for treating cancers resistant to one or more platinum-based drugs or one or more PARP inhibitors in patients in need, comprising administering to the patient an effective amount of the pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises the crystalline form of compound 1 described herein, ii) is prepared using the crystalline form of compound 1 described herein, iii) comprises the solid form as described herein, or iv) is prepared using the solid form described herein.

[0035] In an additional aspect, this document provides methods for treating and / or preventing homologous recombination defect (HRD) cancer in a patient, comprising administering to the patient an effective amount of the crystalline form of compound 1 described herein. In an additional aspect, this document provides methods for treating and / or preventing homologous recombination defect (HRD) cancer in a patient, comprising administering to the patient an effective amount of the solid form of compound 1 described herein.

[0036] In an additional aspect, this document provides a method for treating and / or preventing homologous recombination defect (HRD) cancer in a patient, comprising administering to the patient an effective amount of the pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of compound 1 described herein, ii) is prepared using the crystalline form of compound 1 described herein, iii) comprises a solid form as described herein, or iv) is prepared using the solid form described herein.

[0037] In an additional aspect, this document provides methods for treating and / or preventing cancer in patients, wherein the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, deletion or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins, the method comprising administering to the patient an effective amount of the crystalline form of compound 1 described herein. In an additional aspect, this document provides methods for treating and / or preventing cancer in patients, wherein the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, deletion or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins, the method comprising administering to the patient an effective amount of the solid form of compound 1 described herein.

[0038] In an additional aspect, this document provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, deletion or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins, the method comprising administering to the patient an effective amount of the pharmaceutical composition described herein, wherein the pharmaceutical composition i) comprises a crystalline form of compound 1 described herein, ii) is prepared using the crystalline form of compound 1 described herein, iii) comprises a solid form as described herein, or iv) is prepared using the solid form described herein.

[0039] In an additional aspect, the crystalline forms and pharmaceutical compositions thereof provided herein may be used to treat cancer.

[0040] In an additional aspect, this document provides the use of the crystalline forms and pharmaceutical compositions thereof provided herein for the preparation of medicaments for the treatment of cancer. Attached Figure Description

[0041] Figure 1 The X-ray powder diffraction (XRPD) pattern of the free alkali crystal form I of compound 1 is shown.

[0042] Figure 2 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of free alkali crystal form I of compound 1 are shown.

[0043] Figure 3 A representative polarized light microscopy (PLM) image of the free alkali crystal form I of compound 1 is shown.

[0044] Figure 4 The X-ray powder diffraction (XRPD) pattern of free alkali crystal form II of compound 1 is shown.

[0045] Figure 5 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of free alkali crystal form II of compound 1 are shown.

[0046] Figure 6 A representative polarized light microscopy (PLM) image of free alkali crystal form II of compound 1 is shown.

[0047] Figure 7 The X-ray powder diffraction (XRPD) pattern of the HCl salt crystal form I of compound 1 is shown.

[0048] Figure 8 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of HCl salt crystal form I of compound 1 are shown.

[0049] Figure 9 The dynamic vapor adsorption (DVS) plot of HCl salt crystal form I of compound 1 is shown.

[0050] Figure 10 A representative polarized light microscopy (PLM) image of the HCl salt crystal form I of compound 1 is shown.

[0051] Figure 11 The X-ray powder diffraction (XRPD) pattern of sulfate crystal form I of compound 1 is shown.

[0052] Figure 12 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of sulfate crystal form I of compound 1 are shown.

[0053] Figure 13 A representative polarized light microscopy (PLM) image of sulfate crystal form I of compound 1 is shown.

[0054] Figure 14 The X-ray powder diffraction (XRPD) pattern of toluenesulfonate form I of compound 1 is shown.

[0055] Figure 15 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of toluenesulfonate form I of compound 1 are shown.

[0056] Figure 16 A representative polarized light microscopy (PLM) image of toluenesulfonate form I of compound 1 is shown.

[0057] Figure 17 The X-ray powder diffraction (XRPD) pattern of toluenesulfonate form II of compound 1 is shown.

[0058] Figure 18Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of toluenesulfonate form II of compound 1 are shown.

[0059] Figure 19 A representative polarized light microscopy (PLM) image of toluenesulfonate form II of compound 1 is shown.

[0060] Figure 20 The X-ray powder diffraction (XRPD) pattern of toluenesulfonate form III of compound 1 is shown.

[0061] Figure 21 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of toluenesulfonate form III of compound 1 are shown.

[0062] Figure 22 The dynamic vapor adsorption (DVS) plot of toluenesulfonate form III of compound 1 is shown.

[0063] Figure 23 A representative polarized light microscopy (PLM) image of toluenesulfonate form III of compound 1 is shown.

[0064] Figure 24 The X-ray powder diffraction (XRPD) pattern of benzenesulfonate form I of compound 1 is shown.

[0065] Figure 25 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of benzenesulfonate form I of compound 1 are shown.

[0066] Figure 26 A representative polarized light microscopy (PLM) image of benzenesulfonate form I of compound 1 is shown.

[0067] Figure 27 The X-ray powder diffraction (XRPD) pattern of benzenesulfonate form II of compound 1 is shown.

[0068] Figure 28 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of benzenesulfonate form II of compound 1 are shown.

[0069] Figure 29 A representative polarized light microscopy (PLM) image of benzenesulfonate form II of compound 1 is shown.

[0070] Figure 30 The X-ray powder diffraction (XRPD) pattern of the methanesulfonate crystal form I of compound 1 is shown.

[0071] Figure 31Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of the methanesulfonate crystal form I of compound 1 are shown.

[0072] Figure 32 The dynamic vapor adsorption (DVS) plot of methanesulfonate form I of compound 1 is shown.

[0073] Figure 33 A representative polarized light microscopy (PLM) image of the methanesulfonate crystal form I of compound 1 is shown.

[0074] Figure 34 The X-ray powder diffraction (XRPD) pattern of the methanesulfonate form II of compound 1 is shown.

[0075] Figure 35 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of the methanesulfonate form II of compound 1 are shown.

[0076] Figure 36 A representative polarized light microscopy (PLM) image of the methanesulfonate form II of compound 1 is shown.

[0077] Figure 37 The X-ray powder diffraction (XRPD) pattern of the methanesulfonate crystal form III of compound 1 is shown.

[0078] Figure 38 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of methanesulfonate form III of compound 1 are shown.

[0079] Figure 39 A representative polarized light microscopy (PLM) image of the methanesulfonate crystal form III of compound 1 is shown.

[0080] Figure 40 The X-ray powder diffraction (XRPD) pattern of maleate crystal form I of compound 1 is shown.

[0081] Figure 41 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of maleate crystal form I of compound 1 are shown.

[0082] Figure 42 A representative polarized light microscopy (PLM) image of maleate crystal form I of compound 1 is shown.

[0083] Figure 43 The X-ray powder diffraction (XRPD) pattern of maleate crystal form II of compound 1 is shown.

[0084] Figure 44Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of maleate form II of compound 1 are shown.

[0085] Figure 45 A representative polarized light microscopy (PLM) image of maleate crystal form II of compound 1 is shown.

[0086] Figure 46 The X-ray powder diffraction (XRPD) pattern of citrate form I of compound 1 is shown.

[0087] Figure 47 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of citrate form I of compound 1 are shown.

[0088] Figure 48 A representative polarized light microscopy (PLM) image of citrate form I of compound 1 is shown.

[0089] Figure 49 The X-ray powder diffraction (XRPD) pattern of fumarate crystal form I of compound 1 is shown.

[0090] Figure 50 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of fumarate form I of compound 1 are shown.

[0091] Figure 51 A representative polarized light microscopy (PLM) image of fumarate crystal form I of compound 1 is shown.

[0092] Figure 52 The X-ray powder diffraction (XRPD) pattern of fumarate form II of compound 1 is shown.

[0093] Figure 53 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of fumarate form II of compound 1 are shown.

[0094] Figure 54 A representative polarized light microscopy (PLM) image of fumarate crystal form II of compound 1 is shown.

[0095] Figure 55 The X-ray powder diffraction (XRPD) pattern of fumarate form III of compound 1 is shown.

[0096] Figure 56 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of fumarate form III of compound 1 are shown.

[0097] Figure 57A representative polarized light microscopy (PLM) image of fumarate crystal form III of compound 1 is shown.

[0098] Figure 58 The X-ray powder diffraction (XRPD) pattern of the malate crystal form I of compound 1 is shown.

[0099] Figure 59 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of malate form I of compound 1 are shown.

[0100] Figure 60 A representative polarized light microscopy (PLM) image of the malate crystal form I of compound 1 is shown.

[0101] Figure 61 The X-ray powder diffraction (XRPD) pattern of the malate crystal form II of compound 1 is shown.

[0102] Figure 62 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of malate form II of compound 1 are shown.

[0103] Figure 63 The dynamic vapor adsorption (DVS) plot of malate form II of compound 1 is shown.

[0104] Figure 64 A representative polarized light microscopy (PLM) image of the malate crystal form II of compound 1 is shown.

[0105] Figure 65 The X-ray powder diffraction (XRPD) pattern of succinate crystal form I of compound 1 is shown.

[0106] Figure 66 Differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) of succinate form I of compound 1 are shown.

[0107] Figure 67 A representative polarized light microscopy (PLM) image of succinate crystal form I of compound 1 is shown. Detailed Implementation

[0108] I. Overview This disclosure provides crystalline forms of Compound 1. These crystalline forms are characterized by X-ray powder diffraction (XRPD) patterns. Selected crystalline forms are also characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption analysis (DVS), and / or polarized light microscopy (PLM) patterns. This disclosure also provides pharmaceutical compositions of the crystalline forms of Compound 1 described herein. In some embodiments, this disclosure provides pharmaceutical compositions of the herein i) comprising the crystalline form of Compound 1 described herein, ii) prepared using the crystalline form of Compound 1 described herein, iii) comprising the solid form as described herein, or iv) prepared using the solid form described herein.

[0109] This disclosure also provides a method for inhibiting PARG in a patient, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of compound 1 described herein. This disclosure also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of the crystalline form of compound 1 described herein. This disclosure also provides a method for treating cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of compound 1 described herein. This disclosure also provides a method for treating cancer resistant to one or more platinum-based drugs or one or more PARP inhibitors in a patient in need, the method comprising administering to the patient an effective amount of the crystalline form of compound 1 described herein. This disclosure also provides a method for treating and / or preventing homologous recombination defect (HRD) cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of compound 1 described herein. This disclosure also provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent expression of BRCA1 and / or BRCA2 genes, absence or mutation of BRCA1 and / or BRCA2 genes, or reduced function of BRCA1 and / or BRCA2 proteins, the method comprising administering to an individual a therapeutically effective amount of the crystalline form of compound 1 described herein.

[0110] This disclosure also provides a method for inhibiting PARG in a patient, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition described herein. This disclosure also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of the pharmaceutical composition described herein. This disclosure also provides a method for treating cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition described herein. This disclosure also provides a method for treating cancer resistant to one or more platinum-based drugs or one or more PARP inhibitors in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition described herein. This disclosure also provides a method for treating and / or preventing homologous recombination defect (HRD) cancer in a patient, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition described herein. This disclosure also provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, deletion or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition described herein.

[0111] II. Definition "Very little or no" means that 10% or less of another form is present in a particular desired form, preferably 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or less of another form.

[0112] "Crude product" refers to a mixture containing the desired compound (e.g., compound of formula (I)) and at least one other type (e.g., solvent, reagent (such as acid or base), starting material, or byproduct of the reaction that produces the desired compound).

[0113] "Solvate" refers to a compound or its salt described herein that is bound to a stoichiometric or non-stoichiometric amount of solvent by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0114] "Hydrate" refers to a compound that forms a complex with stoichiometric or non-stoichiometric amounts of water. The compounds of this invention can form complexes with ½ or 1 to 10 water molecules. For example, the compounds of this invention can form complexes with ½ water molecules, with 1 water molecule, or with 2 water molecules.

[0115] "Crystal form" refers to the solid form of a compound in which the constituent molecules are packed in a regular, ordered, and repeating pattern. Crystal forms can include triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal, and cubic crystal geometries. A crystalline form may contain one or more regions with well-defined crystal boundaries (i.e., grains). A crystalline solid may contain two or more crystal geometries.

[0116] "Amorphous form" refers to the solid form of a compound that does not have a definite crystal structure, that is, it lacks the regular, ordered and repeating pattern that constitutes the molecules.

[0117] “FeSSIF” stands for Fed-State Simulated Intestinal Fluid. “FaSSIF” stands for Fasted-State Simulated Intestinal Fluid. “SGF” stands for Simulated Gastric Fluid.

[0118] "Approximately" refers to a series of values ​​that would be reasonably approximated by a person skilled in the art as a specified value. In some embodiments, the term "approximately" refers to within the standard deviation using measurement methods generally accepted in the art. In some embodiments, "approximately" refers to a range extending to + / - 10% of the specified value.

[0119] As used herein, "pharmaceutically acceptable salt" refers to salts containing active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (whether soda ash or a base dissolved in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrobamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.). When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (whether pure acid or acid dissolved in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as those derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids (e.g., arginine salts) and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., “Pharmaceutical Salts,” *Journal of Pharmaceutical Science*). Journal of Pharmaceutical Science (1977, Vol. 66, pp. 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows these compounds to be converted into basic addition salts or acid addition salts.

[0120] "Compound 1" is a chemical compound with the IUPAC name 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide, and has the structure shown below: (Compound 1).

[0121] "The free base of compound 1" or "compound 1 in the form of a free base" refers to compound 1 represented by the following formula: (Compound 1).

[0122] The term “treating” or “treatment” encompasses both disease-modifying treatment and symptomatic treatment, either of which can be preventative (i.e., performed before the onset of symptoms to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., performed after the onset of symptoms to reduce the severity and / or duration of symptoms).

[0123] The terms "individual," "patient," "individual in need," or "patient in need" refer to mammals, including primates (especially humans), domestic companion animals (such as dogs, cats, horses, etc.), and livestock (such as cattle, pigs, sheep, etc.), for which the dosage is as described herein. In some embodiments, the terms "individual," "patient," or "individual in need," or "patient in need," refer to humans. In some embodiments, humans are adults.

[0124] An "effective amount" or "therapeutic effective amount" is an amount sufficient to achieve a predetermined purpose (e.g., to achieve the effect for which it is applied, to treat a disease, to reduce enzyme activity, to alleviate one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to help treat a disease or alleviate one or more symptoms of a disease; this amount may also be referred to as a "therapeutic effective amount." "Alleviating" one or more symptoms (and its grammatical equivalent) means reducing the severity or frequency of one or more symptoms, or eliminating one or more symptoms.

[0125] III. Detailed Description of the Implementation Method This document provides various crystalline forms of compound 1, including free base crystalline and salt crystalline forms, pharmaceutical compositions comprising the compound, methods of use thereof, and methods for preparing the salt crystalline form. Some crystalline forms may be hydrates, solvates, or amorphous forms of compound 1. Some crystalline forms may be hydrates, solvates, or amorphous forms of compound 1 in the free base form. Some crystalline forms may be hydrates, solvates, or amorphous forms of compound 1 in the salt crystalline form.

[0126] Methods for collecting XRPD data are well known in the art, and any such method can be used to characterize the crystal forms described herein. For example, the X-ray powder diffraction patterns described herein can be generated using Cu Kα1 radiation.

[0127] In some embodiments, the crystalline form described herein is also characterized by differential scanning calorimetry (DSC) thermography. In some embodiments, DSC thermography is recorded using a sample weight of approximately 1–3 mg, and the sample is subjected to temperatures ranging from 25 °C to 300 °C using a heating rate of 10 °C / min.

[0128] In some embodiments, the crystalline form described herein is also characterized by thermogravimetric analysis (TGA). In some embodiments, TGA thermograms are recorded using a sample weight of approximately 1–5 mg, and the sample is subjected to temperatures ranging from room temperature to 300 °C using a heating rate of 10 °C / min.

[0129] In some embodiments, the crystal form described herein is also characterized by polarization microscopy (PLM) curves.

[0130] In some embodiments, the crystalline form described herein is also characterized by dynamic vapor adsorption (DVS) curves. In some embodiments, the DVS is recorded according to the methods described herein.

[0131] A. Free base crystal form of compound 1 In some embodiments, the crystalline form is the free base crystal form of compound 1. In some embodiments, the crystalline form is free base crystal form I. In some embodiments, the crystalline form is free base crystal form II.

[0132] i. Free alkali crystal form I In one embodiment, this disclosure provides a free basal form I of compound 1. In some embodiments, free basal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0 and 18.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free basal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 16.4, and 18.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free basal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 16.4, 18.0, and 18.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free basal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 16.4, 18.0, 18.3, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free alkali form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 12.7, 16.4, 18.0, 18.3, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free alkali form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 12.7, 16.4, 18.0, 18.3, 18.9, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free alkali form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free alkali form I is characterized in that its X-ray powder diffraction (XRPD) pattern includes peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form I is characterized by X-ray powder diffraction (XRPD) pattern containing peaks at 9.0, 11.5, 12.7, 13.7, 16.4, 17.2, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0133] In some embodiments, free alkali crystal form I is characterized in that the XRPD spectrum contains three peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free alkali crystal form I is characterized in that the XRPD spectrum contains three or more peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, free alkali crystal form I is characterized in that the XRPD spectrum contains four peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form I is characterized in that the XRPD spectrum contains five peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0134] In some embodiments, the free alkali crystal form I is characterized in that the XRPD pattern further includes one or more peaks (e.g., one, two, or three peaks) selected from 23.2, 23.5, and 24.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes a peak located at 24.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or two peaks selected from 23.5 and 24.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form I is characterized in that the XRPD pattern further includes one or more peaks selected from 22.5, 23.2, 23.5, 24.6, and 27.8 degrees 2θ (± 0.2 degrees 2θ). For example, in some embodiments, free alkali crystal form I is characterized by XRPD spectra containing peaks at 9.0, 16.4, 18.3, 23.5, and 24.6 degrees 2θ (± 0.2 degrees 2θ).

[0135] In some embodiments, free alkali crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 1. In some embodiments, free alkali crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 1. In some embodiments, free alkali crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 1. In some embodiments, free alkali crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 1. In some embodiments, free alkali crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 1.

[0136] In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 1. In some embodiments, free alkali form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 1.

[0137] In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 1. In some embodiments, the free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with relative intensities of at least 20% as listed in Table 1.

[0138] In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 1. In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 1.

[0139] In some embodiments, free alkali form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 18.3, and 24.6 degrees 2θ (± 0.2 degrees 2θ).

[0140] In some embodiments, the free alkali crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 16.4, 18.3, 23.5, and 24.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 12.7, 13.7, 18.0, 18.9, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, 23.5, and 24.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, 19.7, 23.5, and 24.6 degrees 2θ (± 0.2 degrees 2θ).

[0141] In some embodiments, free alkali crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 1 Consistent.

[0142] In some embodiments, free alkali crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 200°C. In some embodiments, free alkali crystal form I is further characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic onset temperature of approximately 199°C and an endothermic peak at approximately 200°C.

[0143] In some embodiments, the free alkali crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 2 Consistent.

[0144] In some embodiments, free alkali crystal form I is further characterized by no weight loss before decomposition upon heating, as measured by thermogravimetric analysis (TGA). In some embodiments, free alkali crystal form I is further characterized by substantially no weight loss before decomposition upon heating, as measured by thermogravimetric analysis (TGA). In some embodiments, free alkali crystal form I is further characterized by a weight loss of no more than 5%, 4%, 3%, 2%, or 1% by weight before decomposition upon heating, as measured by thermogravimetric analysis (TGA).

[0145] In some embodiments, the free alkali crystal form I is further characterized by its thermogravimetric analysis (TGA) chromatogram being essentially the same as... Figure 2 Consistent.

[0146] In some embodiments, the free alkali crystal form I is further characterized by a polarization microscopy (PLM) curve that is essentially as follows: Figure 3 As shown.

[0147] In some embodiments, the free alkali crystal form I is essentially free of other crystals or amorphous forms.

[0148] ii. Free alkali crystal form II In one embodiment, this disclosure provides a free basal form II of compound 1. In some embodiments, the free basal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3 and 18.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free basal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, and 18.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free basal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, 17.1, and 18.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, 17.1, 18.7, and 19.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, 17.1, 18.7, 19.5, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, 16.4, 17.1, 18.7, 19.5, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 13.4, 15.6, 16.4, 17.1, 18.7, 19.5, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 13.4, 14.1, 15.6, 16.1, 16.4, 17.1, 18.7, 19.5, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 13.4, 14.1, 15.6, 16.1, 16.4, 17.1, 18.7, 19.5, 19.7, and 20.0 degrees 2θ (± 0.2 degrees 2θ).In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 13.4, 14.1, 15.6, 16.1, 16.4, 17.1, 17.4, 18.7, 19.5, 19.7 and 20.0 degrees 2θ (± 0.2 degrees 2θ).

[0149] In some embodiments, the free alkali crystal form II is characterized in that the XRPD spectrum contains three peaks selected from 12.3, 15.6, 17.1, 18.7, 19.5, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized in that the XRPD spectrum contains four peaks selected from 12.3, 15.6, 17.1, 18.7, 19.5, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized in that the XRPD spectrum contains five peaks selected from 12.3, 15.6, 17.1, 18.7, 19.5, and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0150] In some embodiments, the free alkali crystal form II is characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 20.7, 23.0, 25.0, 25.7, 26.5, and 31.4 degrees 2θ (± 0.2 degrees 2θ) (e.g., one, two, three, four, five, six, or seven peaks). In some embodiments, the free alkali crystal form II is characterized in that the XRPD spectrum further includes a peak located at 20.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized in that the XRPD spectrum further includes one or two peaks selected from 20.2 and 20.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 20.7, and 25.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystalline form II is characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 20.7, 23.0, and 25.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystalline form II is characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 20.7, 23.0, 25.7, and 26.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystalline form II is characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 20.7, 23.0, 25.0, 25.7, and 26.5 degrees 2θ (± 0.2 degrees 2θ). For example, in some embodiments, the free alkali crystalline form II is characterized in that the XRPD spectrum includes peaks located at 12.3, 15.6, 17.1, 18.7, and 20.7 degrees 2θ (± 0.2 degrees 2θ). For example, in some embodiments, the free alkali crystal form II is characterized by XRPD spectra containing peaks at 12.3, 15.6, 17.1, 18.7, 19.5, 19.7, 20.2, 20.7, 23.0, and 25.7 degrees 2θ (± 0.2 degrees 2θ).

[0151] In some embodiments, free alkali form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 2. In some embodiments, free alkali form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 2. In some embodiments, free alkali form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 2. In some embodiments, free alkali form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 2. In some embodiments, free alkali form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 2.

[0152] In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 15% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 15% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 15% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least five peaks with a relative intensity of at least 15% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least six peaks with a relative intensity of at least 15% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least seven peaks with a relative intensity of at least 15% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least eight peaks with a relative intensity of at least 15% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least ten peaks with a relative intensity of at least 15% as listed in Table 2.

[0153] In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least five peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least six peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least seven peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least eight peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least nine peaks with a relative intensity of at least 20% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least ten peaks with a relative intensity of at least 20% as listed in Table 2.

[0154] In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 30% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 30% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 30% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least five peaks with a relative intensity of at least 30% as listed in Table 2. In some embodiments, the free alkali crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least six peaks with a relative intensity of at least 30% as listed in Table 2.

[0155] In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, and 18.7 degrees 2θ (± 0.2 degrees 2θ).

[0156] In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, 17.1, 18.7, and 20.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD patterns also contain peaks at 19.5, 19.7, 20.2, 23.0, and 25.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the free alkali crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.3, 15.6, 17.1, 18.7, 19.5, 19.7, 20.2, 20.7, 23.0, and 25.7 degrees 2θ (± 0.2 degrees 2θ).

[0157] In some embodiments, free alkali crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 4 Consistent.

[0158] In some embodiments, the free alkali crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at about 148°C and / or a second endothermic peak at about 198°C. In some embodiments, the free alkali crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation peak at about 143°C and 148°C, and / or a second endothermic initiation peak at about 197°C and 198°C, respectively. In some embodiments, the free alkali crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation peak at about 143°C and about 148°C, and / or a second endothermic initiation peak at about 197°C and about 198°C, respectively.

[0159] In some embodiments, the free alkali crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 5 Consistent.

[0160] In some embodiments, the free alkali crystalline form II is characterized by a 15.1% weight loss upon heating to 158°C, as measured by thermogravimetric analysis (TGA).

[0161] In some embodiments, the free alkali crystal form II is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 5 Consistent.

[0162] In some embodiments, the free alkali crystal form II is characterized by a polarization light microscopy (PLM) curve that is substantially as follows: Figure 6 As shown.

[0163] In some embodiments, the free alkali crystal form II is essentially free of other crystalline or amorphous forms.

[0164] B. Salt crystal form of compound 1 This disclosure provides various salt crystal forms of Compound 1, including HCl salts, sulfates, toluenesulfonates, benzenesulfonates, methanesulfonates, maleates, citrates, fumarates, malates, and succinates. In some embodiments, the salt is a single crystalline form substantially free of other crystalline or amorphous forms.

[0165] The specific salts disclosed herein may exist in one or more polycrystalline forms. Each polycrystalline form of the salt is designated as crystal form I, crystal form II, and crystal form III.

[0166] i. HCl salt of compound 1 (crystal form I) In some embodiments, the crystalline form is an HCl salt of compound 1. In some embodiments, the crystalline form is HCl salt crystal form I. In some embodiments, HCl salt crystal form I is anhydrous.

[0167] In some embodiments, HCl salt crystal form I is characterized by XRPD spectra containing peaks at 13.2 and 13.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by XRPD spectra containing peaks at 13.2 and 17.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by XRPD spectra containing peaks at 13.2, 13.7, and 17.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by XRPD spectra containing peaks at 11.7, 13.2, 13.7, and 17.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by XRPD spectra containing peaks at 11.7, 13.2, 13.7, 17.7, and 18.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by its XRPD spectrum containing peaks at 11.7, 13.2, 13.7, 17.2, and 17.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by its XRPD spectrum containing peaks at 11.7, 13.2, 13.7, 17.2, 17.7, and 18.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by its XRPD spectrum containing peaks at 11.7, 13.2, 13.7, 17.2, 17.7, 18.4, and 20.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized in that its XRPD spectrum includes peaks located at 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 20.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized in that its XRPD spectrum includes peaks located at 7.0, 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 20.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized in that its XRPD spectrum includes peaks located at 7.0, 8.0, 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 20.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the HCl salt crystal form I is characterized by XRPD spectra containing peaks at 7.0, 11.7, 12.2, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 20.0 degrees 2θ (± 0.2 degrees 2θ).In some embodiments, HCl salt crystal form I is characterized in that the XRPD spectrum contains peaks located at 7.0, 8.0, 11.7, 12.2, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 20.0 degrees 2θ (± 0.2 degrees 2θ).

[0168] In some embodiments, HCl salt crystal form I is characterized in that the XRPD spectrum contains three peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 19.9. In some embodiments, HCl salt crystal form I is characterized in that the XRPD spectrum contains three or more peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 19.9. In some embodiments, HCl salt crystal form I is characterized in that the XRPD spectrum contains four peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 19.9. In some embodiments, the HCl salt crystal form I is characterized in that the XRPD spectrum contains five peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 19.9.

[0169] In some embodiments of HCl salt crystal form I, the X-ray powder diffraction pattern further includes one or more peaks selected from 20.6, 20.9, 21.2, 21.7, 22.3, 24.3, 25.0, 25.3, 25.6, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ) (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or eleven peaks). In some embodiments, the X-ray powder diffraction pattern further includes a peak located at 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or two peaks selected from 26.1 and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or more peaks selected from 24.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or more peaks selected from 20.9, 24.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or more peaks selected from 20.9, 24.3, 25.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or more peaks selected from 20.6, 20.9, 21.2, 24.3, 25.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or more peaks selected from 20.6, 20.9, 21.2, 24.3, 25.0, 25.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or more peaks selected from 20.6, 20.9, 21.2, 21.7, 24.3, 25.0, 25.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further includes one or more peaks selected from 20.6, 20.9, 21.2, 21.7, 24.3, 25.0, 25.3, 25.6, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). For example, in some embodiments, the HCl salt crystal form I is characterized by XRPD spectra containing peaks at 13.2, 13.7, 17.7, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ).For example, in some embodiments, the HCl salt crystal form I is characterized by XRPD spectra containing peaks at 13.2, 13.7, 17.7, 20.6, 20.9, 21.2, 24.3, 25.3, 26.1 and 28.9 degrees 2θ (±0.2 degrees 2θ).

[0170] In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 3.

[0171] In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 3.

[0172] In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least five peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least six peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 3.

[0173] In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 30% as listed in Table 3. In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 30% as listed in Table 3.

[0174] In some embodiments, HCl salt crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 13.7, 17.7, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 13.7, 17.7, 24.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 13.7, 17.7, 24.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 13.7, 17.7, 20.6, 20.9, 21.2, 24.3, 25.0, 25.3, 26.1, and 28.9 degrees 2θ (±0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 11.7, 13.7, 17.2, 17.7, 18.4, 20.6, 20.9, 21.2, 21.7, 24.3, 25.0, 25.3, 25.6, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0175] In some embodiments, HCl salt crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 13.2, 13.7, 17.7, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 20.6, 20.9, 21.2, 24.3, and 25.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, HCl salt crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 13.2, 13.7, 17.7, 20.6, 20.9, 21.2, 24.3, 25.3, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0176] In some embodiments, HCl salt crystal form I is characterized by an X-ray powder diffraction pattern that is substantially the same as... Figure 7 Consistent.

[0177] In some embodiments, HCl salt crystal form I is characterized in that, prior to decomposition, the differential scanning calorimetry (DSC) thermogram does not contain endothermic peaks.

[0178] In some embodiments, HCl salt crystal form I is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially the same as... Figure 8 Consistent.

[0179] In some embodiments, HCl salt crystal form I is characterized by no weight loss before decomposition upon heating, as measured by thermogravimetric analysis (TGA). In some embodiments, HCl salt crystal form I is characterized by no substantial weight loss before decomposition upon heating, as measured by thermogravimetric analysis (TGA). In some embodiments, HCl salt crystal form I is characterized by a weight loss of no more than 5%, 4%, 3%, 2%, 1%, or 0.5% by weight before decomposition upon heating, as measured by thermogravimetric analysis (TGA).

[0180] In some embodiments, HCl salt crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 8 Consistent.

[0181] In some embodiments, HCl salt crystal form I is characterized by a weight increase of about 0.5% after undergoing a dynamic vapor adsorption curve cycle from about 0% relative humidity (RH) to about 90% RH at 25°C.

[0182] In some embodiments, HCl salt crystal form I is characterized by a dynamic vapor adsorption (DVS) curve that is substantially as follows: Figure 9 As shown.

[0183] In some embodiments, HCl salt crystal form I is characterized by a polarization light microscopy (PLM) curve that is substantially as follows: Figure 10 As shown.

[0184] In some implementations, HCl salt crystal form I is essentially free of other crystalline or amorphous forms.

[0185] ii. The sulfate of compound 1 (crystal form I) In some embodiments, the crystalline form is the sulfate of compound 1. In some embodiments, the crystalline form is sulfate crystal form I. In some embodiments, sulfate crystal form I is a hydrate.

[0186] In one embodiment, this disclosure provides sulfate crystal form I of compound 1. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.0, 8.5, 13.2, 15.6, and 16.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, sulfate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 8.8, 12.9, 15.0, 17.2, and 19.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, sulfate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 20.2, 22.1, 24.3, 25.1, and 26.7 degrees 2θ (± 0.2 degrees 2θ).

[0187] In some embodiments, sulfate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 8.0, 8.5, 13.2, 15.6, and 16.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 8.8, 12.9, 15.0, 19.0, and 24.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, sulfate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 8.0, 8.5, 8.8, 12.9, 13.2, 15.0, 15.6, 16.1, 19.0, and 24.3 degrees 2θ (± 0.2 degrees 2θ).

[0188] In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, seven, ten, or more peaks listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing three peaks listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing five peaks listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing seven peaks listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing ten peaks listed in Table 4.

[0189] In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 4.

[0190] In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 4.

[0191] In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least seven peaks having a relative intensity of at least 30% as listed in Table 4. In some embodiments, sulfate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least eight peaks having a relative intensity of at least 30% as listed in Table 4.

[0192] In some embodiments, sulfate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 11 Consistent.

[0193] In some embodiments, sulfate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at 118°C, a second endothermic peak at 220°C, an exothermic peak at 231°C, and / or a third endothermic peak at 279°C. In some embodiments, sulfate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at approximately 118°C, a second endothermic peak at approximately 220°C, an exothermic peak at approximately 231°C, and / or a third endothermic peak at approximately 279°C. In some embodiments, sulfate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation and peak at 78°C and 118°C, a second endothermic initiation and peak at 206°C and 220°C, an exothermic initiation and peak at 227°C and 231°C, and / or a third endothermic initiation and peak at 273°C and 279°C, respectively. In some embodiments, sulfate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation and peak at about 78°C and about 118°C, a second endothermic initiation and peak at about 206°C and about 220°C, an exothermic initiation and peak at about 227°C and about 231°C, and / or a third endothermic initiation and peak at about 273°C and about 279°C.

[0194] In some embodiments, sulfate crystal form I is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially the same as... Figure 12 Consistent.

[0195] In some embodiments, sulfate crystal form I is characterized by a weight loss of 2.8% upon heating to 130°C, as measured by thermogravimetric analysis (TGA). In some embodiments, sulfate crystal form I is characterized by a weight loss of approximately 2.8% upon heating to approximately 130°C, as measured by thermogravimetric analysis (TGA). In some embodiments, sulfate crystal form I is characterized by a weight loss of no more than approximately 10%, 5%, 4%, or 3% by weight upon heating to approximately 130°C, as measured by thermogravimetric analysis (TGA).

[0196] In some embodiments, sulfate crystal form I is characterized by thermogravimetric analysis.

[0197] In some embodiments, sulfate crystal form I is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 13 As shown.

[0198] In some embodiments, sulfate crystal form I is essentially free of other crystalline or amorphous forms.

[0199] iii. Toluenesulfonate of compound 1 (crystal form I) In some aspects, the crystalline form is the toluenesulfonate of compound 1. In some embodiments, the crystalline form is toluenesulfonate crystal form I. In some embodiments, toluenesulfonate crystal form I is anhydrous.

[0200] In one embodiment, this disclosure provides a toluenesulfonate crystal form I of compound 1. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.8, 9.6, 14.5, 18.2, and 19.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, toluenesulfonate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 4.7, 11.7, 13.7, 15.5, and 15.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, toluenesulfonate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 21.4, 22.8, 24.0, 24.3, and 29.3 degrees 2θ (± 0.2 degrees 2θ).

[0201] In some embodiments, toluenesulfonate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 9.6, 14.5, 18.2, 19.5, and 24.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 6.8, 21.4, 22.8, 24.0, and 29.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, toluenesulfonate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.8, 9.6, 14.5, 18.2, 19.5, 21.4, 22.8, 24.0, 24.3, and 29.3 degrees 2θ (± 0.2 degrees 2θ).

[0202] In some embodiments, toluenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 5.

[0203] In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 5.

[0204] In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least seven peaks having a relative intensity of at least 20% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least eight peaks having a relative intensity of at least 20% as listed in Table 5.

[0205] In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 5. In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 5.

[0206] In some embodiments, toluenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 14 Consistent.

[0207] In some embodiments, toluenesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at about 231°C. In some embodiments, toluenesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of about 222°C and an endothermic peak at about 231°C.

[0208] In some embodiments, toluenesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 15 Consistent.

[0209] In some embodiments, toluenesulfonate crystal form I is characterized by a 1.2% weight loss, as measured by thermogravimetric analysis (TGA), when heated from 110°C to 230°C. In some embodiments, toluenesulfonate crystal form I is characterized by a weight loss of about 1.2% when heated from about 110°C to about 230°C, as measured by thermogravimetric analysis (TGA). In some embodiments, toluenesulfonate crystal form I is characterized by a weight loss of no more than about 10%, 5%, 4%, 3%, or 2% by weight, as measured by thermogravimetric analysis (TGA), when heated from about 110°C to about 230°C.

[0210] In some embodiments, toluenesulfonate crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 15 Consistent.

[0211] In some embodiments, toluenesulfonate crystal form I is characterized by a polarization microscopy (PLM) curve that is substantially as follows: Figure 16 As shown.

[0212] In some embodiments, toluenesulfonate crystal form I is essentially free of other crystalline or amorphous forms.

[0213] iv. Toluenesulfonate of compound 1 (crystal form II) In some embodiments, the crystalline form is the toluenesulfonate of compound 1. In some embodiments, the crystalline form is toluenesulfonate crystal form II. In some embodiments, toluenesulfonate crystal form II is anhydrous.

[0214] In one embodiment, this disclosure provides a toluenesulfonate crystal form II of compound 1. In some embodiments, the toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.7, 14.3, 15.4, 17.3, and 19.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the toluenesulfonate crystal form II is characterized by an XRPD pattern further containing one or more peaks selected from 9.1, 10.2, 13.0, 17.0, and 18.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the toluenesulfonate crystal form II is characterized by an XRPD pattern further containing one or more peaks selected from 20.1, 20.5, 23.8, 24.2, and 26.2 degrees 2θ (± 0.2 degrees 2θ).

[0215] In some embodiments, toluenesulfonate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.7, 15.4, 17.3, 20.1, and 24.2 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 14.3, 17.0, 19.1, 20.5, and 26.2 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, toluenesulfonate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.7, 14.3, 15.4, 17.0, 17.3, 19.1, 20.1, 20.5, 24.2, and 26.2 degrees 2θ (± 0.2 degrees 2θ).

[0216] In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 6.

[0217] In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 6.

[0218] In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least five peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least six peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 6.

[0219] In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 6. In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks having a relative intensity of at least 30% as listed in Table 6.

[0220] In some embodiments, toluenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 17 Consistent.

[0221] In some embodiments, toluenesulfonate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at about 229°C. In some embodiments, toluenesulfonate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of about 223°C and an endothermic peak at about 229°C.

[0222] In some embodiments, toluenesulfonate crystal form II is characterized in that its differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 18 Consistent.

[0223] In some embodiments, toluenesulfonate crystal form II is characterized by a 1.4% weight loss upon heating from 90°C to 230°C, as measured by thermogravimetric analysis (TGA). In some embodiments, toluenesulfonate crystal form II is characterized by a weight loss of approximately 1.4% upon heating from about 90°C to about 230°C, as measured by thermogravimetric analysis (TGA). In some embodiments, toluenesulfonate crystal form II is characterized by a weight loss of no more than about 10%, 5%, 4%, 3%, or 2% by weight upon heating from about 90°C to about 230°C, as measured by thermogravimetric analysis (TGA).

[0224] In some embodiments, toluenesulfonate crystal form II is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 18 Consistent.

[0225] In some embodiments, toluenesulfonate crystal form II is characterized by a polarization microscopy (PLM) curve that is substantially as shown in the figure. Figure 19 As shown.

[0226] In some embodiments, toluenesulfonate crystal form II is essentially free of other crystalline or amorphous forms.

[0227] v. Toluenesulfonate of compound 1 (crystal form III) In some aspects, the crystalline form is the toluenesulfonate of compound 1. In some embodiments, the crystalline form is toluenesulfonate crystal form III. In some embodiments, toluenesulfonate crystal form III is anhydrous.

[0228] In one embodiment, this disclosure provides a toluenesulfonate crystal form III of compound 1. In some embodiments, the toluenesulfonate crystal form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.9, 14.5, 15.5, 18.2, and 19.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the toluenesulfonate crystal form III is characterized by its XRPD pattern further containing one or more peaks selected from 9.7, 14.1, 14.9, 16.0, and 16.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the toluenesulfonate crystal form III is characterized by its XRPD pattern further containing one or more peaks selected from 21.2, 21.4, 22.0, 24.0, and 24.4 degrees 2θ (± 0.2 degrees 2θ).

[0229] In some embodiments, toluenesulfonate crystal form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 18.2, 19.5, 21.2, 22.0, and 24.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD patterns also contain peaks at 6.9, 14.5, 15.5, 21.4, and 24.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, toluenesulfonate crystal form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.9, 14.5, 15.5, 18.2, 19.5, 21.2, 21.4, 22.0, 24.0, and 24.4 degrees 2θ (± 0.2 degrees 2θ).

[0230] In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, seven, ten, or more peaks listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing three peaks listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing five peaks listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing seven peaks listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing ten peaks listed in Table 7.

[0231] In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 7.

[0232] In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 7.

[0233] In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 7. In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with relative intensities of at least 30% as listed in Table 7.

[0234] In some embodiments, toluenesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 20 Consistent.

[0235] In some embodiments, toluenesulfonate crystal form III is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at about 222°C. In some embodiments, toluenesulfonate crystal form III is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of about 206°C and an endothermic peak at about 222°C.

[0236] In some embodiments, toluenesulfonate crystal form III is characterized in that its differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 21 Consistent.

[0237] In some embodiments, toluenesulfonate crystal form III is characterized by a weight loss of 2.6% when heated from about 110°C to about 222°C, as measured by thermogravimetric analysis (TGA). In some embodiments, toluenesulfonate crystal form III is characterized by a weight loss of no more than about 10%, 5%, 4%, or 3% by weight when heated from about 110°C to about 222°C, as measured by thermogravimetric analysis (TGA).

[0238] In some embodiments, toluenesulfonate crystal form III is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 21 Consistent.

[0239] In some embodiments, toluenesulfonate crystal form III is characterized by a weight increase of about 3.2% after undergoing a dynamic vapor adsorption curve cycle from about 0% relative humidity (RH) to about 90% RH at 25°C.

[0240] In some embodiments, toluenesulfonate crystal form III is characterized by a dynamic vapor adsorption (DVS) curve that is substantially as shown in the figure. Figure 22 As shown.

[0241] In some embodiments, toluenesulfonate crystal form III is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 23 As shown.

[0242] In some embodiments, toluenesulfonate crystal form III is essentially free of other crystalline or amorphous forms.

[0243] vi. Benzenesulfonate of compound 1 (crystal form I) In some aspects, the crystalline form is the benzenesulfonate of compound 1. In some embodiments, the crystalline form is benzenesulfonate crystal form I. In some embodiments, benzenesulfonate crystal form I is anhydrous.

[0244] In one embodiment, this disclosure provides a benzenesulfonate crystal form I of compound 1. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.8, 14.5, 15.4, 17.3, and 19.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, benzenesulfonate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 15.0, 15.9, 17.7, 18.3, and 19.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, benzenesulfonate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 20.3, 20.8, 24.0, 25.2, and 26.0 degrees 2θ (± 0.2 degrees 2θ).

[0245] In some embodiments, benzenesulfonate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.8, 17.3, 19.1, 24.0, and 25.2 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 14.5, 15.4, 17.7, 20.3, and 26.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, benzenesulfonate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.8, 14.5, 15.4, 17.3, 17.7, 19.1, 20.3, 24.0, 25.2, and 26.0 degrees 2θ (± 0.2 degrees 2θ).

[0246] In some embodiments, benzenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 8.

[0247] In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 8.

[0248] In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 8.

[0249] In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 30% as listed in Table 8. In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 30% as listed in Table 8.

[0250] In some embodiments, benzenesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 24 Consistent.

[0251] In some embodiments, benzenesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at about 202°C. In some embodiments, benzenesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of about 190°C and an endothermic peak at about 202°C.

[0252] In some embodiments, benzenesulfonate crystal form I is characterized in that its differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 25 Consistent.

[0253] In some embodiments, benzenesulfonate crystal form I is characterized by a weight loss of 0.6% when heated from 100°C to 210°C, as measured by thermogravimetric analysis (TGA). In some embodiments, benzenesulfonate crystal form I is characterized by a weight loss of about 0.6% when heated from about 100°C to about 210°C, as measured by thermogravimetric analysis (TGA). In some embodiments, benzenesulfonate crystal form I is characterized by a weight loss of no more than about 10%, 5%, 4%, 3%, 2%, or 1% by weight when heated from about 100°C to about 210°C, as measured by thermogravimetric analysis (TGA).

[0254] In some embodiments, benzenesulfonate crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 25 Consistent.

[0255] In some embodiments, benzenesulfonate crystal form I is characterized by a polarization microscopy (PLM) curve that is substantially as follows: Figure 26 As shown.

[0256] In some embodiments, benzenesulfonate crystal form I is essentially free of other crystalline or amorphous forms.

[0257] vii. Benzenesulfonate of compound 1 (crystal form II) In some embodiments, the crystalline form is the benzenesulfonate of compound 1. In some embodiments, the crystalline form is benzenesulfonate crystal form II. In some embodiments, benzenesulfonate crystal form II is anhydrous.

[0258] In one embodiment, this disclosure provides a benzenesulfonate crystal form II of compound 1. In some embodiments, the benzenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 7.6, 15.2, 15.7, 19.2, and 19.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the benzenesulfonate crystal form II is characterized by an XRPD pattern further containing one or more peaks selected from 9.0, 10.0, 12.4, 14.7, and 18.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the benzenesulfonate crystal form II is characterized by an XRPD pattern further containing one or more peaks selected from 10.4, 20.1, 22.9, 25.0, and 26.5 degrees 2θ (± 0.2 degrees 2θ).

[0259] In some embodiments, benzenesulfonate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 7.6, 15.2, 19.2, 22.9, and 26.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 15.7, 18.1, 19.7, 20.1, and 25.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, benzenesulfonate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 7.6, 15.2, 15.7, 18.1, 19.2, 19.7, 20.1, 22.9, 25.0, and 26.5 degrees 2θ (± 0.2 degrees 2θ).

[0260] In some embodiments, benzenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 9. In some embodiments, benzenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 9. In some embodiments, benzenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 9. In some embodiments, benzenesulfonate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 9.

[0261] In some embodiments, benzenesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 27 Consistent.

[0262] In some embodiments, benzenesulfonate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 165°C. In some embodiments, benzenesulfonate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 154°C and an endothermic peak at approximately 165°C.

[0263] In some embodiments, benzenesulfonate crystal form II is characterized in that its differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 28 Consistent.

[0264] In some embodiments, benzenesulfonate crystal form II is characterized by a weight loss of 0.5% when heated from 64°C to 185°C, as measured by thermogravimetric analysis (TGA). In some embodiments, benzenesulfonate crystal form II is characterized by a weight loss of about 0.5% when heated from about 64°C to about 185°C, as measured by thermogravimetric analysis (TGA). In some embodiments, benzenesulfonate crystal form II is characterized by a weight loss of no more than about 10%, 5%, 4%, 3%, 2%, or 1% by weight when heated from about 64°C to about 185°C, as measured by thermogravimetric analysis (TGA).

[0265] In some embodiments, benzenesulfonate crystal form II is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 28 Consistent.

[0266] In some embodiments, benzenesulfonate crystal form II is characterized by a polarization microscopy (PLM) curve that is substantially as shown in the figure. Figure 29 As shown.

[0267] In some embodiments, benzenesulfonate crystal form II is essentially free of other crystalline or amorphous forms.

[0268] viii. Methanesulfonate of compound 1 (crystal form I) In some embodiments, the crystalline form is the methanesulfonate of compound 1. In some embodiments, the crystalline form is methanesulfonate crystal form I. In some embodiments, methanesulfonate crystal form I is anhydrous.

[0269] In one embodiment, this disclosure provides a methanesulfonate crystal form I of compound 1. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 14.2, 17.0, 18.0, 18.6, and 19.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, methanesulfonate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 11.0, 11.9, 12.7, 15.1, and 17.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, methanesulfonate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 20.7, 21.2, 22.1, 24.1, and 25.0 degrees 2θ (± 0.2 degrees 2θ).

[0270] In some embodiments, methanesulfonate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 14.2, 17.0, 18.6, 22.1, and 24.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 18.0, 19.3, 21.2, 21.5, and 24.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, methanesulfonate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 14.2, 17.0, 18.0, 18.6, 19.3, 21.2, 21.5, 22.1, 24.1, and 24.9 degrees 2θ (± 0.2 degrees 2θ).

[0271] In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 10.

[0272] In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 10.

[0273] In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 20% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 20% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 20% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least five peaks with a relative intensity of at least 20% as listed in Table 10.

[0274] In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks having a relative intensity of at least 30% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks having a relative intensity of at least 30% as listed in Table 10. In some embodiments, methanesulfonate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks having a relative intensity of at least 30% as listed in Table 10.

[0275] In some embodiments, methanesulfonate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 30 Consistent.

[0276] In some embodiments, methanesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at about 222°C. In some embodiments, methanesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of about 218°C and an endothermic peak at about 222°C.

[0277] In some embodiments, methanesulfonate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 31 Consistent.

[0278] In some embodiments, methanesulfonate crystal form I is characterized by a weight loss of 0.5% when heated from 125°C to 225°C, as measured by thermogravimetric analysis (TGA). In some embodiments, methanesulfonate crystal form I is characterized by a weight loss of about 0.5% when heated from about 125°C to about 225°C, as measured by thermogravimetric analysis (TGA). In some embodiments, methanesulfonate crystal form I is characterized by a weight loss of no more than about 10%, 5%, 4%, 3%, 2%, or 1% by weight when heated from about 125°C to about 225°C, as measured by thermogravimetric analysis (TGA).

[0279] In some embodiments, methanesulfonate crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 31 Consistent.

[0280] In some embodiments, methanesulfonate crystal form I is characterized by a weight increase of about 19% after undergoing a dynamic vapor adsorption curve cycle from about 0% relative humidity (RH) to about 90% RH at 25°C.

[0281] In some embodiments, methanesulfonate crystal form I is characterized by a dynamic vapor adsorption (DVS) curve that is substantially as follows: Figure 32 As shown.

[0282] In some embodiments, methanesulfonate crystal form I is characterized by a polarization light microscopy (PLM) curve that is substantially as follows: Figure 33 As shown.

[0283] In some embodiments, methanesulfonate crystal form I is essentially free of other crystalline or amorphous forms.

[0284] ix. Methanesulfonate of compound 1 (crystal form II) In some embodiments, the crystalline form is the methanesulfonate of compound 1. In some embodiments, the crystalline form is methanesulfonate form II. In some embodiments, methanesulfonate form II is anhydrous.

[0285] In one embodiment, this disclosure provides a methanesulfonate crystal form II of compound 1. In some embodiments, the methanesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.7, 15.4, 17.2, 17.6, and 19.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the methanesulfonate crystal form II is characterized by an XRPD pattern further containing one or more peaks selected from 10.0, 10.3, 11.4, 15.0, and 16.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the methanesulfonate crystal form II is characterized by an XRPD pattern further containing one or more peaks selected from 12.1, 20.2, 22.7, 23.2, and 24.1 degrees 2θ (± 0.2 degrees 2θ).

[0286] In some embodiments, methanesulfonate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 8.7, 15.4, 17.5, 19.1, and 23.2 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 9.9, 10.3, 15.0, 17.2, and 20.2 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, methanesulfonate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 8.7, 9.9, 10.3, 15.0, 15.4, 17.2, 17.5, 19.1, 20.2, and 23.2 degrees 2θ (± 0.2 degrees 2θ).

[0287] In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 11. In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 11. In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 11. In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 11. In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 11.

[0288] In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 15% as listed in Table 11. In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 15% as listed in Table 11. In some embodiments, methanesulfonate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 20% as listed in Table 11.

[0289] In some embodiments, methanesulfonate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 34 Consistent.

[0290] In some embodiments, methanesulfonate form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 190°C. In some embodiments, methanesulfonate form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 176°C and an endothermic peak at approximately 190°C.

[0291] In some embodiments, methanesulfonate crystal form II is characterized in that its differential scanning calorimetry (DSC) thermogram is substantially the same as that of methanesulfonate crystal form II. Figure 35 Consistent.

[0292] In some embodiments, methanesulfonate form II is characterized by a weight loss of 0.2% when heated from 140°C to 205°C, as measured by thermogravimetric analysis (TGA). In some embodiments, methanesulfonate form II is characterized by a weight loss of about 0.2% when heated from about 140°C to about 205°C, as measured by thermogravimetric analysis (TGA). In some embodiments, methanesulfonate form II is characterized by a weight loss of no more than about 10%, 5%, 4%, 3%, 2%, or 1% by weight when heated from about 140°C to about 205°C, as measured by thermogravimetric analysis (TGA).

[0293] In some embodiments, methanesulfonate crystal form II is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 35 Consistent.

[0294] In some embodiments, methanesulfonate crystal form II is characterized by a polarization light microscopy (PLM) curve that is substantially as shown in the figure. Figure 36 As shown.

[0295] In some embodiments, methanesulfonate crystal form II is essentially free of other crystalline or amorphous forms.

[0296] x. Methanesulfonate of compound 1 (crystal form III) In some aspects, the crystalline form is the methanesulfonate of compound 1. In some embodiments, the crystalline form is methanesulfonate crystal form III. In some embodiments, methanesulfonate crystal form III is a solvate or anhydrous form.

[0297] In one embodiment, this disclosure provides a methanesulfonate crystal form III of compound 1. In some embodiments, the methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.5, 8.9, 17.5, 18.5, and 19.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the methanesulfonate crystal form III is characterized by an XRPD pattern further containing one or more peaks selected from 6.1, 13.1, 13.8, 14.4, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the methanesulfonate crystal form III is characterized by an XRPD pattern further containing one or more peaks selected from 13.3, 18.0, 21.4, 23.6, and 26.0 degrees 2θ (± 0.2 degrees 2θ).

[0298] In some embodiments, methanesulfonate crystal form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.5, 8.9, 18.5, 19.6, and 21.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 6.1, 13.8, 17.5, 19.4, and 23.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, methanesulfonate crystal form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 6.1, 6.5, 8.9, 13.8, 17.5, 18.5, 19.4, 19.6, 21.4, and 23.6 degrees 2θ (± 0.2 degrees 2θ).

[0299] In some embodiments, methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, seven, ten, or more peaks listed in Table 12. In some embodiments, methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing three peaks listed in Table 12. In some embodiments, methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing five peaks listed in Table 12. In some embodiments, methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing seven peaks listed in Table 12. In some embodiments, methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing ten peaks listed in Table 12.

[0300] In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 12.

[0301] In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 12. In some embodiments, methanesulfonate crystal form III is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least seven peaks having a relative intensity of at least 20% as listed in Table 12. In some embodiments, methanesulfonate crystal form III is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least eight peaks having a relative intensity of at least 20% as listed in Table 12.

[0302] In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 12. In some embodiments, methanesulfonate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 12. In some embodiments, the methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with relative intensities of at least 30% as listed in Table 12.

[0303] In some embodiments, methanesulfonate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 37 Consistent.

[0304] In some embodiments, methanesulfonate crystal form III is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 173°C. In some embodiments, methanesulfonate crystal form III is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 138°C and an endothermic peak at approximately 173°C.

[0305] In some embodiments, methanesulfonate crystal form III is characterized in that its differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 38 Consistent.

[0306] In some embodiments, methanesulfonate crystal form III is characterized by a 1.5% weight loss upon heating from 80°C to 180°C, as measured by thermogravimetric analysis (TGA). In some embodiments, methanesulfonate crystal form III is characterized by a weight loss of approximately 1.5% upon heating from approximately 80°C to approximately 180°C, as measured by thermogravimetric analysis (TGA). In some embodiments, methanesulfonate crystal form III is characterized by a weight loss of no more than approximately 10%, 5%, 4%, 3%, or 2% by weight upon heating from approximately 80°C to approximately 180°C, as measured by thermogravimetric analysis (TGA).

[0307] In some embodiments, methanesulfonate crystal form III is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 38 Consistent.

[0308] In some embodiments, methanesulfonate crystal form III is characterized by a polarization light microscopy (PLM) curve that is substantially as shown in the figure. Figure 39 As shown.

[0309] In some embodiments, methanesulfonate crystal form III is essentially free of other crystalline or amorphous forms.

[0310] xi. Maleate salt of compound 1 (crystal form I) In some embodiments, the crystalline form is the maleate salt of compound 1. In some embodiments, the crystalline form is maleate crystal form I. In some embodiments, maleate crystal form I is anhydrous.

[0311] In one embodiment, this disclosure provides maleate crystal form I of compound 1. In some embodiments, maleate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.7, 14.8, 15.5, 18.7, and 20.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, maleate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 7.9, 8.3, 9.9, 12.7, and 18.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, maleate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 16.7, 21.2, 22.5, 23.3, and 24.0 degrees 2θ (± 0.2 degrees 2θ).

[0312] In some embodiments, maleate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 14.8, 15.5, 18.7, 22.5, and 23.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 7.9, 8.3, 8.7, 9.9, and 20.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, maleate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 7.9, 8.3, 8.7, 9.9, 14.8, 15.5, 18.7, 20.0, 22.5, and 23.3 degrees 2θ (± 0.2 degrees 2θ).

[0313] In some embodiments, maleate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 13. In some embodiments, maleate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 13. In some embodiments, maleate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 13. In some embodiments, maleate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 13. In some embodiments, maleate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 13.

[0314] In some embodiments, maleate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 40 Consistent.

[0315] In some embodiments, maleate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 195°C. In some embodiments, maleate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 191°C and an endothermic peak at approximately 195°C.

[0316] In some embodiments, maleate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 41 Consistent.

[0317] In some embodiments, maleate crystal form I is characterized by no weight loss prior to decomposition, as measured by thermogravimetric analysis (TGA). In some embodiments, maleate crystal form I is characterized by no substantial weight loss prior to decomposition, as measured by thermogravimetric analysis (TGA). In some embodiments, maleate crystal form I is characterized by a weight loss of no more than 5%, 4%, 3%, 2%, 1%, or 0.5% by weight prior to decomposition upon heating, as measured by thermogravimetric analysis (TGA).

[0318] In some embodiments, maleate crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 41 Consistent.

[0319] In some embodiments, maleate crystal form I is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 42 As shown.

[0320] In some embodiments, maleate crystal form I is essentially free of other crystalline or amorphous forms.

[0321] xii. Maleate salt of compound 1 (crystal form II) In some embodiments, the crystalline form is the maleate salt of compound 1. In some embodiments, the crystalline form is maleate crystal form II. In some embodiments, maleate crystal form II is an acetone solvate.

[0322] In one embodiment, this disclosure provides maleate crystal form II of compound 1. In some embodiments, maleate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern includes peaks at 14.3, 15.3, 17.5, 18.3, and 18.8 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, maleate crystal form II is characterized in that its XRPD pattern also includes one or more peaks selected from 9.6, 11.9, 13.3, 14.2, and 19.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, maleate crystal form II is characterized in that its XRPD pattern also includes one or more peaks selected from 17.9, 21.4, 24.0, 24.3, and 24.7 degrees 2θ (± 0.2 degrees 2θ).

[0323] In some embodiments, maleate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 14.3, 15.3, 17.5, 18.3, and 24.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 11.9, 13.3, 14.2, 18.8, and 21.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, maleate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 11.9, 13.3, 14.2, 14.3, 15.3, 17.5, 18.3, 18.8, 21.4, and 24.0 degrees 2θ (± 0.2 degrees 2θ).

[0324] In some embodiments, maleate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 14. In some embodiments, maleate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 14. In some embodiments, maleate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 14. In some embodiments, maleate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 14. In some embodiments, maleate form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 14.

[0325] In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 14.

[0326] In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 14.

[0327] In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 30% as listed in Table 14. In some embodiments, maleate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 30% as listed in Table 14.

[0328] In some embodiments, maleate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 43 Consistent.

[0329] In some embodiments, maleate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at about 142°C and / or a second endothermic peak at about 162°C. In some embodiments, maleate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic onset and peak temperature of about 135°C and 142°C, respectively, and / or a second endothermic onset and endothermic peak at about 155°C and 162°C, respectively. In some embodiments, maleate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic onset and peak temperature of about 135°C and about 142°C, respectively, and / or a second endothermic onset and endothermic peak at about 155°C and about 162°C, respectively.

[0330] In some embodiments, maleate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 44 Consistent.

[0331] In some embodiments, maleate crystal form II is characterized by a weight loss of 1.6% when heated from 80°C to 144°C, as measured by thermogravimetric analysis (TGA). In some embodiments, maleate crystal form II is characterized by a weight loss of approximately 1.6% when heated from approximately 80°C to approximately 144°C, as measured by thermogravimetric analysis (TGA). In some embodiments, maleate crystal form II is characterized by a weight loss of no more than approximately 10%, 5%, 4%, 3%, or 2% by weight when heated from approximately 80°C to approximately 144°C, as measured by thermogravimetric analysis (TGA).

[0332] In some embodiments, maleate crystal form II is characterized in that its thermogravimetric analysis (TGA) thermogram is substantially the same as that of maleate crystal form II. Figure 44 Consistent.

[0333] In some embodiments, maleate crystal form II is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 45 As shown.

[0334] In some embodiments, maleate crystal form II is essentially free of other crystalline or amorphous forms.

[0335] xiii. Citrate of compound 1 (crystal form I) In some embodiments, the crystalline form is the citrate of compound 1. In some embodiments, the crystalline form is citrate crystal form I. In some embodiments, citrate crystal form I is an acetone solvate or anhydrous form.

[0336] In one embodiment, this disclosure provides citrate crystal form I of compound 1. In some embodiments, citrate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 11.4, 15.8, 17.9, 19.2, and 19.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, citrate crystal form I is characterized by XRPD patterns further containing one or more peaks selected from 10.6, 13.1, 15.1, 17.0, and 18.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, citrate crystal form I is characterized by XRPD patterns further containing one or more peaks selected from 20.3, 22.6, 23.1, 24.5, and 27.1 degrees 2θ (± 0.2 degrees 2θ).

[0337] In some embodiments, citrate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 11.4, 15.8, 19.2, 20.3, and 27.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 17.9, 19.5, 22.6, 23.1, and 24.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, citrate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 11.4, 15.8, 17.9, 19.2, 19.5, 20.3, 22.6, 23.1, 24.5, and 27.1 degrees 2θ (± 0.2 degrees 2θ).

[0338] In some embodiments, citrate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 15. In some embodiments, citrate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 15. In some embodiments, citrate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 15. In some embodiments, citrate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 15. In some embodiments, citrate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 15.

[0339] In some embodiments, citrate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks having a relative intensity of at least 15% as listed in Table 15. In some embodiments, citrate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks having a relative intensity of at least 20% as listed in Table 15.

[0340] In some embodiments, citrate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 46 Consistent.

[0341] In some embodiments, citrate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 167°C. In some embodiments, citrate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 159°C and an endothermic peak at approximately 167°C.

[0342] In some embodiments, citrate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 47 Consistent.

[0343] In some embodiments, citrate crystal form I is characterized by a 22% weight loss upon heating from 95°C to 225°C, as measured by thermogravimetric analysis (TGA). In some embodiments, citrate crystal form I is characterized by a weight loss of approximately 22% upon heating from approximately 95°C to approximately 225°C, as measured by thermogravimetric analysis (TGA). In some embodiments, citrate crystal form I is characterized by a weight loss of no more than approximately 30%, 25%, or 22% by weight upon heating from approximately 95°C to approximately 225°C, as measured by thermogravimetric analysis (TGA).

[0344] In some embodiments, citrate crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 47 Consistent.

[0345] In some embodiments, citrate crystal form I is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 48 As shown.

[0346] In some embodiments, citrate crystal form I is essentially free of other crystalline or amorphous forms.

[0347] xiv. Fumarate of compound 1 (crystal form I) In some aspects, the crystalline form is the fumarate of compound 1. In some embodiments, the crystalline form is fumarate crystal form I. In some embodiments, fumarate crystal form I is a THF solvate.

[0348] In one embodiment, this disclosure provides fumarate crystal form I of compound 1. In some embodiments, fumarate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 4.2, 8.5, 10.6, 18.8, and 19.8 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate crystal form I is characterized by XRPD patterns further containing one or more peaks selected from 12.7, 13.0, 15.9, 17.0, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate crystal form I is characterized by XRPD patterns further containing one or more peaks selected from 21.1, 21.4, 23.4, 25.7, and 27.4 degrees 2θ (± 0.2 degrees 2θ).

[0349] In some embodiments, fumarate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 4.2, 10.6, 19.8, 21.4, and 23.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 8.5, 17.0, 18.8, 19.4, and 25.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 4.2, 8.5, 10.6, 17.0, 18.8, 19.4, 19.8, 21.4, 23.4, and 25.7 degrees 2θ (± 0.2 degrees 2θ).

[0350] In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, seven, ten, or more peaks listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing three peaks listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing five peaks listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing seven peaks listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing ten peaks listed in Table 16.

[0351] In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 16.

[0352] In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 16.

[0353] In some embodiments, fumarate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 30% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 30% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 30% as listed in Table 16. In some embodiments, fumarate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least five peaks with a relative intensity of at least 30% as listed in Table 16.

[0354] In some embodiments, fumarate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 49 Consistent.

[0355] In some embodiments, fumarate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 198°C. In some embodiments, fumarate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 194°C and an endothermic peak at approximately 198°C.

[0356] In some embodiments, fumarate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 50 Consistent.

[0357] In some embodiments, fumarate crystal form I is characterized by a 9.7% weight loss, as measured by thermogravimetric analysis (TGA), when heated from 100°C to 210°C. In some embodiments, fumarate crystal form I is characterized by a weight loss of approximately 9.7% when heated from approximately 100°C to approximately 210°C, as measured by thermogravimetric analysis (TGA). In some embodiments, fumarate crystal form I is characterized by a weight loss of no more than approximately 20%, 15%, or 10% by weight, as measured by thermogravimetric analysis (TGA), when heated from approximately 100°C to approximately 210°C.

[0358] In some embodiments, fumarate crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 50 Consistent.

[0359] In some embodiments, fumarate crystal form I is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 51 As shown.

[0360] In some embodiments, fumarate crystal form I is essentially free of other crystalline or amorphous forms.

[0361] xv. Fumarate of compound 1 (crystal form II) In some embodiments, the crystalline form is the fumarate of compound 1. In some embodiments, the crystalline form is fumarate crystal form II. In some embodiments, fumarate crystal form II is an acetone solvate.

[0362] In one embodiment, this disclosure provides fumarate form II of compound 1. In some embodiments, fumarate form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 4.2, 8.5, 10.5, 12.9, and 18.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate form II is characterized by its XRPD pattern further containing one or more peaks selected from 15.1, 16.0, 18.6, 19.6, and 20.0 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate form II is characterized by its XRPD pattern further containing one or more peaks selected from 21.7, 23.3, 23.6, 26.1, and 27.7 degrees 2θ (± 0.2 degrees 2θ).

[0363] In some embodiments, fumarate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 4.2, 8.5, 12.9, 21.7, and 23.6 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 10.5, 16.0, 18.9, 20.0, and 26.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 4.2, 8.5, 10.5, 12.9, 16.0, 18.9, 20.0, 21.7, 23.6, and 26.1 degrees 2θ (± 0.2 degrees 2θ).

[0364] In some embodiments, fumarate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 17. In some embodiments, fumarate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 17. In some embodiments, fumarate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 17. In some embodiments, fumarate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 17. In some embodiments, fumarate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 17.

[0365] In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 17.

[0366] In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 17.

[0367] In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 17. In some embodiments, fumarate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with relative intensities of at least 30% as listed in Table 17.

[0368] In some embodiments, fumarate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 52 Consistent.

[0369] In some embodiments, fumarate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at about 144°C and / or a second endothermic peak at about 200°C. In some embodiments, fumarate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation peak at about 144°C, and / or second endothermic initiation peaks at about 197°C and 200°C, respectively.

[0370] In some embodiments, fumarate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 53 Consistent.

[0371] In some embodiments, fumarate crystal form II is characterized by a 2.1% weight loss upon heating from 90°C to 175°C, as measured by thermogravimetric analysis (TGA). In some embodiments, fumarate crystal form II is characterized by a weight loss of approximately 2.1% upon heating from approximately 90°C to approximately 175°C, as measured by thermogravimetric analysis (TGA). In some embodiments, fumarate crystal form II is characterized by a weight loss of no more than approximately 10%, 5%, 4%, or 3% by weight upon heating from approximately 90°C to approximately 175°C, as measured by thermogravimetric analysis (TGA).

[0372] In some embodiments, fumarate crystal form II is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 53 Consistent.

[0373] In some embodiments, fumarate crystal form II is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 54 As shown.

[0374] In some embodiments, fumarate crystal form II is essentially free of other crystalline or amorphous forms.

[0375] xvi. Fumarate of compound 1 (crystal form III) In some embodiments, the crystalline form is the fumarate of compound 1. In some embodiments, the crystalline form is fumarate crystal form III. In some embodiments, fumarate crystal form III is an ethyl acetate solvate.

[0376] In one embodiment, this disclosure provides fumarate form III of compound 1. In some embodiments, fumarate form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 5.7, 7.9, 8.9, 10.6, and 17.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate form III is characterized by XRPD patterns further containing one or more peaks selected from 10.3, 11.5, 16.1, 17.9, and 18.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate form III is characterized by XRPD patterns further containing one or more peaks selected from 2.1, 21.9, 24.0, 25.1, and 26.9 degrees 2θ (± 0.2 degrees 2θ).

[0377] In some embodiments, fumarate crystal form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 5.7, 7.9, 8.9, 10.6, and 17.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD patterns also contain peaks at 11.5, 16.1, 17.9, 18.5, and 25.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, fumarate crystal form III is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 5.7, 7.9, 8.9, 10.6, 11.5, 16.1, 17.4, 17.9, 18.5, and 25.1 degrees 2θ (± 0.2 degrees 2θ).

[0378] In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, seven, ten, or more peaks listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing three peaks listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing five peaks listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing seven peaks listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing ten peaks listed in Table 18.

[0379] In some embodiments, fumarate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 18.

[0380] In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 18.

[0381] In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 30% as listed in Table 18. In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 30% as listed in Table 18.

[0382] In some embodiments, fumarate crystal form III is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 55 Consistent.

[0383] In some embodiments, fumarate crystal form III is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at about 113°C and / or a second endothermic peak at about 164°C. In some embodiments, fumarate crystal form III is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation peak at about 106°C and 113°C, and / or a second endothermic initiation peak at about 158°C and 164°C, respectively.

[0384] In some embodiments, fumarate crystal form III is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 56 Consistent.

[0385] In some embodiments, fumarate crystal form III is characterized by a 3.1% weight loss upon heating from 85°C to 135°C, as measured by thermogravimetric analysis (TGA). In some embodiments, fumarate crystal form III is characterized by a weight loss of approximately 3.1% upon heating from approximately 85°C to approximately 135°C, as measured by thermogravimetric analysis (TGA). In some embodiments, fumarate crystal form III is characterized by a weight loss of no more than approximately 10%, 5%, or 4% by weight upon heating from approximately 85°C to approximately 135°C, as measured by thermogravimetric analysis (TGA).

[0386] In some embodiments, fumarate crystal form III is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 56 Consistent.

[0387] In some embodiments, fumarate crystal form III is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 57 As shown.

[0388] In some embodiments, fumarate crystal form III is essentially free of other crystalline or amorphous forms.

[0389] xvii. Malate of compound 1 (crystal form I) In some embodiments, the crystalline form is the malate of compound 1. In some embodiments, the crystalline form is malate crystal form I. In some embodiments, malate crystal form I is an acetone solvate.

[0390] In one embodiment, this disclosure provides a malate crystal form I of compound 1. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 10.9, 12.4, 13.9, 18.7, and 19.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, malate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 4.1, 8.3, 10.5, 16.0, and 16.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, malate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 20.0, 20.5, 21.1, 22.9, and 24.7 degrees 2θ (± 0.2 degrees 2θ).

[0391] In some embodiments, malate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 10.9, 12.4, 19.4, 20.0, and 20.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 10.5, 13.9, 21.1, 22.9, and 24.7 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, malate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 10.5, 10.9, 12.4, 13.9, 19.4, 20.0, 20.5, 21.1, 22.9, and 24.7 degrees 2θ (± 0.2 degrees 2θ).

[0392] In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, seven, ten, or more peaks listed in Table 19. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing three peaks listed in Table 19. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing five peaks listed in Table 19. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing seven peaks listed in Table 19. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing ten peaks listed in Table 19.

[0393] In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 19. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 19. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 19. In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 19.

[0394] In some embodiments, malate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least two peaks with a relative intensity of at least 20% as listed in Table 19. In some embodiments, malate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least three peaks with a relative intensity of at least 20% as listed in Table 19. In some embodiments, malate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains at least four peaks with a relative intensity of at least 20% as listed in Table 19.

[0395] In some embodiments, malate crystal form I is characterized by having an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 19.

[0396] In some embodiments, malate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 58 Consistent.

[0397] In some embodiments, malate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at about 157°C and / or a second endothermic peak at about 206°C. In some embodiments, malate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation peak at about 147°C and 157°C, and / or a second endothermic initiation peak at about 181°C and 206°C, respectively. In some embodiments, malate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic initiation peak at about 147°C and about 157°C, and / or a second endothermic initiation peak at about 181°C and about 206°C, respectively.

[0398] In some embodiments, malate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 59 Consistent.

[0399] In some embodiments, malate crystal form I is characterized by a 1.9% weight loss, as measured by thermogravimetric analysis (TGA), when heated from 75°C to 157°C. In some embodiments, malate crystal form I is characterized by a weight loss of approximately 1.9% when heated from approximately 75°C to approximately 157°C, as measured by thermogravimetric analysis (TGA). In some embodiments, malate crystal form I is characterized by a weight loss of no more than approximately 10%, 5%, 4%, 3%, or 2% by weight, as measured by thermogravimetric analysis (TGA), when heated from approximately 75°C to approximately 157°C.

[0400] In some embodiments, malate crystal form I is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 59 Consistent.

[0401] In some embodiments, malate crystal form I is characterized by a polarization light microscopy (PLM) curve that is substantially as follows: Figure 60 As shown.

[0402] In some embodiments, malate crystal form I is essentially free of other crystalline or amorphous forms.

[0403] xviii. Malate of compound 1 (crystal form II) In some embodiments, the crystalline form is the malate of compound 1. In some embodiments, the crystalline form is malate crystal form II. In some embodiments, malate crystal form II is anhydrous.

[0404] In one embodiment, this disclosure provides a malate crystal form II of compound 1. In some embodiments, the malate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 8.2, 12.4, 14.7, 15.8, and 18.3 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the malate crystal form II is characterized by its XRPD pattern further containing one or more peaks selected from 4.0, 15.6, 16.4, 17.0, and 19.1 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the malate crystal form II is characterized by its XRPD pattern further containing one or more peaks selected from 21.5, 22.2, 22.9, 24.4, and 26.2 degrees 2θ (± 0.2 degrees 2θ).

[0405] In some embodiments, malate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 8.2, 14.7, 15.8, 18.3, and 24.4 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD pattern also contains peaks at 12.4, 19.1, 21.5, 22.9, and 26.2 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, malate crystal form II is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 8.2, 12.4, 14.7, 15.8, 18.3, 19.1, 21.5, 22.9, 24.4, and 26.2 degrees 2θ (± 0.2 degrees 2θ).

[0406] In some embodiments, malate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 20. In some embodiments, malate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 20. In some embodiments, malate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 20. In some embodiments, malate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 20. In some embodiments, malate crystal form II is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 20.

[0407] In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 20.

[0408] In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 20.

[0409] In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 30% as listed in Table 20. In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 30% as listed in Table 20.

[0410] In some embodiments, malate crystal form II is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 61 Consistent.

[0411] In some embodiments, malate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 183°C. In some embodiments, malate crystal form II is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 180°C and an endothermic peak at approximately 183°C.

[0412] In some embodiments, malate crystal form II is characterized in that its differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 62 Consistent.

[0413] In some embodiments, malate form II is characterized by a weight loss of 0.5% when heated from about 95°C to about 170°C, as measured by thermogravimetric analysis (TGA). In some embodiments, malate form II is characterized by a weight loss of about 0.5% when heated from about 95°C to about 170°C, as measured by thermogravimetric analysis (TGA). In some embodiments, malate form II is characterized by a weight loss of no more than about 10%, 5%, 4%, 3%, 2%, or 1% by weight when heated from about 95°C to about 170°C, as measured by thermogravimetric analysis (TGA).

[0414] In some embodiments, malate crystal form II is characterized by a thermogravimetric analysis (TGA) chromatogram that is substantially the same as... Figure 62 Consistent.

[0415] In some embodiments, malate crystal form II is characterized by a weight increase of about 1.8% after undergoing a dynamic vapor adsorption curve cycle from about 0% relative humidity (RH) to about 90% RH at 25°C.

[0416] In some embodiments, malate crystal form II is characterized by a dynamic vapor adsorption (DVS) curve that is substantially as shown in the figure. Figure 63 As shown.

[0417] In some embodiments, malate crystal form II is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 64 As shown.

[0418] In some embodiments, malate crystal form II is essentially free of other crystalline or amorphous forms.

[0419] xix. Succinate of compound 1 (crystal form I) In some embodiments, the crystalline form is the succinate of compound 1. In some embodiments, the crystalline form is succinate crystal form I. In some embodiments, succinate crystal form I is an acetone solvate.

[0420] In one embodiment, this disclosure provides a succinate crystal form I of compound 1. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 10.5, 12.8, 15.0, 18.8, and 19.9 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, succinate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 8.5, 10.7, 12.1, 15.9, and 18.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, succinate crystal form I is characterized by an XRPD pattern further containing one or more peaks selected from 21.4, 22.8, 23.3, 24.5, and 24.8 degrees 2θ (± 0.2 degrees 2θ).

[0421] In some embodiments, succinate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 12.8, 15.0, 18.8, 21.4, and 24.8 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, the XRPD patterns also contain peaks at 10.5, 19.9, 22.8, 23.3, and 24.5 degrees 2θ (± 0.2 degrees 2θ). In some embodiments, succinate crystal form I is characterized by X-ray powder diffraction (XRPD) patterns containing peaks at 10.5, 12.8, 15.0, 18.8, 19.9, 21.4, 22.8, 23.3, 24.5, and 24.8 degrees 2θ (± 0.2 degrees 2θ).

[0422] In some embodiments, succinate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three, four, five, seven, ten, or more peaks listed in Table 21. In some embodiments, succinate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains three peaks listed in Table 21. In some embodiments, succinate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains five peaks listed in Table 21. In some embodiments, succinate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains seven peaks listed in Table 21. In some embodiments, succinate crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern contains ten peaks listed in Table 21.

[0423] In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 15% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 15% as listed in Table 21.

[0424] In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least seven peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least eight peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least nine peaks with a relative intensity of at least 20% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least ten peaks with a relative intensity of at least 20% as listed in Table 21.

[0425] In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks with a relative intensity of at least 30% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks with a relative intensity of at least 30% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks with a relative intensity of at least 30% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks with a relative intensity of at least 30% as listed in Table 21. In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks with a relative intensity of at least 30% as listed in Table 21.

[0426] In some embodiments, succinate crystal form I is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially similar to... Figure 65 Consistent.

[0427] In some embodiments, succinate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak at approximately 136°C. In some embodiments, succinate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram includes an onset temperature of approximately 128°C and an endothermic peak at approximately 136°C.

[0428] In some embodiments, succinate crystal form I is characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 66 Consistent.

[0429] In some embodiments, succinate crystal form I is characterized by a weight loss of 2.8% when heated from 85°C to 145°C, as measured by thermogravimetric analysis (TGA). In some embodiments, succinate crystal form I is characterized by a weight loss of approximately 2.8% when heated from approximately 85°C to approximately 145°C, as measured by thermogravimetric analysis (TGA). In some embodiments, succinate crystal form I is characterized by a weight loss of no more than approximately 10%, 5%, 4%, or 3% by weight when heated from approximately 85°C to approximately 145°C, as measured by thermogravimetric analysis (TGA).

[0430] In some embodiments, succinate crystal form I is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially the same as... Figure 66 Consistent.

[0431] In some embodiments, succinate crystal form I is characterized by polarization microscopy (PLM) curves that are substantially as follows: Figure 67 As shown.

[0432] In some embodiments, succinate crystal form I is essentially free of other crystalline or amorphous forms.

[0433] C. Solid form This document provides various solid forms of compound 1, comprising at least 50 wt% of the specific crystalline form as described herein. In some embodiments, the solid form comprises at least 60 wt% of the specific crystalline form as described herein. In some embodiments, the solid form comprises at least 70 wt% of the specific crystalline form as described herein. In some embodiments, the solid form comprises at least 80 wt% of the specific crystalline form as described herein. In some embodiments, the solid form comprises at least 90 wt% of the specific crystalline form as described herein. In some embodiments, the solid form comprises at least 95 wt% of the specific crystalline form as described herein. In some embodiments, the solid form comprises at least 99 wt% of the specific crystalline form as described herein. In some embodiments, the specific crystalline form is HCl salt crystal form I. In some embodiments, the specific crystalline form is free base crystal form I. In some embodiments, the specific crystalline form is free base crystal form II.

[0434] D. Pharmaceutical Composition This document provides pharmaceutical compositions comprising crystalline form of Compound 1 described herein, or pharmaceutical compositions prepared using crystalline form of Compound 1 described herein. It also provides pharmaceutical compositions comprising solid form as described herein, or pharmaceutical compositions prepared using solid form as described herein. The pharmaceutical compositions comprise one or more pharmaceutically acceptable excipients. In some embodiments, this document provides pharmaceutical compositions comprising crystalline form of Compound 1 described herein and one or more pharmaceutically acceptable excipients. In some embodiments, this document provides pharmaceutical compositions prepared using crystalline form of Compound 1 described herein and one or more pharmaceutically acceptable excipients. In some embodiments, this document provides pharmaceutical compositions comprising solid form as described herein and one or more pharmaceutically acceptable excipients. In some embodiments, this document provides pharmaceutical compositions prepared using solid form as described herein and one or more pharmaceutically acceptable excipients.

[0435] The pharmaceutical compositions provided herein can be used in the methods disclosed herein; therefore, for example, the pharmaceutical compositions can be administered to a subject ex vivo or in vivo to perform the treatment methods and uses described herein.

[0436] The pharmaceutical composition may be in a form suitable for administration to a patient. The pharmaceutical composition may be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein. Furthermore, the pharmaceutical composition may be used in combination with other therapeutically active agents or compounds as described herein to treat the diseases, conditions, and illnesses covered by this disclosure.

[0437] The composition may be in the form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), suitable for inhalation administration (e.g., as fine powders or liquid aerosols), suitable for inhalation administration (e.g., as fine powders), or suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0438] The composition can be obtained using conventional pharmaceutical excipients known in the art through conventional procedures. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives. Tablets, capsules, etc., contain an active ingredient mixed with non-toxic and pharmaceutically acceptable excipients suitable for manufacturing tablets, capsules, etc. These excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0439] Tablets, capsules, etc., suitable for oral administration can be uncoated or coated using known techniques to delay their disintegration and absorption in the gastrointestinal tract, thereby providing sustained release. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Tablets can also be coated using techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional pharmaceutical agents include biodegradable or biocompatible particles, or polymeric substances such as polyesters, polyamino acids, hydrogels, polyvinylpyrrolidone, polyanhydride, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or copolymers of lactide and glycolide, polylactide and glycolide, or ethylene-vinyl acetate copolymers, to control the delivery of the administered composition. For example, oral pharmaceutical agents can be encapsulated in microcapsules prepared by coagulation techniques or by interfacial polymerization (using hydroxymethylcellulose or gelatin-microcapsules or polymethyl methacrylate microcapsules, respectively), or encapsulated in colloidal drug delivery systems. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid-based systems (including oil-in-water emulsions, micelles, mixed micelles, and liposomes). The preparation methods for the above formulations are all known in the art.

[0440] Oral formulations can also be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose); or soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0441] Aqueous suspensions contain active substances mixed with excipients suitable for their preparation. These excipients can be suspending agents, such as sodium carboxymethyl cellulose, methylcellulose, (hydroxypropyl)methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecetylidene cetyl alcohol), or condensation products of ethylene oxide and fatty acids and hexadiol-derived metaesters (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and fatty acids and hexadiol-derived metaesters (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0442] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (as described above) and flavorings may be added to provide a palatable oral formulation.

[0443] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients, which are mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are illustrated herein.

[0444] The pharmaceutical composition may also be an oil-in-water emulsion. The oil phase may be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean lecithin; and esters or metaesters derived from fatty acids; hexitanic anhydrides, such as sorbitan monooleate; and condensation products of metaesters and ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0445] This invention also covers liquid compositions for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration). Suitable pharmaceutically acceptable excipients include, but are not limited to: antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethylparaben, or n-propylparaben), emulsifiers, suspending agents, dispersants, solvents, fillers, swelling agents, detergents, buffers, carriers, diluents, and / or adjuvants. For example, suitable carriers may be physiological saline solutions or citrate-buffered saline solutions, supplemented as appropriate with other substances commonly found in pharmaceutical compositions for parenteral administration. Neutral buffered saline solutions or saline solutions mixed with serum albumin are also exemplary carriers. Those skilled in the art will readily identify a variety of buffers that can be used in the pharmaceutical compositions and dosage forms covered herein. Typical buffers include, but are not limited to: pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, the buffer component can be a water-soluble substance such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), sodium 2-(N-morpholino)ethanesulfonate (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0446] After formulation, the pharmaceutical composition can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in ready-to-use form, lyophilized form requiring reconstitution before use, liquid form requiring dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is provided in single-use containers (e.g., single-use vials, ampoules, syringes, or auto-injectors (similar to, for example, EpiPen®)), while in other embodiments, multiple-use containers (e.g., multiple-use vials) are provided.

[0447] Formulations may also include carriers to protect their components from rapid degradation or rapid clearance from the body, such as controlled-release formulations, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, time-delayed materials such as glyceryl monostearate or glyceryl stearate may be used alone or in combination with waxes. Any drug delivery device may be used to deliver the compositions described herein, including implants (e.g., implantable pumps) and catheter systems, slow infusion pumps, and devices, all of which are well known to those skilled in the art.

[0448] An effective amount of the crystalline form of compound 1 used for treatment described herein is sufficient to treat or prevent the proliferative condition described herein, delay its progression, and / or alleviate symptoms associated with the condition.

[0449] An effective amount of the pharmaceutical composition described herein for treatment (i.e., a pharmaceutical composition comprising the crystalline form of compound 1 described herein, a pharmaceutical composition prepared using the crystalline form of compound 1 described herein, a pharmaceutical composition comprising the solid form as described herein, or a pharmaceutical composition prepared using the solid form described herein) is an amount of compound 1 sufficient to treat or prevent the proliferative condition described herein, delay its progression, and / or alleviate symptoms associated with the condition.

[0450] Based on well-known medical principles, the dosage of the crystalline form of Compound 1 described herein for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration. Based on well-known medical principles, the dosage of the pharmaceutical composition described herein for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0451] When using the crystalline form of Compound 1 described herein for therapeutic or preventative purposes, it is typically administered such that a total daily dose of Compound 1 is acceptable, for example, ranging from 0.01 mg / kg to 100 mg / kg body weight. When using the pharmaceutical composition described herein for therapeutic or preventative purposes, it is typically administered such that a total daily dose of Compound 1 is acceptable, for example, ranging from 0.01 mg / kg to 100 mg / kg body weight. Oral administration may also be suitable, particularly in tablet form.

[0452] E. Treatment methods This article provides the crystalline forms of compounds that serve as PARG inhibitors.

[0453] Therefore, the present invention provides a method for inhibiting PARG enzyme activity in vitro or in vivo, the method comprising contacting cells with an effective amount of the crystalline form of compound 1 described herein or a pharmaceutical composition thereof as defined and described herein.

[0454] This invention also provides a method for treating a disease or condition in which a patient requiring such treatment involves PARG activity, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of compound 1 described herein or a pharmaceutical composition thereof as defined and described herein. In one embodiment, the disease or condition is an advanced or metastatic solid tumor. In one embodiment, the disease or condition is cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is non-small cell lung cancer (NSCLC). In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is triple-negative breast cancer (TNBC). In one embodiment, the cancer is homologous recombination defective (HRD) cancer.

[0455] This document provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein.

[0456] This document provides a method for treating a proliferative disease in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein. In one embodiment, the proliferative disease is a solid tumor. In one embodiment, the proliferative disease is a metastatic solid tumor. In one embodiment, the proliferative disease is cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is prostate cancer, colorectal cancer, or endometrial cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is endometrial cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, or endometrial cancer. In one embodiment, the cancer is homologous recombination defective (HRD) cancer.

[0457] This document provides a method for treating cancer in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of compound 1 described herein or a pharmaceutical composition thereof as defined and described herein. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is homologous recombination defective (HRD) cancer.

[0458] This document provides a method for treating and / or preventing homologous recombination defect (HRD) cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of compound 1 described herein or a pharmaceutical composition thereof as defined and described herein. In one embodiment, the patient has been identified as needing such treatment. In one embodiment, the homologous recombination defect (HRD) cancer is breast cancer, ovarian cancer, gastric cancer, prostate cancer, lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the homologous recombination defect (HRD) cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, or endometrial cancer.

[0459] In some embodiments, a method is provided for treating and / or preventing cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, thereby treating the cancer in the subject, wherein the cancer is homologous recombination defective (HRD) cancer and the cancer is estrogen receptor (ER) positive. In one embodiment, the cancer is breast cancer or ovarian cancer.

[0460] In some embodiments, a method of treating and / or preventing cancer in a subject of need is provided, the method comprising administering to the subject a crystalline form of compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, thereby treating the subject's cancer, wherein the cancer is HRD cancer, the cancer is ER-positive, and the cancer is optionally progesterone receptor (PR) positive. In one embodiment, the cancer is breast cancer or ovarian cancer.

[0461] In some embodiments, a method of treating and / or preventing cancer in a subject of need is provided, the method comprising administering to the subject a crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, thereby treating the subject's cancer, wherein the cancer is HRD cancer, the cancer is ER-positive, and the cancer is optionally human epidermal growth factor receptor 2 (HER2) negative. In one embodiment, the cancer is breast cancer or ovarian cancer.

[0462] In some embodiments, a method of treating and / or preventing cancer in a subject in need is provided, the method comprising administering to the subject a crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, thereby treating the subject for cancer, wherein the cancer is HRD cancer, the cancer is ER-positive, the cancer is optionally PR-positive, and the cancer is optionally HER2-negative. In one embodiment, the cancer is breast cancer or ovarian cancer.

[0463] In some embodiments, a method of treating and / or preventing breast cancer in a subject in need is provided, the method comprising administering to the subject a crystalline form of compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, thereby treating the subject for cancer, wherein the cancer is HRD cancer, the cancer is ER positive, the cancer is optionally PR positive, and the cancer is optionally HER2 negative.

[0464] This article provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, deletion or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer.

[0465] In one embodiment, the cancer is resistant to a PARP inhibitor. In some embodiments, the cancer resistant to a PARP inhibitor is resistant to any one or more of niraparib, olaparib, rucaparib, taprazole, veriparib, AZD5305, and AZD9574. In some embodiments, the cancer resistant to a PARP inhibitor is resistant to niraparib. In some embodiments, the cancer resistant to a PARP inhibitor is olaparib. In some embodiments, the cancer resistant to a PARP inhibitor is ovarian cancer, breast cancer, or pancreatic cancer.

[0466] In one embodiment, the cancer is resistant to platinum-based drugs. In some embodiments, the platinum-resistant cancer is resistant to any one or more of cisplatin, carboplatin, satroplatin, heptaplatin, picoloplatin, nedaplatin, triplatin, liposomal platinum, and oxaliplatin. In some embodiments, the platinum-resistant cancer is resistant to cisplatin. In some embodiments, the platinum-resistant cancer is resistant to carboplatin.

[0467] This document provides a method for treating cancer in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, wherein the patient has been identified as resistant to one or more PARP inhibitors. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, wherein the patient has been diagnosed as resistant to one or more PARP inhibitors.

[0468] This document provides a method for treating cancer in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, wherein the patient has been identified as resistant to platinum-based chemotherapy drugs. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein or a pharmaceutical composition thereof as defined and described herein, wherein the patient has been diagnosed as resistant to one or more platinum-based chemotherapy drugs.

[0469] This document provides the crystalline form of compound 1 described herein, or its pharmaceutical compositions as defined and described herein, for use in therapy.

[0470] This document provides the crystalline form of compound 1 described herein, or its pharmaceutical compositions as defined and described herein, for the treatment of proliferative conditions.

[0471] This document provides the crystalline form of Compound 1 described herein, or pharmaceutical compositions thereof as defined and described herein, for the treatment of cancer. In one particular embodiment, the cancer is a human cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is homologous recombination defective (HRD) cancer.

[0472] This document provides the crystalline form of compound 1 described herein, or its pharmaceutical compositions as defined and described herein, for the purpose of inhibiting PARG enzyme activity.

[0473] This document provides the crystalline form of compound 1 described herein, or its pharmaceutical compositions as defined and described herein, for the treatment of diseases or conditions in which PARG activity is involved.

[0474] This document provides information on the use of the crystalline form of Compound 1 described herein, or its pharmaceutical compositions as defined and described herein, in the preparation of a medicament for the treatment of proliferative conditions.

[0475] This document provides the use of the crystalline form of Compound 1 described herein, or its pharmaceutical compositions as defined and described herein, in the preparation of a medicament for treating cancer. Suitably, the medicament is used to treat human cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is homologous recombination defective (HRD) cancer.

[0476] This document provides information on the use of the crystalline form of compound 1 described herein, or its pharmaceutical compositions as defined and described herein, in the preparation of a medicament for inhibiting PARG enzyme activity.

[0477] This document provides for the use of the crystalline form of Compound 1 described herein, or its pharmaceutical compositions as defined and described herein, in the preparation of a medicament for treating a disease or condition in which PARG activity is involved.

[0478] This disclosure also covers the use of the crystalline form of Compound 1 described herein, or its pharmaceutical compositions as defined and described herein, in combination with other therapeutically active agents or compounds as described herein, to treat diseases, symptoms, and conditions covered by this disclosure. In some embodiments, the additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the additional therapeutic agent is a MAT2A inhibitor. In some embodiments, the additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor is an MTA-synergistic PRMT5 inhibitor. In some embodiments, the additional therapeutic agent is a cell cycle checkpoint inhibitor. In some embodiments, the additional therapeutic agent is an immune checkpoint inhibitor.

[0479] The terms “proliferative disorder” and “proliferative condition” are used interchangeably herein and refer to unwanted or uncontrolled cell proliferation of undesirable, excessive, or abnormal cells, such as neoplastic or proliferative growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, precancerous and malignant cell proliferation, including but not limited to neoplasms and tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis. Any type of cell can be treated, including but not limited to lung, colon, breast, ovarian, prostate, stomach, liver, pancreas, brain, and skin cells. Proliferative disorders also include, for example, advanced or metastatic solid tumors.

[0480] The crystalline form of Compound 1 described herein, or the antiproliferative effects of its pharmaceutical compositions as defined and described herein, have specific applications in the treatment of human cancers (due to their inhibition of PARG enzyme activity).

[0481] Anti-cancer effects can be produced through one or more mechanisms, including but not limited to: regulating cell proliferation, inhibiting angiogenesis (formation of new blood vessels), inhibiting metastasis (spread of tumors from their primary site), inhibiting invasion (spread of tumor cells to adjacent normal tissues), or promoting apoptosis (programmed cell death).

[0482] In one particular embodiment of this disclosure, the proliferative condition to be treated is cancer.

[0483] F. Preparation method Compound 1 can be prepared, for example, as described in Example 1.

[0484] The various salt crystal forms described herein can be prepared, for example, as shown in the provided examples. It should be understood that more than one crystallization method may be available, which will produce the described free base, HCl salt, sulfate, toluenesulfonate, benzenesulfonate, methanesulfonate, maleate, citrate, fumarate, malate, and succinate crystal forms.

[0485] In one aspect, this disclosure provides a method for preparing compound 1 in crystalline form. In another aspect, this disclosure provides a method for preparing compound 1 in crystalline salt form. In some embodiments, the method includes: 1) Forming a first mixture comprising compound 1 and a first solvent; 2) Add acid to the first mixture to form a second mixture; 3) Optionally, a second solvent is added to the second mixture; 4) Stir the second mixture; 5) Separation of precipitates; and 6) Dry the precipitate to provide the crystalline form of the salt of compound 1.

[0486] In some embodiments, the method for preparing compound 1 in crystalline form includes: 1) Forming a first mixture comprising compound 1 and a first solvent; 2) Add acid to the first mixture to form a second mixture; 3) Optionally, a second solvent is added to the second mixture to form a third mixture; 4) Stir the second mixture after steps 1) and 2) are completed, or stir the third mixture after steps 1) to 3) are completed; 5) Separation of precipitates; and 6) Dry the precipitate to provide the crystalline form of the salt of compound 1.

[0487] In another aspect, this disclosure provides a method for preparing the crystalline free base form of compound 1. In some embodiments, the method includes: 1) Forming a first mixture comprising compound 1 and a first solvent; 2) Optionally, a second solvent is added to the first mixture; 3) Stir the first mixture; 4) Separation of precipitates; and 5) Dry the precipitate to provide compound 1 in crystalline form.

[0488] In some embodiments, the method for preparing the crystalline free base form of compound 1 includes: 1) Forming a first mixture comprising compound 1 and a first solvent; 2) Optionally, a second solvent is added to the first mixture to form a second mixture; 3) Stir the first mixture after step 1) is completed, or stir the second mixture after steps 1) and 2) are completed; 4) Separation of precipitates; and 5) Dry the precipitate to provide compound 1 in crystalline form.

[0489] In some embodiments, all the above steps are performed at room temperature. In some embodiments, all the above steps are performed at a temperature between 10°C and 40°C.

[0490] In some embodiments, the first mixture is formed at room temperature. In some embodiments, the first mixture is heated to a temperature between about 40°C and about 70°C. In some embodiments, the first mixture is heated to a temperature of about 50°C. In some embodiments, the first mixture is heated to a temperature of about 60°C.

[0491] In some embodiments, the first solvent is selected from acetone, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, and tetrahydrofuran. In some embodiments, the first solvent is selected from acetone, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), and tetrahydrofuran.

[0492] In some embodiments, the acid is selected from HCl, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, maleic acid, citric acid, fumaric acid, L-malic acid, and succinic acid.

[0493] In some embodiments, the second solvent is selected from heptane, methyl tert-butyl ether (MTBE), and water. In some embodiments, the second solvent is selected from hexane, heptane, methyl tert-butyl ether (MTBE), and water.

[0494] In some embodiments, a method for preparing the HCl salt crystal form I of compound 1 is provided. In some embodiments, the method includes: 1) forming a first mixture comprising compound 1 and methanol, and heating the first mixture to a temperature of approximately 50°C; 2) adding HCl to form a second mixture; 3) adding MTBE to the second mixture; 4) stirring the second mixture at room temperature; 5) separating the solid; and 6) drying the solid. In some embodiments, the method includes: 1) forming a first mixture comprising compound 1 and methanol, and heating the first mixture to a temperature of approximately 50°C; 2) adding HCl to form a second mixture; 3) adding MTBE to the second mixture to form a third mixture; 4) stirring the third mixture at room temperature; 5) separating the solid; and 6) drying the solid. In some embodiments, the solid is dried under vacuum. In some embodiments, the solid is dried at an elevated temperature. In some embodiments, the solid is dried under vacuum at a temperature of approximately 50°C.

[0495] In some embodiments, a method is provided for preparing the free basal crystalline form I of compound 1. In some embodiments, the method includes: 1) forming a first mixture comprising compound 1 and an alcohol solvent; 3) stirring the first mixture; 4) separating the precipitate; and 5) drying the precipitate. In some embodiments, the alcohol solvent is methanol or ethanol. In some embodiments, the method includes slurrying compound 1 in methanol or ethanol at an elevated temperature. In some embodiments, the method includes slurrying compound 1 in methanol or ethanol at about 50°C. In some embodiments, the method includes slurrying compound 1 in ethanol at about 50°C. In some embodiments, the method includes separating the solid, for example, by filtration. In some embodiments, the solid is dried under vacuum. In some embodiments, the solid is dried at an elevated temperature. In some embodiments, the solid is dried under vacuum at about 50°C.

[0496] In some embodiments, a method for preparing the free basal form II of compound 1 is provided. In some embodiments, the method includes: 1) forming a first mixture comprising compound 1 and DMSO; 2) adding water to the first mixture; 3) stirring the first mixture; 4) separating the precipitate; and 5) drying the precipitate. In some embodiments, the method includes: 1) forming a first mixture comprising compound 1 and DMSO; 2) adding water to the first mixture to form a second mixture; 3) stirring the second mixture; 4) separating the precipitate; and 5) drying the precipitate. In some embodiments, the method includes separating the solid, for example, by filtration. In some embodiments, the solid is dried under vacuum. In some embodiments, the solid is dried at an elevated temperature. In some embodiments, the solid is dried under vacuum at a temperature of about 50°C.

[0497] G. Non-limiting exemplary implementation Implementation Method 1. A crystalline form of compound 1 or a salt thereof. (Compound 1).

[0498] Implementation Method 2. The crystal form according to Implementation Method 1, wherein the crystal form is a single crystal form that substantially does not contain other crystal or amorphous forms.

[0499] Implementation Method 3. The crystal form according to Implementation Method 1 or Implementation Method 2, wherein the crystal form is HCl salt crystal form I.

[0500] Embodiment 4. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks located at 13.2 and 17.7 degrees 2θ (± 0.2 degrees 2θ).

[0501] Embodiment 5. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains three peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 19.9.

[0502] Embodiment 6. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains four peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 19.9.

[0503] Embodiment 7. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains five peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 19.9.

[0504] Embodiment 8. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 13.2, 13.7 and 17.7 degrees 2θ (± 0.2 degrees 2θ).

[0505] Embodiment 9. The HCl salt crystal form I according to Embodiment 3 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 11.7, 13.2, 13.7 and 17.7 degrees 2θ (± 0.2 degrees 2θ).

[0506] Embodiment 10. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 11.7, 13.2, 13.7, 17.7 and 18.4 degrees 2θ (± 0.2 degrees 2θ).

[0507] Implementation Method 11. According to the HCl salt crystal form I of Implementation Method 3, the X-ray powder diffraction (XRPD) pattern contains peaks at 11.7, 13.2, 13.7, 17.2, 17.7 and 18.4 degrees 2θ (± 0.2 degrees 2θ).

[0508] Embodiment 12. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 11.7, 13.2, 13.7, 17.2, 17.7, 18.4 and 20.0 degrees 2θ (± 0.2 degrees 2θ).

[0509] Embodiment 13. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks located at 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 20.0 degrees 2θ (± 0.2 degrees 2θ).

[0510] Embodiment 14. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 7.0, 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 20.0 degrees 2θ (± 0.2 degrees 2θ).

[0511] Embodiment 15. According to Embodiment 3, the HCl salt crystal form I is characterized in that the XRPD spectrum contains peaks located at 7.0, 11.7, 12.2, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4 and 20.0 degrees 2θ (± 0.2 degrees 2θ).

[0512] Embodiment 16. The HCl salt crystal form I according to any one of Embodiments 8 to 15, characterized in that the XRPD spectrum further includes one or more peaks selected from 20.9, 24.3, 25.3, 26.1 and 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0513] Embodiment 17. According to any one of Embodiments 8 to 15, the HCl salt crystal form I is characterized in that the XRPD spectrum further includes one or more peaks selected from 20.6, 20.9, 21.2, 21.7, 22.3, 24.3, 25.0, 25.3, 25.6, 26.1, 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0514] Embodiment 18. According to any one of Embodiments 8 to 15, the HCl salt crystal form I is characterized in that the XRPD spectrum further includes a peak located at 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0515] Embodiment 19. The HCl salt crystal form I according to any one of Embodiments 8 to 15, characterized in that the XRPD spectrum further includes peaks located at 26.1 and 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0516] Embodiment 20. According to any one of Embodiments 8 to 15, the HCl salt crystal form I is characterized in that the XRPD spectrum further includes peaks located at 24.3, 26.1 and 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0517] Embodiment 21. According to any one of Embodiments 8 to 15, the HCl salt crystal form I is characterized in that the XRPD spectrum further includes peaks located at 20.9, 24.3, 26.1 and 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0518] Embodiment 22. According to any one of Embodiments 8 to 15, the HCl salt crystal form I is characterized in that the XRPD spectrum further includes peaks located at 20.9, 24.3, 25.3, 26.1 and 28.9 degrees 2θ (± 0.2 degrees 2θ).

[0519] Embodiment 23. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains at least five peaks having a relative intensity of at least 15% as listed in Table 3.

[0520] Embodiment 24. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains at least five peaks having a relative intensity of at least 20% as listed in Table 3.

[0521] Embodiment 25. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern contains at least five peaks having a relative intensity of at least 30% as listed in Table 3.

[0522] Embodiment 26. According to Embodiment 3, the HCl salt crystal form I is characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 7 Consistent.

[0523] Embodiment 27. HCl salt crystal form I according to any one of Embodiments 3 to 26, characterized in that it does not contain a differential scanning calorimeter (DSC) with endothermic peaks before decomposition.

[0524] Embodiment 28. HCl salt crystal form I according to any one of Embodiments 3 to 26, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 8 Consistent.

[0525] Embodiment 29. HCl salt crystal form I according to any one of Embodiments 3 to 28, characterized in that there is no weight loss before decomposition under heating, as measured by thermogravimetric analysis (TGA).

[0526] Embodiment 30. HCl salt crystal form I according to any one of Embodiments 3 to 28, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 8 Consistent.

[0527] Embodiment 31. HCl salt crystal form I according to any one of Embodiments 3 to 30, characterized in that it has a weight increase of about 0.5% after undergoing a dynamic vapor adsorption cycle from about 0% relative humidity (RH) to about 90% RH at 25°C.

[0528] Embodiment 32. HCl salt crystal form I according to any one of Embodiments 3 to 31, characterized in that the dynamic vapor adsorption curve is substantially as follows: Figure 9 As shown.

[0529] Embodiment 33. HCl salt crystal form I according to any one of Embodiments 3 to 32, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 10 As shown.

[0530] Implementation Method 34. The crystal form according to Implementation Method 1 or Implementation Method 2, wherein the crystal form is free alkali crystal form I.

[0531] Embodiment 35. Free alkali crystal form I according to Embodiment 34, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0 and 18.3 degrees 2θ (± 0.2 degrees 2θ).

[0532] Embodiment 36. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains three peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0533] Embodiment 37. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains four peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0534] Embodiment 38. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains five peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0535] Embodiment 39. Free alkali crystal form I according to Embodiment 34, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 16.4 and 18.3 degrees 2θ (± 0.2 degrees 2θ).

[0536] Embodiment 40. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 16.4, 18.0 and 18.3 degrees 2θ (± 0.2 degrees 2θ).

[0537] Embodiment 41. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 16.4, 18.0, 18.3 and 19.4 degrees 2θ (± 0.2 degrees 2θ).

[0538] Embodiment 42. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 12.7, 16.4, 18.0, 18.3 and 19.4 degrees 2θ (± 0.2 degrees 2θ).

[0539] Embodiment 43. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 12.7, 16.4, 18.0, 18.3, 18.9 and 19.4 degrees 2θ (± 0.2 degrees 2θ).

[0540] Embodiment 44. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9 and 19.4 degrees 2θ (± 0.2 degrees 2θ).

[0541] Embodiment 45. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0542] Embodiment 46. The free alkali crystal form I according to Embodiment 34 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 11.5, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4 and 19.7 degrees 2θ (±0.2 degrees 2θ).

[0543] Embodiment 47. The free alkali crystal form I according to any one of Embodiments 39 to 46, characterized in that the XRPD spectrum further includes one or more peaks selected from 22.5, 23.2, 23.5, 24.6 and 27.8 degrees 2θ (± 0.2 degrees 2θ).

[0544] Embodiment 48. The free alkali crystal form I according to any one of Embodiments 39 to 46, characterized in that the XRPD spectrum further includes one or more peaks selected from 23.2, 23.5 and 24.6 degrees 2θ (± 0.2 degrees 2θ).

[0545] Embodiment 49. The free alkali crystal form I according to Embodiment 34, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 1 Consistent.

[0546] Embodiment 50. Free alkali crystal form I according to any one of Embodiments 34 to 49, characterized in that the differential scanning calorimetry (DSC) thermogram contains a melting point peak at about 200°C.

[0547] Embodiment 51. The free alkali crystal form I according to any one of Embodiments 34 to 49, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 2 Consistent.

[0548] Embodiment 52. Free alkali crystal form I according to any one of Embodiments 34 to 51, characterized in that there is no weight loss before decomposition under heating, as measured by thermogravimetric analysis (TGA).

[0549] Embodiment 53. The free alkali crystal form I according to any one of Embodiments 34 to 51, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 2 Consistent.

[0550] Embodiment 54. The free alkali crystal form I according to any one of Embodiments 34 to 53, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 3 As shown.

[0551] Embodiment 55. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is free alkali crystal form II.

[0552] Embodiment 56. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks located at 12.3 and 18.7 degrees 2θ (± 0.2 degrees 2θ).

[0553] Embodiment 57. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains three peaks selected from 12.3, 15.6, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0554] Embodiment 58. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains four peaks selected from 12.3, 15.6, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0555] Embodiment 59. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains five peaks selected from 12.3, 15.6, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0556] Embodiment 60. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 15.6 and 18.7 degrees 2θ (± 0.2 degrees 2θ).

[0557] Embodiment 61. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 15.6, 17.1 and 18.7 degrees 2θ (± 0.2 degrees 2θ).

[0558] Embodiment 62. The free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 15.6, 17.1, 18.7 and 19.5 degrees 2θ (± 0.2 degrees 2θ).

[0559] Embodiment 63. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 15.6, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0560] Embodiment 64. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 15.6, 16.4, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0561] Embodiment 65. The free alkali crystal form II according to Embodiment 55 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 13.4, 15.6, 16.4, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0562] Embodiment 66. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 13.4, 15.6, 16.1, 16.4, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0563] Embodiment 67. Free alkali crystal form II according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 12.3, 13.4, 14.1, 15.6, 16.1, 16.4, 17.1, 18.7, 19.5 and 19.7 degrees 2θ (±0.2 degrees 2θ).

[0564] Embodiment 68. Free alkali crystal form II according to any one of Embodiments 60 to 67, characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 20.7, 23.0, 25.0, 25.7, 26.5 and 31.4 degrees 2θ (± 0.2 degrees 2θ).

[0565] Embodiment 69. Free alkali crystal form II according to any one of Embodiments 60 to 67, characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 20.7, 23.0, 25.7 and 26.5 degrees 2θ (± 0.2 degrees 2θ).

[0566] Embodiment 70. The free alkali crystal form I according to Embodiment 55, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 4 Consistent.

[0567] Embodiment 71. Free alkali crystal form II according to any one of Embodiments 55 to 70, characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at about 148°C and / or a second endothermic peak at about 198°C.

[0568] Embodiment 72. The free alkali crystal form II according to any one of Embodiments 55 to 70, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 5 Consistent.

[0569] Embodiment 73. Free alkali crystal form II according to any one of Embodiments 55 to 72, characterized by a weight loss of 15.1% when heated to about 158°C, as measured by thermogravimetric analysis (TGA).

[0570] Embodiment 74. The free alkali crystal form II according to any one of Embodiments 55 to 72, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 5 Consistent.

[0571] Embodiment 75. The free alkali crystal form II according to any one of Embodiments 55 to 74, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 6 As shown.

[0572] Implementation 76. The crystal form according to Implementation 1 or Implementation 2, wherein the crystal form is sulfate crystal form I.

[0573] Embodiment 77. The sulfate crystal form I according to Embodiment 76 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 8.0, 8.5, 13.2, 15.6 and 16.1 degrees 2θ (± 0.2 degrees 2θ).

[0574] Embodiment 78. The sulfate crystal form I according to Embodiment 77 is characterized in that the XRPD spectrum further includes one or more peaks selected from 8.8, 12.9, 15.0, 17.2 and 19.0 degrees 2θ (± 0.2 degrees 2θ).

[0575] Embodiment 79. The sulfate crystal form I according to Embodiment 77 or 78, characterized in that the XRPD spectrum further includes one or more peaks selected from 20.2, 22.1, 24.3, 25.1 and 26.7 degrees 2θ (± 0.2 degrees 2θ).

[0576] Embodiment 80. Sulfate crystal form I according to Embodiment 76, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 11 Consistent.

[0577] Embodiment 81. Sulfate crystal form I according to any one of Embodiments 76 to 80, characterized in that the differential scanning calorimetry (DSC) thermogram includes a first endothermic peak at about 118°C, a second endothermic peak at about 220°C, an exothermic peak at about 231°C, and / or a third endothermic peak at about 279°C.

[0578] Embodiment 82. Sulfate crystal form I according to any one of Embodiments 76 to 80, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 12 Consistent.

[0579] Embodiment 83. Sulfate crystal form I according to any one of Embodiments 76 to 82, characterized by a weight loss of about 2.8% when heated to about 130°C, as measured by thermogravimetric analysis (TGA).

[0580] Embodiment 84. Sulfate crystal form I according to any one of Embodiments 76 to 82, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 12 Consistent.

[0581] Embodiment 85. Sulfate crystal form I according to any one of Embodiments 76 to 84, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 13 As shown.

[0582] Implementation 86. The crystal form according to Implementation 1 or Implementation 2, wherein the crystal form is toluenesulfonate crystal form I.

[0583] Embodiment 87. Toluenesulfonate crystal form I according to Embodiment 86, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 6.8, 9.6, 14.5, 18.2 and 19.5 degrees 2θ (± 0.2 degrees 2θ).

[0584] Embodiment 88. Toluenesulfonate crystal form I according to Embodiment 87, characterized in that the XRPD spectrum further includes one or more peaks selected from 4.7, 11.7, 13.7, 15.5 and 15.9 degrees 2θ (± 0.2 degrees 2θ).

[0585] Embodiment 89. Toluenesulfonate crystal form I according to Embodiment 87 or 88, characterized in that the XRPD spectrum further includes one or more peaks selected from 21.4, 22.8, 24.0, 24.3 and 29.3 degrees 2θ (± 0.2 degrees 2θ).

[0586] Embodiment 90. Toluenesulfonate crystal form I according to Embodiment 86, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 14 Consistent.

[0587] Embodiment 91. Toluenesulfonate crystal form I according to any one of Embodiments 86 to 90, characterized in that the differential scanning calorimetry (DSC) thermogram contains a melting point peak at about 231°C.

[0588] Embodiment 92. Toluenesulfonate crystal form I according to any one of Embodiments 86 to 90, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 15 Consistent.

[0589] Embodiment 93. Toluenesulfonate crystal form I according to any one of Embodiments 86 to 92, characterized by a weight loss of about 1.2% when heated from about 110°C to about 230°C, as measured by thermogravimetric analysis (TGA).

[0590] Embodiment 94. Toluenesulfonate crystal form I according to any one of Embodiments 86 to 92, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 15 Consistent.

[0591] Embodiment 95. Toluenesulfonate crystal form I according to any one of Embodiments 86 to 94, characterized in that the polarization light microscopy (PLM) curve is substantially as follows: Figure 16 As shown.

[0592] Embodiment 96. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is toluenesulfonate crystal form II.

[0593] Embodiment 97. Toluenesulfonate crystal form II according to Embodiment 96, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 6.7, 14.3, 15.4, 17.3 and 19.1 degrees 2θ (± 0.2 degrees 2θ).

[0594] Embodiment 98. Toluenesulfonate crystal form II according to Embodiment 97, characterized in that the XRPD spectrum further includes one or more peaks selected from 9.1, 10.2, 13.0, 17.0 and 18.4 degrees 2θ (± 0.2 degrees 2θ).

[0595] Embodiment 99. Toluenesulfonate crystal form II according to Embodiment 97 or 98, characterized in that the XRPD spectrum further includes one or more peaks selected from 20.1, 20.5, 23.8, 24.2 and 26.2 degrees 2θ (± 0.2 degrees 2θ).

[0596] Embodiment 100. Toluenesulfonate crystal form II according to Embodiment 96, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 17 Consistent.

[0597] Embodiment 101. Toluenesulfonate crystal form II according to any one of Embodiments 96 to 100, characterized in that the differential scanning calorimetry (DSC) thermogram contains a melting point peak at about 229°C.

[0598] Embodiment 102. Toluenesulfonate crystal form II according to any one of Embodiments 96 to 100, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 18 Consistent.

[0599] Embodiment 103. Toluenesulfonate crystal form II according to any one of Embodiments 96 to 102, characterized by a weight loss of about 1.4% when heated from about 90°C to about 230°C, as measured by thermogravimetric analysis (TGA).

[0600] Embodiment 104. Toluenesulfonate crystal form II according to any one of Embodiments 96 to 102, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 18 Consistent.

[0601] Embodiment 105. Toluenesulfonate crystal form II according to any one of Embodiments 96 to 104, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 19 As shown.

[0602] Embodiment 106. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is toluenesulfonate crystal form III.

[0603] Embodiment 107. Toluenesulfonate crystal form III according to Embodiment 106, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 6.9, 14.5, 15.5, 18.2 and 19.5 degrees 2θ (± 0.2 degrees 2θ).

[0604] Embodiment 108. Toluenesulfonate crystal form III according to Embodiment 107, characterized in that the XRPD spectrum further includes one or more peaks selected from 9.7, 14.1, 14.9, 16.0 and 16.9 degrees 2θ (± 0.2 degrees 2θ).

[0605] Embodiment 109. Toluenesulfonate crystal form III according to Embodiment 107 or 108, characterized in that the XRPD spectrum further includes one or more peaks selected from 21.2, 21.4, 22.0, 24.0 and 24.4 degrees 2θ (± 0.2 degrees 2θ).

[0606] Embodiment 110. Toluenesulfonate crystal form III according to Embodiment 106, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 20 Consistent.

[0607] Embodiment 111. Toluenesulfonate crystal form III according to any one of Embodiments 106 to 110, characterized in that the differential scanning calorimetry (DSC) thermogram contains a melting point peak at 222°C.

[0608] Embodiment 112. Toluenesulfonate crystal form III according to any one of Embodiments 106 to 110, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 21 Consistent.

[0609] Embodiment 113. Toluenesulfonate crystal form III according to any one of Embodiments 106 to 112, characterized by a weight loss of about 2.6% when heated from about 110°C to about 222°C, as measured by thermogravimetric analysis (TGA).

[0610] Embodiment 114. Toluenesulfonate crystal form III according to any one of Embodiments 106 to 112, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 21 Consistent.

[0611] Embodiment 115. Toluenesulfonate crystal form III according to any one of Embodiments 106 to 114, characterized in that it has a weight increase of about 3.2% after undergoing a dynamic vapor adsorption cycle from about 0% relative humidity (RH) to about 90% RH at 25°C.

[0612] Embodiment 116. Toluenesulfonate crystal form III according to any one of Embodiments 106 to 114, characterized in that the dynamic vapor adsorption curve is substantially as follows: Figure 22 As shown.

[0613] Embodiment 117. Toluenesulfonate crystal form III according to any one of Embodiments 106 to 116, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 23 As shown.

[0614] Embodiment 118. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is benzenesulfonate crystal form I.

[0615] Embodiment 119. The benzenesulfonate crystal form I according to Embodiment 118 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 6.8, 14.5, 15.4, 17.3 and 19.1 degrees 2θ (± 0.2 degrees 2θ).

[0616] Embodiment 120. The benzenesulfonate crystal form I according to Embodiment 119 is characterized in that the XRPD spectrum further includes one or more peaks selected from 15.0, 15.9, 17.7, 18.3 and 19.6 degrees 2θ (± 0.2 degrees 2θ).

[0617] Embodiment 121. The benzenesulfonate crystal form I according to Embodiment 119 or 120, characterized in that the XRPD spectrum further includes one or more peaks selected from 20.3, 20.8, 24.0, 25.2 and 26.0 degrees 2θ (± 0.2 degrees 2θ).

[0618] Embodiment 122. The benzenesulfonate crystal form I according to Embodiment 118, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 24 Consistent.

[0619] Embodiment 123. The benzenesulfonate crystal form I according to any one of Embodiments 119 to 122, characterized in that the differential scanning calorimetry (DSC) thermogram contains an endothermic peak at about 202°C.

[0620] Embodiment 124. The benzenesulfonate crystal form I according to any one of Embodiments 118 to 122, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 25 Consistent.

[0621] Embodiment 125. The benzenesulfonate crystal form I according to any one of Embodiments 118 to 124, characterized by a weight loss of about 0.6% when heated from about 100°C to about 210°C, as measured by thermogravimetric analysis (TGA).

[0622] Embodiment 126. The benzenesulfonate crystal form I according to any one of Embodiments 118 to 124, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 25 Consistent.

[0623] Embodiment 127. The benzenesulfonate crystal form I according to any one of Embodiments 118 to 126, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 26 As shown.

[0624] Embodiment 128. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is benzenesulfonate crystal form II.

[0625] Embodiment 129. The benzenesulfonate crystal form II according to Embodiment 128, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 7.6, 15.2, 15.7, 19.2 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

[0626] Embodiment 130. The benzenesulfonate crystal form II according to Embodiment 129, characterized in that the XRPD spectrum further includes one or more peaks selected from 9.0, 10.0, 12.4, 14.7 and 18.1 degrees 2θ (± 0.2 degrees 2θ).

[0627] Embodiment 131. The benzenesulfonate crystal form II according to Embodiment 129 or 130, characterized in that the XRPD spectrum further includes one or more peaks selected from 10.4, 20.1, 22.9, 25.0 and 26.5 degrees 2θ (± 0.2 degrees 2θ).

[0628] Embodiment 132. The benzenesulfonate crystal form II according to Embodiment 128, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 27 Consistent.

[0629] Embodiment 133. The benzenesulfonate crystal form II according to any one of Embodiments 128 to 132, characterized in that the differential scanning calorimetry (DSC) thermogram contains an endothermic peak at about 165°C.

[0630] Embodiment 134. The benzenesulfonate crystal form II according to any one of Embodiments 128 to 132, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 28 Consistent.

[0631] Embodiment 135. The benzenesulfonate crystal form II according to any one of Embodiments 128 to 134, characterized by a weight loss of about 0.5% when heated from about 64°C to about 185°C, as measured by thermogravimetric analysis (TGA).

[0632] Embodiment 136. The benzenesulfonate crystal form II according to any one of Embodiments 128 to 134, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 28 Consistent.

[0633] Embodiment 137. The benzenesulfonate crystal form II according to any one of Embodiments 128 to 136, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 29 As shown.

[0634] Embodiment 138. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is methanesulfonate crystal form I.

[0635] Embodiment 139. The methanesulfonate crystal form I according to Embodiment 138 is characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 14.2, 17.0, 18.0, 18.6 and 19.3 degrees 2θ (± 0.2 degrees 2θ).

[0636] Embodiment 140. The methanesulfonate crystal form I according to Embodiment 139, characterized in that the XRPD spectrum further includes one or more peaks selected from 11.0, 11.9, 12.7, 15.1 and 17.5 degrees 2θ (± 0.2 degrees 2θ).

[0637] Embodiment 141. The methanesulfonate crystal form I according to Embodiment 139 or 140, characterized in that the XRPD spectrum further includes one or more peaks selected from 20.7, 21.2, 22.1, 24.1 and 25.0 degrees 2θ (± 0.2 degrees 2θ).

[0638] Embodiment 142. The methanesulfonate crystal form I according to Embodiment 139, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 30 Consistent.

[0639] Embodiment 143. Methanesulfonate crystal form I according to any one of Embodiments 138 to 142, characterized in that the differential scanning calorimetry (DSC) thermogram contains an endothermic peak at about 222°C.

[0640] Embodiment 144. Methanesulfonate crystal form I according to any one of Embodiments 138 to 142, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 31 Consistent.

[0641] Embodiment 145. Methanesulfonate crystal form I according to any one of Embodiments 138 to 144, characterized by a weight loss of about 0.5% when heated from about 125°C to about 225°C, as measured by thermogravimetric analysis (TGA).

[0642] Embodiment 146. Methanesulfonate crystal form I according to any one of Embodiments 138 to 144, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 31 Consistent.

[0643] Embodiment 147. Methanesulfonate crystal form I according to any one of Embodiments 138 to 146, characterized in that it has a weight increase of about 19% after undergoing a dynamic vapor adsorption cycle from about 0% relative humidity (RH) to about 90% RH at 25°C.

[0644] Embodiment 148. The methanesulfonate crystal form I according to any one of Embodiments 138 to 146, characterized in that the dynamic vapor adsorption curve is substantially as follows: Figure 32 As shown.

[0645] Embodiment 149. Methanesulfonate crystal form I according to any one of Embodiments 138 to 148, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 33 As shown.

[0646] Embodiment 150. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is methanesulfonate crystal form II.

[0647] Embodiment 151. The methanesulfonate crystal form II according to Embodiment 150, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 8.7, 15.4, 17.2, 17.6 and 19.1 degrees 2θ (± 0.2 degrees 2θ).

[0648] Embodiment 152. The methanesulfonate crystal form II according to Embodiment 151, characterized in that the XRPD spectrum further includes one or more peaks selected from 10.0, 10.3, 11.4, 15.0 and 16.5 degrees 2θ (± 0.2 degrees 2θ).

[0649] Embodiment 153. The methanesulfonate crystal form II according to Embodiment 151 or 153 is characterized in that the XRPD spectrum further includes one or more peaks selected from 12.1, 20.2, 22.7, 23.2 and 24.1 degrees 2θ (± 0.2 degrees 2θ).

[0650] Embodiment 154. The methanesulfonate crystal form II according to Embodiment 150, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 34 Consistent.

[0651] Embodiment 155. Methanesulfonate crystal form II according to any one of Embodiments 150 to 154, characterized in that the differential scanning calorimetry (DSC) thermogram contains an endothermic peak at about 190°C.

[0652] Embodiment 156. Methanesulfonate crystal form II according to any one of Embodiments 150 to 154, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 35 Consistent.

[0653] Embodiment 157. Methanesulfonate crystal form II according to any one of Embodiments 150 to 156, characterized by a weight loss of about 0.2% when heated from about 140°C to about 205°C, as measured by thermogravimetric analysis (TGA).

[0654] Embodiment 158. Methanesulfonate crystal form II according to any one of Embodiments 150 to 156, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 35 Consistent.

[0655] Embodiment 159. Methanesulfonate crystal form II according to any one of Embodiments 150 to 158, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 36 As shown.

[0656] Embodiment 160. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is methanesulfonate crystal form III.

[0657] Embodiment 161. The methanesulfonate crystal form III according to Embodiment 160, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 6.5, 8.9, 17.5, 18.5 and 19.6 degrees 2θ (± 0.2 degrees 2θ).

[0658] Embodiment 162. The methanesulfonate crystal form III according to Embodiment 161, characterized in that the XRPD spectrum further includes one or more peaks selected from 6.1, 13.1, 13.8, 14.4 and 19.4 degrees 2θ (± 0.2 degrees 2θ).

[0659] Embodiment 163. The methanesulfonate crystal form III according to Embodiment 161 or 162, characterized in that the XRPD spectrum further includes one or more peaks selected from 13.3, 18.0, 21.4, 23.6 and 26.0 degrees 2θ (± 0.2 degrees 2θ).

[0660] Embodiment 164. The methanesulfonate crystal form III according to Embodiment 160, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially the same as... Figure 37 Consistent.

[0661] Embodiment 165. Methanesulfonate crystal form III according to any one of Embodiments 160 to 164, characterized in that the differential scanning calorimetry (DSC) thermogram contains a melting peak at about 173°C.

[0662] Embodiment 166. Methanesulfonate crystal form III according to any one of Embodiments 160 to 164, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially the same as... Figure 38 Consistent.

[0663] Embodiment 167. Methanesulfonate crystal form III according to any one of Embodiments 160 to 166, characterized by a weight loss of 1.5% when heated from about 80°C to about 180°C, as measured by thermogravimetric analysis (TGA).

[0664] Embodiment 168. Methanesulfonate crystal form III according to any one of Embodiments 160 to 166, characterized in that the thermogravimetric analysis (TGA) chromatogram is substantially the same as... Figure 38 Consistent.

[0665] Embodiment 169. Methanesulfonate crystal form III according to any one of Embodiments 160 to 168, characterized in that the polarization microscopy (PLM) curve is substantially as follows: Figure 39 As shown.

[0666] Embodiment 170. The crystal form according to Embodiment 1 or Embodiment 2, wherein the crystal form is maleate crystal form I.

[0667] Embodiment 171. Maleate crystal form I according to Embodiment 170, characterized in that the X-ray powder diffraction (XRPD) pattern contains peaks at 8.7, 14.8, 15.5, 18.7 and 20.0 degrees 2θ (± 0.2 degrees 2θ).

[0668] Embodiment 172. Maleate crystal form I according to Embodiment 171, characterized in that the XRPD spectrum further includes one or more peaks selected from 7.9, 8.3, 9.9, 12.7 and 18.1 degrees 2θ (± 0.2 degrees 2θ).

[0669] Embodiment 173. Maleate crystal form I according to Embodiment 171 or 172, characterized in that the XRPD spectrum further includes one or more peaks selected from 16.7, 21.2, 22.5, 23.3 and 24.0 degrees 2θ (± 0.2 degrees 2θ).

[0670] Embodiment 174. Maleate crystal form I according to Embodiment 170, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially t...

Claims

1. A crystalline form of compound 1 or a salt thereof. (Compound 1).

2. The crystal form as claimed in claim 1, wherein the crystal form is a single crystal form that substantially contains no other crystal or amorphous forms.

3. The crystal form as described in claim 1 or claim 2, wherein the crystal form is HCl salt crystal form I.

4. The crystal form as claimed in claim 3, wherein the crystal form is a single crystal form that substantially contains no other crystal or amorphous forms.

5. The HCl salt crystal form I according to claim 3 or 4, characterized in that... The X-ray powder diffraction (XRPD) pattern contains three or more peaks selected from 11.7, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 19.9 degrees 2θ (± 0.2 degrees 2θ).

6. The HCl salt crystal form I according to claim 3 or 4, characterized in that... The X-ray powder diffraction (XRPD) pattern contains peaks at 11.7, 13.2, 13.7, 17.7, and 18.4 degrees 2θ (± 0.2 degrees 2θ).

7. The HCl salt crystal form I according to claim 3 or 4, characterized in that... The XRPD spectrum contains peaks at 7.0, 11.7, 12.2, 13.2, 13.7, 15.3, 17.2, 17.7, 18.4, and 20.0 degrees 2θ (± 0.2 degrees 2θ).

8. The HCl salt crystal form I according to any one of claims 3 to 7, wherein the XRPD spectrum further comprises one or more peaks selected from 20.6, 20.9, 21.2, 21.7, 22.3, 24.3, 25.0, 25.3, 25.6, 26.1 and 28.9 degrees 2θ (± 0.2 degrees 2θ).

9. The HCl salt crystal form I according to claim 3 or 4, characterized in that... The X-ray powder diffraction (XRPD) pattern contains at least five peaks with relative intensities of at least 15%, as listed in Table 3.

10. The HCl salt crystal form I according to claim 3 or 4, characterized in that... The X-ray powder diffraction (XRPD) pattern contains peaks at 13.2, 13.7, 17.7, 26.1, and 28.9 degrees 2θ (± 0.2 degrees 2θ).

11. The HCl salt crystal form I according to claim 10, wherein the XRPD spectrum further comprises peaks located at 20.6, 20.9, 21.2, 24.3 and 25.3 degrees 2θ (± 0.2 degrees 2θ).

12. The HCl salt crystal form I according to claim 3 or 4, characterized in that... The X-ray powder diffraction (XRPD) pattern is basically consistent with Figure 7.

13. The HCl salt crystal form I according to any one of claims 3 to 12, characterized in that... Differential scanning calorimetry (DSC) thermograms prior to decomposition do not contain endothermic signals.

14. The HCl salt crystal form I according to any one of claims 3 to 12, characterized in that... The differential scanning calorimetry (DSC) thermogram is basically consistent with Figure 8.

15. The HCl salt crystal form I according to any one of claims 3 to 14, characterized in that... As measured by thermogravimetric analysis (TGA), there is no weight loss before decomposition under heating.

16. The HCl salt crystal form I according to any one of claims 3 to 14, characterized in that... The thermogravimetric analysis (TGA) chromatogram is basically consistent with Figure 8.

17. The HCl salt crystal form I according to any one of claims 3 to 16, characterized in that... At 25°C, there is a weight gain of approximately 0.5% after undergoing a dynamic vapor adsorption cycle from approximately 0% relative humidity (RH) to approximately 90% RH.

18. The HCl salt crystal form I according to any one of claims 3 to 16, characterized in that... The dynamic vapor adsorption curve is basically as shown in Figure 9.

19. The crystal form as claimed in claim 1 or claim 2, wherein the crystal form is free alkali crystal form I.

20. The crystal form of claim 19, wherein the crystal form is a single crystal form that substantially contains no other crystal or amorphous forms.

21. The free alkali crystal form I as described in claim 19 or 20, characterized in that... The X-ray powder diffraction (XRPD) pattern contains three or more peaks selected from 9.0, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4 and 19.7 degrees 2θ (± 0.2 degrees 2θ).

22. The free alkali crystal form I as described in claim 19 or 20, characterized in that... The X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 16.4, 18.0, 18.3, and 19.4 degrees 2θ (± 0.2 degrees 2θ).

23. The free alkali crystal form I as described in claim 19 or 20, characterized in that... The X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 11.5, 12.7, 13.7, 16.4, 18.0, 18.3, 18.9, 19.4, and 19.7 degrees 2θ (± 0.2 degrees 2θ).

24. The free alkali crystal form I according to any one of claims 21 to 23, wherein the XRPD spectrum further comprises one or more peaks selected from 22.5, 23.2, 23.5, 24.6 and 27.8 degrees 2θ (± 0.2 degrees 2θ).

25. The free alkali crystal form I according to claim 19 or 20, characterized in that... The X-ray powder diffraction (XRPD) pattern contains peaks at 9.0, 16.4, 18.3, 23.5, and 24.6 degrees 2θ (± 0.2 degrees 2θ).

26. The free alkali crystal form I according to claim 25, wherein the XRPD spectrum further comprises peaks located at 12.7, 13.7, 18.0, 18.9 and 19.4 degrees 2θ (± 0.2 degrees 2θ).

27. The free alkali crystal form I as described in claim 19 or 20, characterized in that... The X-ray powder diffraction (XRPD) pattern is basically consistent with Figure 1.

28. The free alkali crystal form I according to any one of claims 19 to 27, characterized in that... Differential scanning calorimetry (DSC) thermogram containing an endothermic peak at approximately 200°C.

29. The free alkali crystal form I according to any one of claims 19 to 27, characterized in that... The differential scanning calorimetry (DSC) thermogram is basically consistent with Figure 2.

30. The free alkali crystal form I according to any one of claims 19 to 29, characterized in that... As measured by thermogravimetric analysis (TGA), there is no weight loss before decomposition under heating.

31. The free alkali crystal form I according to any one of claims 19 to 29, characterized in that... The thermogravimetric analysis (TGA) chromatogram is basically consistent with Figure 2.

32. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 31 and at least one pharmaceutically acceptable excipient.

33. A pharmaceutical composition prepared by combining a crystalline form according to any one of claims 1 to 31 with at least one pharmaceutically acceptable excipient.

34. A compound 1 or a salt thereof in a solid form, wherein the solid form comprises at least 50 wt.% of a specific crystalline form, at least 60 wt.% of a specific crystalline form, at least 70 wt.% of a specific crystalline form, at least 80 wt.% of a specific crystalline form, at least 90 wt.% of a specific crystalline form, at least 95 wt.% of a specific crystalline form, or at least 99 wt.% of a specific crystalline form, wherein the specific crystalline form is as described in any one of claims 1 to 31.

35. The solid form as claimed in claim 34, wherein the specific crystal form is HCl salt crystal form I.

36. The solid form as described in claim 34, wherein the specific crystal form is free alkali crystal form I.

37. A pharmaceutical composition comprising a solid form as described in any one of claims 34 to 36 and at least one pharmaceutically acceptable excipient.

38. A pharmaceutical composition prepared by combining a solid form as described in any one of claims 34 to 36 with at least one pharmaceutically acceptable excipient.

39. A method of treating cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a crystalline form as described in any one of claims 1 to 31, or a pharmaceutical composition as described in any one of claims 32, 33, 37, and 38.

40. A method of treating and / or preventing homologous recombination defect (HRD) cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a crystalline form as claimed in any one of claims 1 to 31, or a pharmaceutical composition as claimed in any one of claims 32, 33, 37, and 38.

41. A method for treating and / or preventing cancer in a patient in need, wherein the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, absence or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins, the method comprising administering to the patient a therapeutically effective amount of a crystalline form as described in any one of claims 1 to 31, or a pharmaceutical composition as described in any one of claims 32, 33, 37, and 38.

42. The crystalline form as defined in any one of claims 1 to 31, or the pharmaceutical composition as described in any one of claims 32, 33, 37 and 38, for the treatment of cancer.

43. The use of the crystalline form as defined in any one of claims 1 to 31, or the use of the pharmaceutical composition as described in any one of claims 32, 33, 37 and 38 in the preparation of a medicament for treating cancer.

44. The method of any one of claims 39 to 41, or the use as described in claim 42 or 43, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer.

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